Compositions and methods for targeted delivery

Abstract

This disclosure relates to compounds comprising a targeting moiety and a payload moiety and modulatory nucleic acid agents (e.g., antisense oligonucleotides and double-stranded RNAs) and their compositions and methods useful for reducing SLC6A19 mRNA and / or B0AT1 protein expression, particularly in kidney cells and treating diseases or disorders, including renal and metabolic diseases and disorders (e.g., PKU, urea cycle disorders, tyrosinemias, maple syrup urine disease, propionic acidemia, histidinemia, chronic kidney disease, renal tubular acidosis, etc.).

Description

Attorney Docket No. JUDO-005WOCOMPOSITIONS AND METHODS FOR TARGETED DELIVERYRELATED APPLICATIONS

[0001] The present application claims priority to U. S. Provisional Patent Application No.63 / 778,376, filed March 26, 2025, U. S. Provisional Patent Application No. 63 / 778,377, filed March 26, 2025, U. S. Provisional Patent Application No. 63 / 782,545, filed April 2, 2025, and U. S. Provisional Patent Application No. 63 / 782,553, filed April 2, 2025, the entire contents of each of which are hereby incorporated by reference for all purposes.FIELD OF THE INVENTION

[0002] The instant disclosure relates generally to molecular targeting of compositions, such as SLC6A19-targeting modulatory compositions, to kidney cells, and associated methods.BACKGROUND

[0003] Modulatory nucleic acid therapeutics have demonstrated significant clinical and commercial success in treating liver disease, at least in part because fenestrations in liver sinusoidal epithelial cells render such cells particularly accessible to injected nucleic acids (especially those carrying N-acetylgalactosamine (GalNAc) modifications). Non-liver tissues, including kidney, have tended to be less accessible to modulatory nucleic acid therapeutics. However, recent discoveries have described successful use of moieties targeting kidney cell surface factors to promote efficient delivery of moiety-linked modulatory nucleic acids to kidney cells (see, e.g., PCT / US23 / 16319).

[0004] A need exists for an expanded range of kidney cell-targeting agents capable of delivering payload moieties (e.g., modulatory nucleic acids) to kidney cells.

[0005] The human Solute Carrier Family 6 Member 19 (SLC6A19) gene encodes the sodiumdependent neutral amino acid transporter B0AT1. B0AT1 has been shown to mediate absorption of neutral amino acids in the small intestine and in the kidneys, where it is primarily expressed in early proximal tubules; and a role for SLC6A19 knockout or inhibition in treatment of metabolic disorders, including nephropathy, has been suggested.

[0006] While likely involvement of SLC6A19 and the encoded B0AT1 protein in kidney disease has recently been described, there remains a need for an agent possessing high biological activity - 1 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOand in vivo stability - particularly a kidney cell-directed agent - that can selectively and efficiently modulate (e.g., inhibit) the SLC6A19 gene.SUMMARY

[0007] The present disclosure provides, among other things, aminoglycoside compounds, aminoglycoside-related compounds, glucosamine compounds, glucosamine related compounds, polymyxin compounds, and polymyxin-related, believed to interact with the Megalin cell surface receptor and useful for targeted delivery of therapeutic agents (e.g., nucleic acid agents) to cells, particularly kidney cells. Also provided are modulatory nucleic acid agent compositions which block, degrade, promote or inhibit specific splicing, and / or otherwise alter expression of a SLC6A19 target RNA with sequence-specific targeting precision. Also provided are compositions and methods for targeted delivery of therapeutic agents and / or of nucleic acid agents (e.g., SLC6A19-targeting modulatory nucleic acid agents) to cells, particularly to kidney cells, via inclusion of aminoglycoside compounds, aminoglycoside-related compounds, glucosamine compounds, glucosamine related compounds, polymyxin compounds, and polymyxin-related compounds.

[0008] In one aspect, provided herein are compounds comprising a targeting moiety B, wherein the targeting moiety B comprises or has the following structure of Formula (XI) or (XI’):(XF)wherein each of the variables in Formula (XI) and (XF) is described herein.

[0009] In some embodiments, the targeting moiety B comprises or has one of the following structures of Formula (Xia), (Xlb), and (XIc):IPTS / 200358788.1Attorney Docket No. JUDO-005WO(Xia) (Xlb) (XIc) wherein each of the variables in Formula (Xia), (Xlb), and (XIc) is described herein.

[0010] In some embodiments, the targeting moiety B comprises or has the following structure of Formula (Xl’a):H2NNHo(Xl’a)wherein each of the variables in Formula (XI’) is described herein.

[0011] Also provided herein are compounds comprising a targeting moiety B, where the targeting moiety B comprises or has the following structure of Formula (XII):R2-ll Rb‘"yLRa-HH° I0HO^ Y^O-R1’"R3’"(XII)wherein each of the variables in Formula (XII) is described herein.

[0012] Also provided are compounds comprising a targeting moiety B, wherein the targeting moiety B comprises or has the following structure of Formula (VI):IPTS / 200358788.1Attorney Docket No. JUDO-005WORN1-V(VI)wherein each of the variables in Formula (VI) is described herein.

[0013] In some embodiments, the compound comprises 1, 2, 3, 4, 5, or 6 of the targeting moiety B, and wherein when more than one targeting moiety B is present, each targeting moiety B is independently the same as or different from the other targeting moieties B.

[0014] In some embodiments, the compound further comprises a nucleic acid A and / or a linker. In some embodiments, the targeting moiety B is conjugated to the nucleic acid A via the linker. In some embodiments, the linker between the nucleic acid A and the targeting moiety B has the following structure:Z1A I Lo— P11— L— | I BZ2wherein each of the variables Zi, Z2, Lo, and P is described herein.

[0015] Also provided herein are compounds comprising a nucleic acid A conjugated to one or more targeting moieties B via one or more linkers, wherein:each targeting moiety B independently comprises a glucosamine moiety, an aminoglycoside moiety, a polymyxin moiety, or an analog thereof;each linker may be attached to more than one targeting moiety B; andeach linker independently has the following structure:Z1A I |— Lo— P11— L— J I BZ2IPTS / 200358788.1Attorney Docket No. JUDO-005WOwherein each of the variables Zi, Z2, Lo, and P is described herein.

[0016] In some embodiments, when more than one targeting moiety B is present, each targeting moiety B is independently the same as or different from the other targeting moieties B.

[0017] In some embodiments, the linker comprises or has a structure selected from: (i) Table 10a, Ila, 12a, and 13a; (ii) Table 10b, lib, 12b, and 13b; (iii) Table 10c, lib, 12c, and 13c; (iv) Table 14a or 14b; (v) Table 31; (vi) moieties 3-13, 3-15, 3-28, and 3-37; (vii) moieties 3-13a, 3-13b, 3-15a, 3-28a, and 3-37a; or (viii) moieties 3-13a’, 3- 13b’, 3-15a’, 3-28a’, and 3-37a’.

[0018] In some embodiments, at least one targeting moiety B comprises or has a neamine, nebramine, gentamine, gentamicin (e.g., gentamicin Cl), kanamycin, neomycin, or paromomycin moiety, or an analog thereof.

[0019] In some embodiments, at least one targeting moiety B comprises or has a structure of Formula (VI) as described herein.

[0020] In some embodiments, at least one targeting moiety B comprises or has a structure of Formula (XII) as described herein.

[0021] In some embodiments, at least one targeting moiety B comprises or has a structure of Formula (XI) as described herein. In some embodiments, at least one targeting moiety B comprises or has a structure of Formula (XI’) as described herein.

[0022] Also provided herein are compounds comprising a nucleic acid A conjugated to one or more targeting moieties B via one or more linkers, wherein each linker may be attached to more than one targeting moiety B, and wherein:(i) each targeting moiety B independently comprises or has a structure of Formula (XI), (XF), (XII), or (VI) as described herein; and(ii) the nucleic acid A comprises an antisense strand of 12 to 60 linked nucleotides in length targeted to a solute carrier family 6 member 19 (SLC6A19) RNA, wherein(a) the antisense strand comprises a region of complementarity to the SLC6A19 RNA, and wherein the region of complementarity comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from a nucleotide sequence of 15 contiguous nucleotides comprised in any one of the antisense nucleotide sequences of SEQ IDNOs: 8-777 and 1555-2331; or (b) the antisense strand has at least about 80% complementarity to a target region of the SLC6A19 RNA and is capable of hybridizing with 12 or more nucleotides of nucleotides 3 to 25, nucleotides 8 to 30, nucleotides 13 to 35, nucleotides 38 to 60, nucleotides 43 to 65, nucleotides - 5 - IPTS / 200358788.1Attorney Docket No. JUDO-005WO48 to 70, nucleotides 93 to 115, nucleotides 98 to 120, nucleotides 103 to 125, nucleotides 108 to 130, nucleotides 111 to 133, nucleotides 113 to 135, nucleotides 118 to 140, nucleotides 214 to 236, nucleotides 219 to 241, nucleotides 244 to 266, nucleotides 249 to 271, nucleotides 252 to 274, nucleotides 252 to 274, nucleotides 253 to 275, nucleotides 254 to 276, nucleotides 255 to 277, nucleotides 256 to 278, nucleotides 257 to 286, nucleotides 259 to 281, nucleotides 264 to 286, nucleotides 289 to 311, nucleotides 294 to 316, nucleotides 339 to 361, nucleotides 397 to 419, nucleotides 460 to 480, nucleotides 461 to 481, nucleotides 481 to 503, nucleotides 486 to 508, nucleotides 491 to 513, nucleotides 557 to 579, nucleotides 561 to 583, nucleotides 562 to 584, nucleotides 564 to 586, nucleotides 566 to 586, nucleotides 567 to 589, nucleotides 616 to 638, nucleotides 617 to 639, nucleotides 618 to 640, nucleotides 621 to 643, nucleotides 626 to 648, nucleotides 670 to 692, nucleotides 671 to 691, nucleotides 672 to 694, nucleotides 674 to 694, nucleotides 675 to 697, nucleotides 680 to 702, nucleotides 685 to 707, nucleotides 690 to 712, nucleotides 695 to 717, nucleotides 700 to 722, nucleotides 705 to 727, nucleotides 710 to 732, nucleotides 715 to 737, nucleotides 720 to 742, nucleotides 725 to 747, nucleotides 730 to 752, nucleotides 735 to 757, nucleotides 738 to 760, nucleotides 739 to 761, nucleotides 740 to 762, nucleotides 741 to 763, nucleotides 742 to 764, nucleotides 745 to 767, nucleotides 750 to 772, nucleotides 751 to 773, nucleotides 752 to 774, nucleotides 753 to 775, nucleotides 754 to 776, nucleotides 755 to 777, nucleotides 756 to 778, nucleotides 757 to 779, nucleotides 760 to 782, nucleotides 765 to 787, nucleotides 770 to 792, nucleotides 775 to 797, nucleotides 798 to 823, nucleotides 800 to 822, nucleotides 825 to 847, nucleotides 826 to 848, nucleotides 877 to 899, nucleotides 890 to 912, nucleotides 895 to 917, nucleotides 900 to 922, nucleotides 905 to 927, nucleotides 910 to 932, nucleotides 911 to 937, nucleotides 915 to 937, nucleotides 918 to 940, nucleotides 972 to 994, nucleotides 973 to 995, nucleotides 974 to 996, nucleotides 975 to 997, nucleotides 977 to 1000, nucleotides 977 to 999, nucleotides 978 to 1000, nucleotides 981 to 1003, nucleotides 983 to 1005, nucleotides 984 to 1006, nucleotides 1033 to 1055, nucleotides 1034 to 1056, nucleotides 1035 to 1057, nucleotides 1058 to 1080, nucleotides 1059 to 1081, nucleotides 1060 to 1082, nucleotides 1063 to 1085, nucleotides 1064 to 1086, nucleotides 1065 to 1087, nucleotides 1066 to 1088, nucleotides 1067 to 1089, nucleotides 1068 to 1090, nucleotides 1070 to 1092, nucleotides 1070 to 1092, nucleotides 1074 to 1096, nucleotides 1075 to 1097, nucleotides 1077 to 1099, nucleotides 1078 to 1100, nucleotides 1079 to 1101, nucleotides 1080 to 1102, nucleotides 1081 to 1103, nucleotides 1082 to 1104, nucleotides 1085 to 1107,-6- IPTS / 200358788.1Attorney Docket No. JUDO-005WOnucleotides 1086 to 1106, nucleotides 1090 to 1112, nucleotides 1095 to 1117, nucleotides 1100 to 1122, nucleotides 1105 to 1127, nucleotides 1110 to 1132, nucleotides 1115 to 1137, nucleotides 1115 to 1137, nucleotides 1117 to 1139, nucleotides 1177 to 1199, nucleotides 1178 to 1200, nucleotides 1179 to 1201, nucleotides 1182 to 1204, nucleotides 1187 to 1209, nucleotides 1191 to 1214, nucleotides 1192 to 1214, nucleotides 1195 to 1217, nucleotides 1233 to 1255, nucleotides 1234 to 1256, nucleotides 1235 to 1257, nucleotides 1236 to 1258, nucleotides 1239 to 1261, nucleotides 1242 to 1264, nucleotides 1244 to 1266, nucleotides 1247 to 1268, nucleotides 1249 to 1271, nucleotides 1251 to 1270, nucleotides 1254 to 1276, nucleotides 1259to 1281, nucleotides 1263 to 1282, nucleotides 1264 to 1286, nucleotides 1266 to 1285, nucleotides 1269 to 1291, nucleotides 1326 to 1348, nucleotides 1331 to 1353, nucleotides 1334 to 1356, nucleotides 1342 to 1364, nucleotides 1335 to 1357, nucleotides 1336 to 1358, nucleotides 1337 to 1359, nucleotides 1337 to 1359, nucleotides 1338 to 1360, nucleotides 1340 to 1362, nucleotides 1341 to 1363, nucleotides 1342 to 1364, nucleotides 1346 to 1368, nucleotides 1351 to 1373, nucleotides 1353 to 1372, nucleotides 1377 to 1399, nucleotides 1382 to 1404, nucleotides 1383 to 1403, nucleotides 1387 to 1409, nucleotides 1392 to 1414, nucleotides 1397 to 1419, nucleotides 1402 to 1424, nucleotides 1407 to 1429, nucleotides 1412 to 1434, nucleotides 1417 to 1439, nucleotides 1456 to 1478, nucleotides 1458 to 1477, nucleotides 1481 to 1503, nucleotides 1486 to 1508, nucleotides 1491 to 1513, nucleotides 1496 to 1518, nucleotides 1521 to 1543, nucleotides 1568 to 1590, nucleotides 1569 to 1591, nucleotides 1574 to 1596, nucleotides 1578 to 1621, nucleotides 1579 to 1601, nucleotides 1583 to 1605, nucleotides 1583 to 1605, nucleotides 1584 to 1606, nucleotides 1584 to 1606, nucleotides 1585 to 1607, nucleotides 1585 to 1607, nucleotides 1587 to 1609, nucleotides 1588 to 1610, nucleotides 1589 to 1611, nucleotides 1594 to 1616, nucleotides 1595 to 1617, nucleotides 1599 to 1621, nucleotides 1601 to 1620, nucleotides 1602 to 1624, nucleotides 1642 to 1664, nucleotides 1749 to 1775, nucleotides 1750 to 1772, nucleotides 1755 to 1777, nucleotides 1757 to 1779, nucleotides 1758 to 1780, nucleotides 1760 to 1782, nucleotides 1761 to 1792, nucleotides 1764 to 1783, nucleotides 1765 to 1787, nucleotides 1770 to 1792, nucleotides 1809 to 1831, nucleotides 1810 to 1829, nucleotides 1812 to 1832, nucleotides 1814 to 1836, nucleotides 1852 to 1881, nucleotides 1853 to 1875, nucleotides 1854 to 1876, nucleotides 1858 to 1880, nucleotides 2168 to2188, nucleotides 2333 to 2353, nucleotides 2454 to 2474, nucleotides 2507 to 2527, nucleotides 2593 to 2613, nucleotides 3244 to 3264, nucleotides 3288 to 3308, nucleotides 3304 to 3324, nucleotides 3332 to 3352, nucleotides 3333 to 3353, nucleotides 3501- 7 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOto 3523, nucleotides 3595 to 3615, nucleotides 3595 to 3617, nucleotides 3643 to 3671, nucleotides 3646 to 3668, nucleotides 3646 to 3668, nucleotides 3647 to 3669, nucleotides 3648 to 3668, nucleotides 3648 to 3670, nucleotides 3648 to 3670, nucleotides 3649 to 3671, nucleotides 3651 to 3670, nucleotides 3651 to 3673, nucleotides 3651 to 3673, nucleotides 3652 to 3671, nucleotides 3712 to 3733, nucleotides 3713 to 3735, nucleotides 3763 to 3786, nucleotides 3763 to 3785, nucleotides 3764 to 3786, nucleotides 3791 to 3811, nucleotides 3796 to 3816, nucleotides 3801 to 3829, nucleotides 3801 to 3820, nucleotides 3802 to 3821, nucleotides 3804 to 3826, nucleotides 3809 to 3831, nucleotides 3810 to 3832, nucleotides 3812 to 3833, nucleotides 3812 to 3834, nucleotides 3813 to 3835, nucleotides 3814 to 3833, nucleotides 3814 to 3836, nucleotides 3814 to 3836, nucleotides 3839 to 3859, nucleotides 3840 to 3862, nucleotides 3902 to 3924, nucleotides 3965 to 3987, nucleotides 3995 to 4015, nucleotides 3998 to 4020, nucleotides 4100 to 4124, nucleotides 4102 to 4124, nucleotides 4141 to 4163, nucleotides 4141 to 4163, nucleotides 4142 to 4164, nucleotides 4143 to 4165, nucleotides 4144 to 4166, nucleotides 4146 to 4168, nucleotides 4150 to 4172, nucleotides 4151 to 4173, nucleotides 4192 to 4214, nucleotides 4197 to 4219, nucleotides 4201 to 4223, nucleotides 4265 to 4287, nucleotides 4270 to 4292, nucleotides 4318 to 4338, nucleotides 4319 to 4341, nucleotides 4329 to 4349, nucleotides 4348 to 4386, nucleotides 4349 to 4371, nucleotides 4350 to 4369, nucleotides 4350 to 4372, nucleotides 4350 to 4372, nucleotides 4351 to 4370, nucleotides 4352 to 4371, nucleotides 4352 to 4374, nucleotides 4353 to4372, nucleotides 4353 to 4375, nucleotides 4354 to 4376, nucleotides 4359 to 4381, nucleotides 4361 to 4383, nucleotides 4362 to 4384, nucleotides 4362 to 4384, nucleotides 4364 to 4386, nucleotides 4365 to 4387, nucleotides 4395 to 4415, nucleotides 4396 to 4416, nucleotides 4409 to 4431, nucleotides 4410 to 4432, nucleotides 4412 to 4434, nucleotides 4637 to 4657, nucleotides 4638 to 4658, nucleotides 4640 to 4660, nucleotides 5103 to 5123, nucleotides 5124 to 5144, nucleotides 5126 to 5146, or nucleotides 5127 to 5147 of SEQ ID NO: 1.

[0023] In some embodiments, when more than one targeting moiety B is present, each targeting moiety B is independently the same as or different from the other targeting moieties B.

[0024] In some embodiments, at least one targeting moiety B comprises or has a structure of Formula (XI), and wherein R2is RG-(CH2)t-*, RG-(CH2)t-(CH2OCH2)s-(CH2)t-*, or RG-(CH2)t-NHC(O)-(CH2)t-*, whereinindicates the attachment point to the oxygen atom; R6is hydrogen; R9is hydrogen or -CH20H; and RN1is hydrogen, Ci-Ce alkyl optionally substituted with one or more halogen, Ci-Ce alkylene-OH, -C(O)-RNA, -C(O)-ORNA, -N(RNA)2-C(0), - - 8 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOC(=NH)NH2, or -S(O)Z-RNA; and RN2is hydrogen, Ci-Ce alkyl, or -C(O)-Ci-Ce alkyl, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; or RN1and RN2together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring.

[0025] In some embodiments, at least one targeting moiety B comprises or has a structure of Formula (XI), and wherein R2is hydrogen; R6is RG-(CH2)t-*, RG-(CH2)t-(CH2OCH2)s-(CH2)t-*, or RG-(CH2)t-NHC(O)-(CH2)t-*, whereinindicates the attachment point to the oxygen atom; R9is hydrogen or -CH2OH; and RN1is hydrogen, Ci-Ce alkyl optionally substituted with one or more halogen, Ci-C6alkylene-OH, -C(O)-RNA, -C(O)-ORNA, -N(RNA)2-C(O), -C(=NH)NH2, or -S(O)2-RNA; and RN2is hydrogen, Ci-Ce alkyl, or C(O) Ci-Ce alkyl, wherein the Ci-Ce alkyl or -C(O)-Ci-C6 alkyl is optionally substituted with one or more halogen; or RN1and RN2together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring.

[0026] In some embodiments, at least one targeting moiety B comprises or has a structure of Formula (XI), and wherein R2is hydrogen; R6is hydrogen; R9is -CH2S-(CH2)t-RG; and RN1is hydrogen, Ci-Ce alkyl optionally substituted with one or more halogen, Ci-Ce alkylene-OH, -C(O)-RNA, -C(O)-ORNA, -N(RNA)2-C(O), -C(=NH)NH2, or -S(O)2-RNA; and RN2is hydrogen, Ci-Ce alkyl, or -C(O)-Ci-Ce alkyl, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; or RN1and R2together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring.

[0027] In some embodiments, at least one targeting moiety B comprises or has a structure of Formula (XI), and wherein R2is hydrogen; R6is hydrogen; R9is hydrogen or -CH2OH; RN1is RG-(CH2)t-NHC(O)-*, RG-(CH2)t-C(O)-*, RG-(CH2)t-(CH2OCH2)s-(CH2 -C(O)-*, or RG-(CH2)t-(CH2OCH2)s-(CH2)t-*, whereinindicates the attachment point to the nitrogen atom; and RN2is hydrogen or Ci-Ce alkyl.

[0028] In some embodiments, when the compound comprises exactly one nucleic acid A, exactly one linker, and exactly one, two, or three identical targeting moiety B each comprising or having a structure of Formula (XI), if RN1is not RG-GX- then (a) at least one of RN3, RN4, RN5, RN6, RN7, and RN8is not hydrogen, and / or (b) -NRN1RN2is not -NH2 or -NHCH3.

[0029] In some embodiments, when the compound comprises exactly one nucleic acid A, exactly one linker, and exactly one, two, or three identical targeting moiety B each comprising or having -9- IPTS / 200358788.1Attorney Docket No. JUDO-005WOa structure of Formula (XI), if RN1is RG-GN- then (a) at least one of RN3, RN4, RN5, RN6, RN7, and RN8is not hydrogen, and / or (b) RN2is not hydrogen or -CH3.

[0030] In some embodiments, at least one targeting moiety B is an aminoglycoside moiety derived from a compound in Table 2a; optionally wherein the targeting moiety B is an aminoglycoside moiety derived from compound AG2-0, AG4-0, AG4-6, AG4-7, AG5-0, or AG7-0. In some embodiments, the aminoglycoside moiety is attached to the rest of the molecule at position 5, position 6’, position 2”, position 6”, or position 5”.

[0031] In some embodiments, at least one targeting moiety B comprises or has a structure selected from Table 2b, optionally wherein the targeting moiety B comprises or has a structure selected from AG2-0a, AG4-0a, AG4-6a, AG4-7a, AG5-0a, AG5-0c, and AG7-0a.

[0032] In some embodiments, at least one targeting moiety B comprises or has a structure selected from Table 2c, optionally wherein the targeting moiety B comprises or has a structure selected from AG2-0a-l, AG2-0a-2, AG4-0a-l, AG4-0a-2, AG4-6a-l, AG4-6a-2, AG4-7a-l, AG4-7a-2, AG5-0a-l, AG5-0a-2, AG5-0c-2, AG7-0a-l, and AG7-0a-2.

[0033] In some embodiments, the linker comprises or has a structure of moiety 3-13, and the targeting B comprises or has a structure selected from AG2-0a-2, AG4-0a-2, AG4-6a-2, AG4-7a-2, AG5-0a-2, AG5-0c-2, and AG7-0a-2.

[0034] In some embodiments, the linker comprises or has a structure of moiety 3-13, 3-15, 3-27, 3-28, or 3-37, and the targeting B comprises or has a structure selected from AG2-0a-l, AG4-0a-1, AG4-6a-l, AG4-7a-l, AG5-0a-l, AG5-0c-2, and AG7-0a-l.

[0035] In some embodiments, when the compound comprises exactly one nucleic acid A, exactly one linker, and exactly one, two, or three identical targeting moiety B each comprising or having a structure of Formula (XI), each targeting moiety B does not a structure of Formula (A) as described herein.

[0036] In some embodiments, at least one targeting moiety B comprises or has a structure of Formula (XII), and the targeting moiety B is a moiety derived from a compound in Table 2e. In some embodiments, at least one targeting moiety B comprises or has a structure of Formula (XII), and the targeting moiety B comprises or has a structure selected from Table 2f. In some embodiments, at least one targeting moiety B comprises or has a structure of Formula (XII), and the targeting moiety B comprises or has a structure selected from Table 31.- 10 - IPTS / 200358788.1Attorney Docket No. JUDO-005WO

[0037] In some embodiments, when a disclosed compound comprises exactly one nucleic acid A, exactly one linker, and exactly one, two, or three identical targeting moieties B each comprising or having a structure of Formula (VI), if RN1 V, RN2‘V, RN3‘V, RN4'V, RN5 V, and RN6are each hydrogen, Al is present, and A2 and A3 are absent, then -NN7'VRN8'Vis not -NH2 or -NHC(=NH)NH2.

[0038] In some embodiments, when a disclosed compound comprises exactly one nucleic acid A, exactly one linker, and exactly one, two, or three identical targeting moieties B each comprising or having a structure of Formula (VI), if RN1'V, RN2'V, RN3'V, RN4'V, RN5 V, and RN6'Vare each hydrogen, and Al, A2, and A3 are present, then -NRN7RN8and -NRN9'vRN10are not both -NH2 and are not both -NHC(=NH)NH2.

[0039] In some embodiments, at least one targeting moiety B comprises or has a structure of Formula (VI), and wherein the targeting moiety B is derived from a compound in Table 2a-V. In some embodiments, at least one targeting moiety B comprises or has a structure of Formula (VI), and wherein the targeting moiety B comprises or has a structure selected from Table 2b-V. In some embodiments, at least one targeting moiety B comprises or has a structure of Formula (VI), and wherein the targeting moiety B comprises or has a structure selected from Table 31-V.

[0040] In some embodiments, the nucleic acid A has a 3’ terminus and a 5’ terminus, and is conjugated to one or more targeting moieties B at the 3’ terminus, the 5’ terminus, or both the 3’ and 5’ termi.

[0041] In some embodiments, the nucleic acid A is single stranded or double stranded. In some embodiments, the single stranded nucleic acid A is a single stranded antisense oligonucleotide (ASO) or a single-stranded RNAi (ssRNAi). In some embodiments, the double stranded nucleic acid A is a double stranded RNA (e.g., a double stranded siRNA).

[0042] In some embodiments, the nucleic acid A is or comprises RNA, DNA, and / or peptide nucleic acid (PNA).

[0043] In some embodiments, the RNA is an RNA inhibitory (RNAi) agent. In some embodiments, the RNAi agent is or comprises a short interfering RNA (siRNA).

[0044] In some embodiments, the DNA is or comprises a DNA analog. In some embodiments, the DNA analog comprises one or more morpholino subunits linked together by phosphorus-containing linkage(s). In some embodiments, the DNA analog is or comprises a phosphorodiamidate morpholino nucleic acid (PMO).- 11 - IPTS / 200358788.1Attorney Docket No. JUDO-005WO

[0045] In some embodiments, the nucleic acid A comprises a modification selected from: a modified backbone, a modified nucleobase, a modified ribose, a modified deoxyribose, or a combination thereof.

[0046] In some embodiments, the nucleic acid A comprises a sequence element that is at least 80% complementary to a portion of a target sequence. In some embodiments, the target sequence is a solute carrier family 6 member 19 (SLC6A19) RNA. In some embodiments, the SLC6A19 RNA is the human SLC6A19 RNA of SEQ ID NO: 1. In some embodiments, the nucleic acid A comprises an antisense strand having 12 to 60 linked nucleotides in length.

[0047] In some embodiments, the antisense strand has at least about 80% complementarity to a target region of the human SLC6A19 RNA.

[0048] In some embodiments, nucleic acid A comprises an antisense strand having 12 to 60 linked nucleotides in length targeted to a solute carrier family 6 meember 19 (SLC6A19).

[0049] In some embodiments, the antisense strand has at least about 80% complementarity to a target region of the human SLC6A19 RNA, and hybridizes with 12 or more nucleotides of nucleotides 3 to 25, nucleotides 8 to 30, nucleotides 13 to 35, nucleotides 38 to 60, nucleotides 43 to 65, nucleotides 48 to 70, nucleotides 93 to 115, nucleotides 98 to 120, nucleotides 103 to 125, nucleotides 108 to 130, nucleotides 111 to 133, nucleotides 113 to 135, nucleotides 118 to 140, nucleotides 214 to 236, nucleotides 219 to 241, nucleotides 244 to 266, nucleotides 249 to 271, nucleotides 252 to 274, nucleotides 252 to 274, nucleotides 253 to 275, nucleotides 254 to 276, nucleotides 255 to 277, nucleotides 256 to 278, nucleotides 257 to 286, nucleotides 259 to 281, nucleotides 264 to 286, nucleotides 289 to 311, nucleotides 294 to 316, nucleotides 339 to 361, nucleotides 397 to 419, nucleotides 460 to 480, nucleotides 461 to 481, nucleotides 481 to 503, nucleotides 486 to 508, nucleotides 491 to 513, nucleotides 557 to 579, nucleotides 561 to 583, nucleotides 562 to 584, nucleotides 564 to 586, nucleotides 566 to 586, nucleotides 567 to 589, nucleotides 616 to 638, nucleotides 617 to 639, nucleotides 618 to 640, nucleotides 621 to 643, nucleotides 626 to 648, nucleotides 670 to 692, nucleotides 671 to 691, nucleotides 672 to 694, nucleotides 674 to 694, nucleotides 675 to 697, nucleotides 680 to 702, nucleotides 685 to 707, nucleotides 690 to 712, nucleotides 695 to 717, nucleotides 700 to 722, nucleotides 705 to 727, nucleotides 710 to 732, nucleotides 715 to 737, nucleotides 720 to 742, nucleotides 725 to 747, nucleotides 730 to 752, nucleotides 735 to 757, nucleotides 738 to 760, nucleotides 739 to 761, nucleotides 740 to 762, nucleotides 741 to 763, nucleotides 742 to 764, nucleotides 745 to 767,- 12 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOnucleotides 750 to 772, nucleotides 751 to 773, nucleotides 752 to 774, nucleotides 753 to 775, nucleotides 754 to 776, nucleotides 755 to 777, nucleotides 756 to 778, nucleotides 757 to 779, nucleotides 760 to 782, nucleotides 765 to 787, nucleotides 770 to 792, nucleotides 775 to 797, nucleotides 798 to 823, nucleotides 800 to 822, nucleotides 825 to 847, nucleotides 826 to 848, nucleotides 877 to 899, nucleotides 890 to 912, nucleotides 895 to 917, nucleotides 900 to 922, nucleotides 905 to 927, nucleotides 910 to 932, nucleotides 911 to 937, nucleotides 915 to 937, nucleotides 918 to 940, nucleotides 972 to 994, nucleotides 973 to 995, nucleotides 974 to 996, nucleotides 975 to 997, nucleotides 977 to 1000, nucleotides 977 to 999, nucleotides 978 to 1000, nucleotides 981 to 1003, nucleotides 983 to 1005, nucleotides 984 to 1006, nucleotides 1033 to 1055, nucleotides 1034 to 1056, nucleotides 1035 to 1057, nucleotides 1058 to 1080, nucleotides 1059 to 1081, nucleotides 1060 to 1082, nucleotides 1063 to 1085, nucleotides 1064 to 1086, nucleotides 1065 to 1087, nucleotides 1066 to 1088, nucleotides 1067 to 1089, nucleotides 1068 to 1090, nucleotides 1070 to 1092, nucleotides 1070 to 1092, nucleotides 1074 to 1096, nucleotides 1075 to 1097, nucleotides 1077 to 1099, nucleotides 1078 to 1100, nucleotides 1079 to 1101, nucleotides 1080 to 1102, nucleotides 1081 to 1103, nucleotides 1082 to 1104, nucleotides 1085 to 1107, nucleotides 1086 to 1106, nucleotides 1090 to 1112, nucleotides 1095 to 1117, nucleotides 1100 to 1122, nucleotides 1105 to 1127, nucleotides 1110 to 1132, nucleotides 1115 to 1137, nucleotides 1115 to 1137, nucleotides 1117 to 1139, nucleotides 1177 to 1199, nucleotides 1178 to 1200, nucleotides 1179 to 1201, nucleotides 1182 to 1204, nucleotides 1187 to 1209, nucleotides 1191 to 1214, nucleotides 1192 to 1214, nucleotides 1195 to 1217, nucleotides 1233 to 1255, nucleotides 1234 to 1256, nucleotides 1235 to 1257, nucleotides 1236 to 1258, nucleotides 1239 to 1261, nucleotides 1242 to 1264, nucleotides 1244 to 1266, nucleotides 1247 to 1268, nucleotides 1249 to 1271, nucleotides 1251 to 1270, nucleotides 1254 to 1276, nucleotides 1259 to 1281, nucleotides 1263 to 1282, nucleotides 1264 to 1286, nucleotides 1266 to 1285, nucleotides 1269 to 1291, nucleotides 1326 to 1348, nucleotides 1331 to 1353, nucleotides 1334to 1356, nucleotides 1342 to 1364, nucleotides 1335 to 1357, nucleotides 1336 to 1358, nucleotides 1337 to 1359, nucleotides 1337 to 1359, nucleotides 1338 to 1360, nucleotides 1340 to 1362, nucleotides 1341 to 1363, nucleotides 1342 to 1364, nucleotides 1346 to 1368, nucleotides 1351 to 1373, nucleotides 1353 to 1372, nucleotides 1377 to 1399, nucleotides 1382 to 1404, nucleotides 1383 to 1403, nucleotides 1387 to 1409, nucleotides 1392 to 1414, nucleotides 1397 to 1419, nucleotides 1402 to 1424, nucleotides 1407 to 1429, nucleotides 1412 to 1434, nucleotides 1417 to 1439,- 13 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOnucleotides 1456 to 1478, nucleotides 1458 to 1477, nucleotides 1481 to 1503, nucleotides 1486 to 1508, nucleotides 1491 to 1513, nucleotides 1496 to 1518, nucleotides 1521 to 1543, nucleotides 1568 to 1590, nucleotides 1569 to 1591, nucleotides 1574 to 1596, nucleotides 1578 to 1621, nucleotides 1579 to 1601, nucleotides 1583 to 1605, nucleotides 1583 to 1605, nucleotides 1584 to 1606, nucleotides 1584 to 1606, nucleotides 1585 to 1607, nucleotides 1585 to 1607, nucleotides 1587 to 1609, nucleotides 1588 to 1610, nucleotides 1589 to 1611, nucleotides 1594 to 1616, nucleotides 1595 to 1617, nucleotides 1599 to 1621, nucleotides 1601 to 1620, nucleotides 1602 to 1624, nucleotides 1642 to 1664, nucleotides 1749 to 1775, nucleotides 1750 to 1772, nucleotides 1755 to 1777, nucleotides 1757 to 1779, nucleotides 1758 to 1780, nucleotides 1760 to 1782, nucleotides 1761 to 1792, nucleotides 1764 to 1783, nucleotides 1765 to 1787, nucleotides 1770 to 1792, nucleotides 1809 to 1831, nucleotides 1810 to 1829, nucleotides 1812 to 1832, nucleotides 1814 to 1836, nucleotides 1852 to 1881, nucleotides 1853 to 1875, nucleotides 1854 to 1876, nucleotides 1858 to 1880, nucleotides 2168 to 2188, nucleotides 2333 to 2353, nucleotides 2454 to 2474, nucleotides 2507 to 2527, nucleotides 2593 to 2613, nucleotides 3244 to 3264, nucleotides 3288 to 3308, nucleotides 3304 to 3324, nucleotides 3332 to 3352, nucleotides 3333 to 3353, nucleotides 3501 to 3523, nucleotides 3595 to 3615, nucleotides 3595 to 3617, nucleotides 3643 to 3671, nucleotides 3646 to 3668, nucleotides 3646 to 3668, nucleotides 3647 to 3669, nucleotides 3648 to 3668, nucleotides 3648 to 3670, nucleotides 3648 to 3670, nucleotides 3649 to 3671, nucleotides 3651 to 3670, nucleotides 3651 to 3673, nucleotides 3651 to 3673, nucleotides 3652 to 3671, nucleotides 3712 to 3733, nucleotides 3713 to 3735, nucleotides 3763 to 3786, nucleotides 3763 to 3785, nucleotides 3764 to 3786, nucleotides 3791 to 3811, nucleotides 3796 to 3816, nucleotides 3801 to 3829, nucleotides 3801 to 3820, nucleotides 3802 to 3821, nucleotides 3804 to 3826, nucleotides 3809 to 3831, nucleotides 3810 to 3832, nucleotides 3812 to 3833, nucleotides 3812 to 3834, nucleotides 3813 to 3835, nucleotides 3814 to 3833, nucleotides 3814 to 3836, nucleotides 3814 to 3836, nucleotides 3839 to 3859, nucleotides 3840 to 3862, nucleotides 3902 to 3924, nucleotides 3965 to 3987, nucleotides 3995 to 4015, nucleotides 3998 to 4020, nucleotides 4100 to 4124, nucleotides 4102 to 4124, nucleotides 4141 to 4163, nucleotides 4141 to 4163, nucleotides 4142 to 4164, nucleotides 4143 to 4165, nucleotides 4144 to 4166, nucleotides 4146 to 4168, nucleotides 4150 to 4172, nucleotides 4151 to 4173, nucleotides 4192 to 4214, nucleotides 4197 to 4219, nucleotides 4201 to 4223, nucleotides 4265 to 4287, nucleotides 4270 to 4292, nucleotides 4318 to 4338, nucleotides 4319 to 4341, nucleotides 4329 to 4349, nucleotides 4348- 14 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOto 4386, nucleotides 4349 to 4371, nucleotides 4350 to 4369, nucleotides 4350 to 4372, nucleotides 4350 to 4372, nucleotides 4351 to 4370, nucleotides 4352 to 4371, nucleotides 4352 to 4374, nucleotides 4353 to 4372, nucleotides 4353 to 4375, nucleotides 4354 to 4376, nucleotides 4359 to4381, nucleotides 4361 to 4383, nucleotides 4362 to 4384, nucleotides 4362 to 4384, nucleotides 4364 to 4386, nucleotides 4365 to 4387, nucleotides 4395 to 4415, nucleotides 4396 to 4416, nucleotides 4409 to 4431, nucleotides 4410 to 4432, nucleotides 4412 to 4434, nucleotides 4637 to 4657, nucleotides 4638 to 4658, nucleotides 4640 to 4660, nucleotides 5103 to 5123, nucleotides 5124 to 5144, nucleotides 5126 to 5146, or nucleotides 5127 to 5147 of SEQ ID NO: 1.

[0050] In some embodiments, the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides, no more than 2 nucleotides, or no more than 1 nucleotide from a nucleotide sequence of 15 contiguous nucleotides and comprised in any one of the nucleotide sequences of SEQ ID NOs: 8-777 and 1555-2331.

[0051] In some embodiments, the nucleic acid A comprises a sense strand of 12 to 60 nucleobases in length. In some embodiments, the nucleic acid A comprises a double stranded ribonucleic acid (dsRNA), wherein the dsRNA comprises a sense strand and an antisense strand forming a double stranded region.

[0052] In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from a nucleotide sequence of 15 contiguous nucleotides and comprised in SEQ ID NO: 1.

[0053] In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the nucleotide sequences of nucleotides 3 to 23, nucleotides 8 to 28, nucleotides 13 to 33, nucleotides 38 to 58, nucleotides 43 to 63, nucleotides 48 to 68, nucleotides 93 to 113, nucleotides 98 to 118, nucleotides 103 to 123, nucleotides 108 to 128, nucleotides 111 to 131, nucleotides 113 to 133, nucleotides 118 to 138, nucleotides 214 to 234, nucleotides 219 to 239, nucleotides 244 to 264, nucleotides 249 to 269, nucleotides 252 to 272, nucleotides 252 to 272, nucleotides 253 to 273, nucleotides 254 to 274, nucleotides 255 to 275, nucleotides 256 to 276, nucleotides 259 to 279, nucleotides 264 to 284, nucleotides 289 to 309, nucleotides 294 to 314, nucleotides 339 to 359, nucleotides 397 to 417, nucleotides 460 to 480, nucleotides 461 to 481, nucleotides 481 to 501, nucleotides 486 to 506, nucleotides 491 to 511, nucleotides 557 to 577, nucleotides 561 to 581, nucleotides 562 to 582, nucleotides 564 to 584, nucleotides 567 to 587, nucleotides 616 to 636, nucleotides 617 to 637,- 15 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOnucleotides 618 to 638, nucleotides 621 to 641, nucleotides 626 to 646, nucleotides 670 to 690, nucleotides 672 to 692, nucleotides 675 to 695, nucleotides 680 to 700, nucleotides 685 to 705, nucleotides 690 to 710, nucleotides 695 to 715, nucleotides 700 to 720, nucleotides 705 to 725, nucleotides 710 to 730, nucleotides 715 to 735, nucleotides 720 to 740, nucleotides 725 to 745, nucleotides 730 to 750, nucleotides 735 to 755, nucleotides 738 to 758, nucleotides 739 to 759, nucleotides 740 to 760, nucleotides 741 to 761, nucleotides 742 to 762, nucleotides 745 to 765, nucleotides 748 to 768, nucleotides 749 to 769, nucleotides 750 to 770, nucleotides 751 to 771, nucleotides 752 to 772, nucleotides 753 to 773, nucleotides 754 to 774, nucleotides 755 to 775, nucleotides 756 to 776, nucleotides 757 to 777, nucleotides 760 to 780, nucleotides 765 to 785, nucleotides 770 to 790, nucleotides 775 to 795, nucleotides 800 to 820, nucleotides 825 to 845, nucleotides 826 to 846, nucleotides 887 to 907, nucleotides 890 to 910, nucleotides 895 to 915, nucleotides 900 to 920, nucleotides 905 to 925, nucleotides 910 to 930, nucleotides 915 to 935, nucleotides 918 to 938, nucleotides 972 to 992, nucleotides 973 to 993, nucleotides 974 to 994, nucleotides 975 to 995, nucleotides 977 to 997, nucleotides 978 to 998, nucleotides 981 to 1001, nucleotides 982 to 1002, nucleotides 983 to 1003, nucleotides 984 to 1004, nucleotides 1033 to 1053, nucleotides 1034 to 1054, nucleotides 1035 to 1055, nucleotides 1058 to 1078, nucleotides 1059 to 1079, nucleotides 1060 to 1080, nucleotides 1063 to 1083, nucleotides 1064 to 1084, nucleotides 1065 to 1085, nucleotides 1066 to 1086, nucleotides 1067 to 1087, nucleotides 1070 to 1090, nucleotides 1074 to 1094, nucleotides 1075 to 1095, nucleotides 1076 to 1096, nucleotides 1077 to 1097, nucleotides 1078 to 1098, nucleotides 1079 to 1099, nucleotides 1080 to 1100, nucleotides 1081 to 1101, nucleotides 1082 to 1102, nucleotides 1085 to 1105, nucleotides 1090 to 1110, nucleotides 1095 to 1115, nucleotides 1100 to 1120, nucleotides 1105 to 1125, nucleotides 1110 to 1130, nucleotides 1115 to 1135, nucleotides 1117 to 1137, nucleotides 1177 to 1197, nucleotides 1178 to 1198, nucleotides 1179 to 1199, nucleotides 1182 to 1202, nucleotides 1187 to 1207, nucleotides 1192 to 1212, nucleotides 1195 to 1215, nucleotides 1233 to 1253, nucleotides 1234 to 1254, nucleotides 1235 to 1255, nucleotides 1236 to 1256, nucleotides 1239 to 1259, nucleotides 1242 to 1262, nucleotides 1244 to 1264, nucleotides 1249 to 1269, nucleotides 1254 to 1274, nucleotides 1259 to 1279, nucleotides 1264 to 1284, nucleotides 1269 to 1289, nucleotides 1326 to 1346, nucleotides 1331 to 1351, nucleotides 1334 to 1354, nucleotides 1334 to 1354, nucleotides 1335 to 1355, nucleotides 1336 to 1356, nucleotides 1337 to 1357, nucleotides 1337 to 1357, nucleotides 1338 to 1358, nucleotides 1340 to 1360, nucleotides 1341 to 1361, nucleotides - 16 - IPTS / 200358788.1Attorney Docket No. JUDO-005WO1342 to 1362, nucleotides 1343 to 1363, nucleotides 1346 to 1366, nucleotides 1351 to 1371, nucleotides 1377 to 1397, nucleotides 1382 to 1402, nucleotides 1385 to 1405, nucleotides 1386 to 1406, nucleotides 1387 to 1407, nucleotides 1388 to 1408, nucleotides 1389 to 1409, nucleotides 1392 to 1412, nucleotides 1397 to 1417, nucleotides 1402 to 1422, nucleotides 1407 to 1427, nucleotides 1412 to 1432, nucleotides 1417 to 1437, nucleotides 1456 to 1476, nucleotides 1481 to 1501, nucleotides 1486 to 1506, nucleotides 1491 to 1511, nucleotides 1496 to 1516, nucleotides 1521 to 1541, nucleotides 1567 to 1587, nucleotides 1568 to 1588, nucleotides 1568 to 1588, nucleotides 1569 to 1589, nucleotides 1574 to 1594, nucleotides 1575 to 1595, nucleotides 1576 to 1596, nucleotides 1577 to 1597, nucleotides 1578 to 1598, nucleotides 1579 to 1599, nucleotides 1580 to 1600, nucleotides 1581 to 1601, nucleotides 1582 to 1602, nucleotides 1583 to 1603, nucleotides 1583 to 1603, nucleotides 1584 to 1604, nucleotides 1584 to 1604, nucleotides 1585 to 1605, nucleotides 1585 to 1605, nucleotides 1586 to 1606, nucleotides 1587 to 1607, nucleotides 1587 to 1607, nucleotides 1588 to 1608, nucleotides 1589 to 1609, nucleotides 1594 to 1614, nucleotides 1595 to 1615, nucleotides 1598 to 1618, nucleotides 1599 to 1619, nucleotides 1600 to 1620, nucleotides 1601 to 1621, nucleotides 1602 to 1622, nucleotides 1641 to 1661, nucleotides 1642 to 1662, nucleotides 1643 to 1663, nucleotides 1644 to 1664, nucleotides 1750 to 1770, nucleotides 1755 to 1775, nucleotides 1757 to 1777, nucleotides 1758 to 1778, nucleotides 1760 to 1780, nucleotides 1761 to 1781, nucleotides 1762 to 1782, nucleotides 1764 to 1784, nucleotides 1765 to 1785, nucleotides 1768 to 1788, nucleotides 1769 to 1789, nucleotides 1770 to 1790, nucleotides 1771 to 1791, nucleotides 1772 to 1792, nucleotides 1808 to 1828, nucleotides 1809 to 1829, nucleotides 1810to 1830, nucleotides 1811 to 1831, nucleotides 1812to 1832, nucleotides 1813 to 1833, nucleotides 1814 to 1834, nucleotides 1815 to 1835, nucleotides 1816 to 1836, nucleotides 1853 to 1873, nucleotides 1854 to 1874, nucleotides 1856 to 1876, nucleotides 1857 to 1877, nucleotides 1858 to 1878, nucleotides 1859 to 1879, nucleotides 1860 to 1880, nucleotides 2168 to 2188, nucleotides 2333 to 2353, nucleotides 2454 to 2474, nucleotides 2507 to 2527, nucleotides 2593 to 2613, nucleotides 3244 to 3264, nucleotides 3288 to 3308, nucleotides 3304 to 3324, nucleotides 3332 to 3352, nucleotides 3333 to 3353, nucleotides 3501 to 3521, nucleotides 3595 to 3615, nucleotides 3643 to 3663, nucleotides 3644 to 3664, nucleotides 3645 to 3665, nucleotides 3646 to 3666, nucleotides 3646 to 3666, nucleotides 3647 to 3667, nucleotides 3648 to 3668, nucleotides 3648 to 3668, nucleotides 3648 to 3668, nucleotides 3649 to 3669, nucleotides 3650 to 3670, nucleotides 3651 to 3671, nucleotides 3651 to 3671, nucleotides 3651 to 3671,- 17 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOnucleotides 3652 to 3672, nucleotides 3713 to 3733, nucleotides 3763 to 3783, nucleotides 3764 to 3784, nucleotides 3765 to 3785, nucleotides 3766 to 3786, nucleotides 3791 to 3811, nucleotides 3796 to 3816, nucleotides 3801 to 3821, nucleotides 3802 to 3822, nucleotides 3803 to 3823, nucleotides 3804 to 3824, nucleotides 3805 to 3825, nucleotides 3806 to 3826, nucleotides 3807 to 3827, nucleotides 3808 to 3828, nucleotides 3809 to 3829, nucleotides 3809 to 3829, nucleotides 3810 to 3830, nucleotides 3811 to 3831, nucleotides 3812 to 3832, nucleotides 3812 to 3832, nucleotides 3813 to 3833, nucleotides 3813 to 3833, nucleotides 3814 to 3834, nucleotides 3814 to 3834, nucleotides 3814 to 3834, nucleotides 3840 to 3860, nucleotides 3902 to 3922, nucleotides 3965 to 3985, nucleotides 3998 to 4018, nucleotides 4102 to 4122, nucleotides 4140 to 4160, nucleotides 4141 to 4161, nucleotides 4141 to 4161, nucleotides 4142 to 4162, nucleotides 4142 to4162, nucleotides 4143 to4163, nucleotides 4144 to4164, nucleotides 4146 to 4166, nucleotides 4151 to 4171, nucleotides 4192 to 4212, nucleotides 4197 to 4217, nucleotides 4198 to 4218, nucleotides 4199 to 4219, nucleotides 4200 to 4220, nucleotides 4201 to 4221, nucleotides 4265 to 4285, nucleotides 4266 to 4286, nucleotides 4267 to 4287, nucleotides 4270 to 4290, nucleotides 4318 to 4338, nucleotides 4319 to 4339, nucleotides 4319 to 4339, nucleotides 4329 to 4349, nucleotides 4349 to 4369, nucleotides 4350 to 4370, nucleotides 4350 to 4370, nucleotides 4350 to 4370, nucleotides 4351 to 4371, nucleotides 4352 to 4372, nucleotides 4352 to 4372, nucleotides 4353 to 4373, nucleotides 4353 to 4373, nucleotides 4354 to 4374, nucleotides 4355 to 4375, nucleotides 4356 to 4376, nucleotides 4357 to 4377, nucleotides 4358 to 4378, nucleotides 4359 to4379, nucleotides 4360 to 4380, nucleotides 4361 to 4381, nucleotides 4362 to 4382, nucleotides 4362 to 4382, nucleotides 4363 to 4383, nucleotides 4364 to 4384, nucleotides 4364 to 4384, nucleotides 4365 to 4385, nucleotides 4395 to 4415, nucleotides 4396 to 4416, nucleotides 4410 to 4430, nucleotides 4412 to 4432, nucleotides 4637 to 4657, nucleotides 4638 to 4658, nucleotides 4640 to 4660, nucleotides 5103 to 5123, nucleotides 5124 to 5144, nucleotides 5126 to 5146, or nucleotides 5127 to 5147 of SEQ ID NO: 1.

[0054] In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the nucleotide sequences of nucleotides 3 to 25, nucleotides 8 to 30, nucleotides 13 to 35, nucleotides 38 to 60, nucleotides 43 to 65, nucleotides 48 to 70, nucleotides 93 to 115, nucleotides 98 to 120, nucleotides 103 to 125, nucleotides 108 to 130, nucleotides 111 to 133, nucleotides 113 to 135, nucleotides 118 to 140, nucleotides 214 to 236, nucleotides 219 to 241, nucleotides 244 to 266, nucleotides 249 to 271,- 18 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOnucleotides 252 to 274, nucleotides 252 to 274, nucleotides 253 to 275, nucleotides 254 to 276, nucleotides 257 to 286, nucleotides 259 to 281, nucleotides 264 to 286, nucleotides 289 to 311, nucleotides 294 to 316, nucleotides 339 to 361, nucleotides 397 to 419, nucleotides 460 to 480, nucleotides 461 to 481, nucleotides 481 to 503, nucleotides 486 to 508, nucleotides 491 to 513, nucleotides 557 to 579, nucleotides 561 to 583, nucleotides 562 to 584, nucleotides 564 to 586, nucleotides 566 to 586, nucleotides 567 to 589, nucleotides 616 to 638, nucleotides 621 to 643, nucleotides 626 to 648, nucleotides 670 to 692, nucleotides 671 to 691, nucleotides 672 to 694, nucleotides 674 to 694, nucleotides 675 to 697, nucleotides 680 to 702, nucleotides 685 to 707, nucleotides 690 to 712, nucleotides 695 to 717, nucleotides 700 to 722, nucleotides 705 to 727, nucleotides 710 to 732, nucleotides 715 to 737, nucleotides 720 to 742, nucleotides 725 to 747, nucleotides 730 to 752, nucleotides 735 to 757, nucleotides 740 to 762, nucleotides 745 to 767, nucleotides 750 to 772, nucleotides 751 to 776, nucleotides 755 to 777, nucleotides 760 to 782, nucleotides 765 to 787, nucleotides 770 to 792, nucleotides 775 to 797, nucleotides 798 to 823, nucleotides 800 to 822, nucleotides 825 to 847, nucleotides 890 to 912, nucleotides 895 to 917, nucleotides 900 to 922, nucleotides 905 to 927, nucleotides 910 to 932, nucleotides 911 to 937, nucleotides 915 to 937, nucleotides 972 to 994, nucleotides 973 to 995, nucleotides 977 to 1000, nucleotides 977 to 999, nucleotides 978 to 1000, nucleotides 983 to 1005, nucleotides 1035 to 1057, nucleotides 1058 to 1080, nucleotides 1059 to 1081, nucleotides 1060 to 1082, nucleotides 1063 to 1082, nucleotides 1065 to 1087, nucleotides 1068 to 1087, nucleotides 1070 to 1094, nucleotides 1070 to 1092, nucleotides 1074 to 1096, nucleotides 1075 to 1097, nucleotides 1077 to 1096, nucleotides 1080 to 1102, nucleotides 1085 to 1107, nucleotides 1086 to 1106, nucleotides 1090 to 1112, nucleotides 1095 to 1117, nucleotides 1100 to 1122, nucleotides 1105 to 1127, nucleotides 1110 to 1132, nucleotides 1115 to 1137, nucleotides 1115 to 1137, nucleotides 1117 to 1139, nucleotides 1177 to 1199, nucleotides 1182 to 1204, nucleotides 1187 to 1209, nucleotides 1191 to 1214, nucleotides 1192 to 1214, nucleotides 1195 to 1217, nucleotides 1234 to 1256, nucleotides 1239 to 1261, nucleotides 1242 to 1264, nucleotides 1244 to 1266, nucleotides 1247 to 1268, nucleotides 1249 to 1271, nucleotides 1251 to 1270, nucleotides 1254 to 1276, nucleotides 1259 to 1281, nucleotides 1263 to 1282, nucleotides 1264 to 1286, nucleotides 1266 to 1285, nucleotides 1269 to 1291, nucleotides 1326 to 1348, nucleotides 1331 to 1353, nucleotides 1334 to 1361, nucleotides 1334 to 1356, nucleotides 1334 to 1356, nucleotides 1335 to 1357, nucleotides 1336 to 1358, nucleotides 1337 to 1359, nucleotides 1337 to 1359, nucleotides 1338 to 1360,- 19 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOnucleotides 1340 to 1362, nucleotides 1341 to 1363, nucleotides 1346 to 1368, nucleotides 1351 to 1373, nucleotides 1353 to 1372, nucleotides 1377 to 1399, nucleotides 1382 to 1404, nucleotides 1383 to 1403, nucleotides 1387 to 1409, nucleotides 1392 to 1414, nucleotides 1397 to 1419, nucleotides 1402 to 1424, nucleotides 1407 to 1429, nucleotides 1412 to 1434, nucleotides 1417 to 1439, nucleotides 1456 to 1478, nucleotides 1458 to 1477, nucleotides 1481 to 1503, nucleotides 1486 to 1508, nucleotides 1491 to 1513, nucleotides 1496 to 1518, nucleotides 1521 to 1543, nucleotides 1568 to 1590, nucleotides 1569 to 1591, nucleotides 1574 to 1596, nucleotides 1578 to 1621, nucleotides 1579 to 1601, nucleotides 1583 to 1605, nucleotides 1583 to 1605, nucleotides 1584 to 1606, nucleotides 1584 to 1606, nucleotides 1585 to 1607, nucleotides 1585 to 1607, nucleotides 1587 to 1609, nucleotides 1588 to 1610, nucleotides 1589 to 1611, nucleotides 1594 to 1616, nucleotides 1595 to 1617, nucleotides 1599 to 1621, nucleotides 1601 to 1620, nucleotides 1602 to 1624, nucleotides 1642 to 1664, nucleotides 1749 to 1775, nucleotides 1750 to 1772, nucleotides 1755 to 1777, nucleotides 1757 to 1779, nucleotides 1758 to 1780, nucleotides 1760 to 1782, nucleotides 1761 to 1792, nucleotides 1764 to 1783, nucleotides 1765 to 1787, nucleotides 1770 to 1792, nucleotides 1809 to 1831, nucleotides 1810 to 1829, nucleotides 1812 to 1832, nucleotides 1814 to 1836, nucleotides 1852 to 1881, nucleotides 1853 to 1875, nucleotides 1854 to 1876, nucleotides 1858 to 1880, nucleotides 2168 to 2188, nucleotides 2333 to 2353, nucleotides 2454 to 2474, nucleotides 2507 to 2527, nucleotides 2593 to 2613, nucleotides 3244 to 3264, nucleotides 3288 to 3308, nucleotides 3304 to 3324, nucleotides 3332 to 3352, nucleotides 3333 to 3353, nucleotides 3501 to 3523, nucleotides 3595 to 3615, nucleotides 3595 to 3617, nucleotides 3643 to 3671, nucleotides 3646 to 3668, nucleotides 3646 to 3668, nucleotides 3647 to 3669, nucleotides 3648 to 3668, nucleotides 3648 to 3670, nucleotides 3648 to 3670, nucleotides 3649 to 3671, nucleotides 3651 to 3670, nucleotides 3651 to 3673, nucleotides 3651 to 3673, nucleotides 3652 to 3671, nucleotides 3712 to 3733, nucleotides 3713 to 3735, nucleotides 3763 to 3786, nucleotides 3763 to 3785, nucleotides 3764 to 3786, nucleotides 3791 to 3811, nucleotides 3796 to 3816, nucleotides 3801 to 3829, nucleotides 3801 to 3820, nucleotides 3802 to 3821, nucleotides 3804 to 3826, nucleotides 3809 to 3831, nucleotides 3810 to 3832, nucleotides 3812 to 3833, nucleotides 3812 to 3834, nucleotides 3813 to 3835, nucleotides 3814 to 3833, nucleotides 3814 to 3836, nucleotides 3814 to 3836, nucleotides 3839 to 3859, nucleotides 3840 to 3862, nucleotides 3902 to 3924, nucleotides 3965 to 3987, nucleotides 3995 to 4015, nucleotides 3998 to 4020, nucleotides 4100 to 4124, nucleotides 4102 to 4124, nucleotides 4141 to 4163, nucleotides 4141- 20 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOto 4163, nucleotides 4142 to 4164, nucleotides 4143 to 4165, nucleotides 4144 to 4166, nucleotides 4146 to 4168, nucleotides 4150 to 4172, nucleotides 4151 to 4173, nucleotides 4192 to 4214, nucleotides 4197 to 4219, nucleotides 4201 to 4223, nucleotides 4265 to 4287, nucleotides 4270 to 4292, nucleotides 4318 to 4338, nucleotides 4319 to 4341, nucleotides 4329 to 4349, nucleotides 4348 to 4386, nucleotides 4349 to 4371, nucleotides 4350 to 4369, nucleotides 4350 to 4372, nucleotides 4350 to 4372, nucleotides 4351 to 4370, nucleotides 4352 to 4371, nucleotides 4352 to 4374, nucleotides 4353 to 4372, nucleotides 4353 to 4375, nucleotides 4354 to 4376, nucleotides 4359 to 4381, nucleotides 4361 to 4383, nucleotides 4362 to 4384, nucleotides 4362 to 4384, nucleotides 4364 to 4386, nucleotides 4365 to 4387, nucleotides 4395 to 4415, nucleotides 4396 to 4416, nucleotides 4409 to 4431, nucleotides 4410 to 4432, nucleotides 4412 to 4434, nucleotides 4637 to 4657, nucleotides 4638 to 4658, nucleotides 4640 to 4660, nucleotides 5103 to 5123, nucleotides 5124 to 5144, nucleotides 5126 to 5146, or nucleotides 5127 to 5147 of SEQ ID NO: 1, and the antisense strand comprises at least 15 contiguous nucleotides from the corresponding nucleotide sequence of SEQ ID NO: 2.

[0055] In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from a nucleotide sequence of 15 contiguous nucleotides and comprised in any one of the nucleotide sequences of SEQ ID NOs: 778-1554. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 2 nucleotides from a nucleotide sequence of 15 contiguous nucleotides and comprised in any one of the nucleotide sequences of SEQ ID NOs: 778-1554. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 1 nucleotide from a nucleotide sequence of 15 contiguous nucleotides and comprised in any one of the nucleotide sequences of SEQ ID NOs: 778-1554. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides of a nucleotide sequence selected from any one of the nucleotide sequences SEQ ID NOs: 778-1554.

[0056] In some embodiments, the nucleic acid A comprises a antisense strand of 12 to 60 linked nucleotides in length, and a sense strand of 12 to 60 linked nucleotides in length. In some embodiments, the antisense strand comprises a nucleotide sequence at least 75%, 80%, 85%, 90%, or 95% identical to any one of the nucleotide sequences of SEQ ID NOs: 1555-2331; and the sense strand comprises a nucleotide sequence at least 75%, 80%, 85%, 90%, or 95% identical to any one of the nucleotide sequences of SEQ ID NOs: 778-1554. In some embodiments, the antisense strand - 21 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOcomprises a nucleotide sequence selected from any one of SEQ IDNOs: 1555-2331 or a nucleotide sequence differing in 1, 2, or 3 amino acids therefrom; the sense strand comprises a nucleotide sequence selected from any one of SEQ ID NOs: 778-1554 or a nucleotide sequence differing in 1, 2, or 3 amino acids therefrom. In some embodiments, the antisense strand comprises or is a nucleotide sequence selected from any one of SEQ ID NOs: 1555-2331; and the sense strand comprises or is a nucleotide sequence selected from any one of SEQ ID NOs: 778-1554.

[0057] In some embodiments, the nucleic acid A comprises an antisense strand and a sense strand, wherein the sense strand and the antisense strand comprise nucleotide sequences of SEQ ID NOs: 780 and 1557, respectively; SEQ ID NOs: 781 and 1558, respectively; SEQ ID NOs: 782 and 1559, respectively; SEQ ID NOs: 783 and 1560, respectively; SEQ ID NOs: 784 and 1561, respectively; SEQ ID NOs: 785 and 1562, respectively; SEQ ID NOs: 786 and 1563, respectively; SEQ IDNOs: 787 and 1564, respectively; SEQ IDNOs: 788 and 1565, respectively; SEQ IDNOs: 789 and 1566, respectively; SEQ ID NOs: 790 and 1567, respectively; SEQ ID NOs: 791 and 1568, respectively; SEQ ID NOs: 792 and 1569, respectively; SEQ ID NOs: 793 and 1570, respectively; SEQ ID NOs: 794 and 1571, respectively; SEQ ID NOs: 795 and 1572, respectively; SEQ IDNOs: 796 and 1573, respectively; SEQ IDNOs: 797 and 1574, respectively; SEQ IDNOs: 798 and 1575, respectively; SEQ ID NOs: 799 and 1576, respectively; SEQ ID NOs: 800 and 1577, respectively; SEQ ID NOs: 801 and 1578, respectively; SEQ ID NOs: 802 and 1579, respectively; SEQ ID NOs: 803 and 1580, respectively; SEQ ID NOs: 804 and 1581, respectively; SEQ ID NOs: 805 and 1582, respectively; SEQ ID NOs: 806 and 1583, respectively; SEQ ID NOs: 807 and 1584, respectively; SEQ ID NOs: 808 and 1585, respectively; SEQ ID NOs: 809 and 1586, respectively; SEQ ID NOs: 810 and 1587, respectively; SEQ ID NOs: 811 and 1588, respectively; SEQ IDNOs: 812 and 1589, respectively; SEQ IDNOs: 813 and 1590, respectively; SEQ IDNOs: 814 and 1591, respectively; SEQ IDNOs: 815 and 1592, respectively; SEQ ID NOs: 816 and 1593, respectively; SEQ ID NOs: 817 and 1594, respectively; SEQ ID NOs: 818 and 1595, respectively; SEQ ID NOs: 819 and 1596, respectively; SEQ ID NOs: 820 and 1597, respectively; SEQ ID NOs: 821 and 1598, respectively; SEQ ID NOs: 822 and 1599, respectively; SEQ IDNOs: 823 and 1600, respectively; SEQ ID NOs: 824 and 1601, respectively; SEQ IDNOs: 825 and 1602, respectively; SEQ ID NOs: 826 and 1603, respectively; SEQ ID NOs: 827 and 1604, respectively; SEQ ID NOs: 828 and 1605, respectively; SEQ ID NOs: 829 and 1606, respectively; SEQ IDNOs: 830 and 1607, respectively; SEQ IDNOs: 831 and 1608, respectively;- 22 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOSEQ IDNOs: 832 and 1609, respectively; SEQIDNOs: 833 and 1610, respectively; SEQ IDNOs: 834 and 1611, respectively; SEQ ID NOs: 835 and 1612, respectively; SEQ ID NOs: 836 and 1613, respectively; SEQ ID NOs: 837 and 1614, respectively; SEQ ID NOs: 838 and 1615, respectively; SEQ ID NOs: 839 and 1616, respectively; SEQ ID NOs: 840 and 1617, respectively; SEQ IDNOs: 841 and 1618, respectively; SEQ IDNOs: 842 and 1619, respectively; SEQ IDNOs: 843 and 1620, respectively; SEQ ID NOs: 844 and 1621, respectively; SEQ ID NOs: 845 and 1622, respectively; SEQ ID NOs: 846 and 1623, respectively; SEQ ID NOs: 847 and 1624, respectively; SEQ ID NOs: 848 and 1625, respectively; SEQ ID NOs: 849 and 1626, respectively; SEQ IDNOs: 850 and 1627, respectively; SEQIDNOs: 851 and 1628, respectively; SEQ IDNOs: 852 and 1629, respectively; SEQ ID NOs: 853 and 1630, respectively; SEQ ID NOs: 854 and 1631, respectively; SEQ ID NOs: 855 and 1632, respectively; SEQ ID NOs: 856 and 1633, respectively; SEQ ID NOs: 857 and 1634, respectively; SEQ ID NOs: 858 and 1635, respectively; SEQ IDNOs: 859 and 1636, respectively; SEQ IDNOs: 860 and 1637, respectively; SEQ IDNOs: 861 and 1638, respectively; SEQ ID NOs: 862 and 1639, respectively; SEQ ID NOs: 863 and 1640, respectively; SEQ ID NOs: 864 and 1641, respectively; SEQ ID NOs: 865 and 1642, respectively; SEQ ID NOs: 866 and 1643, respectively; SEQ ID NOs: 867 and 1644, respectively; SEQ ID NOs: 868 and 1645, respectively; SEQ ID NOs: 869 and 1646, respectively; SEQ ID NOs: 870 and 1647, respectively; SEQ ID NOs: 871 and 1648, respectively; SEQ ID NOs: 872 and 1649, respectively; SEQ ID NOs: 873 and 1650, respectively; SEQ ID NOs: 874 and 1651, respectively; SEQ IDNOs: 875 and 1652, respectively; SEQ IDNOs: 876 and 1653, respectively; SEQ IDNOs: 877 and 1654, respectively; SEQ IDNOs: 878 and 1655, respectively; SEQ IDNOs: 879 and 1656, respectively; SEQ ID NOs: 880 and 1657, respectively; SEQ ID NOs: 881 and 1658, respectively; SEQ ID NOs: 882 and 1659, respectively; SEQ ID NOs: 883 and 1660, respectively; SEQ ID NOs: 884 and 1661, respectively; SEQ ID NOs: 885 and 1662, respectively; SEQ ID NOs: 886 and 1663, respectively; SEQ ID NOs: 887 and 1664, respectively; SEQ ID NOs: 888 and 1665, respectively; SEQ ID NOs: 889 and 1666, respectively; SEQ ID NOs: 890 and 1667, respectively; SEQ ID NOs: 891 and 1668, respectively; SEQ ID NOs: 892 and 1669, respectively; SEQ IDNOs: 893 and 1670, respectively; SEQ IDNOs: 894 and 1671, respectively; SEQ IDNOs: 895 and 1672, respectively; SEQ IDNOs: 896 and 1673, respectively; SEQ IDNOs: 897 and 1674, respectively; SEQ ID NOs: 898 and 1675, respectively; SEQ ID NOs: 899 and 1676, respectively; SEQ ID NOs: 900 and 1677, respectively; SEQ ID NOs: 901 and 1678,- 23 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOrespectively; SEQ IDNOs: 902 and 1679, respectively; SEQ IDNOs: 903 and 1680, respectively; SEQ IDNOs: 904 and 1681, respectively; SEQ IDNOs: 905 and 1682, respectively; SEQ IDNOs: 906 and 1683, respectively; SEQ ID NOs: 907 and 1684, respectively; SEQ ID NOs: 908 and 1685, respectively; SEQ ID NOs: 909 and 1686, respectively; SEQ ID NOs: 910 and 1687, respectively; SEQ ID NOs: 911 and 1688, respectively; SEQ ID NOs: 912 and 1689, respectively; SEQ IDNOs: 913 and 1690, respectively; SEQ ID NOs: 914 and 1691, respectively; SEQ IDNOs: 915 and 1692, respectively; SEQ ID NOs: 916 and 1693, respectively; SEQ ID NOs: 917 and 1694, respectively; SEQ ID NOs: 918 and 1695, respectively; SEQ ID NOs: 919 and 1696, respectively; SEQ ID NOs: 920 and 1697, respectively; SEQ ID NOs: 921 and 1698, respectively; SEQ IDNOs: 922 and 1699, respectively; SEQ IDNOs: 923 and 1700, respectively; SEQ IDNOs: 924 and 1701, respectively; SEQ ID NOs: 925 and 1702, respectively; SEQ ID NOs: 926 and 1703, respectively; SEQ ID NOs: 927 and 1704, respectively; SEQ ID NOs: 928 and 1705, respectively; SEQ ID NOs: 929 and 1706, respectively; SEQ ID NOs: 930 and 1707, respectively; SEQ ID NOs: 931 and 1708, respectively; SEQ ID NOs: 932 and 1709, respectively; SEQ ID NOs: 933 and 1710, respectively; SEQ ID NOs: 934 and 1711, respectively; SEQ ID NOs: 935 and 1712, respectively; SEQ ID NOs: 936 and 1713, respectively; SEQ ID NOs: 937 and 1714, respectively; SEQ IDNOs: 938 and 1715, respectively; SEQ IDNOs: 939 and 1716, respectively; SEQ IDNOs: 940 and 1717, respectively; SEQ IDNOs: 941 and 1718, respectively; SEQ IDNOs: 942 and 1719, respectively; SEQ ID NOs: 943 and 1720, respectively; SEQ ID NOs: 944 and 1721, respectively; SEQ ID NOs: 945 and 1722, respectively; SEQ ID NOs: 946 and 1723, respectively; SEQ ID NOs: 947 and 1724, respectively; SEQ ID NOs: 948 and 1725, respectively; SEQ IDNOs: 949 and 1726, respectively; SEQ IDNOs: 950 and 1727, respectively; SEQ IDNOs: 951 and 1728, respectively; SEQ ID NOs: 952 and 1729, respectively; SEQ ID NOs: 953 and 1730, respectively; SEQ ID NOs: 954 and 1731, respectively; SEQ ID NOs: 955 and 1732, respectively; SEQ IDNOs: 956 and 1733, respectively; SEQ IDNOs: 957 and 1734, respectively; SEQ IDNOs: 958 and 1735, respectively; SEQ IDNOs: 959 and 1736, respectively; SEQ IDNOs: 960 and 1737, respectively; SEQ ID NOs: 961 and 1738, respectively; SEQ ID NOs: 962 and 1739, respectively; SEQ ID NOs: 963 and 1740, respectively; SEQ ID NOs: 964 and 1741, respectively; SEQ ID NOs: 965 and 1742, respectively; SEQ ID NOs: 966 and 1743, respectively; SEQ IDNOs: 967 and 1744, respectively; SEQ IDNOs: 968 and 1745, respectively; SEQ IDNOs: 969 and 1746, respectively; SEQ ID NOs: 970 and 1747, respectively; SEQ ID NOs: 971 and - 24 - IPTS / 200358788.1Attorney Docket No. JUDO-005WO1748, respectively; SEQ ID NOs: 972 and 1749, respectively; SEQ ID NOs: 973 and 1750, respectively; SEQ ID NOs: 974 and 1751, respectively; SEQ ID NOs: 975 and 1752, respectively; SEQ ID NOs: 976 and 1753, respectively; SEQ ID NOs: 977 and 1754, respectively; SEQ ID NOs: 978 and 1755, respectively; SEQ ID NOs: 979 and 1756, respectively; SEQ ID NOs: 980 and 1757, respectively; SEQ ID NOs: 981 and 1758, respectively; SEQ ID NOs: 982 and 1759, respectively; SEQ ID NOs: 983 and 1760, respectively; SEQ ID NOs: 984 and 1761, respectively; SEQ ID NOs: 985 and 1762, respectively; SEQ ID NOs: 986 and 1763, respectively; SEQ ID NOs: 987 and 1764, respectively; SEQ ID NOs: 988 and 1765, respectively; SEQ ID NOs: 989 and 1766, respectively; SEQ ID NOs: 990 and 1767, respectively; SEQ ID NOs: 991 and 1768, respectively; SEQ ID NOs: 992 and 1769, respectively; SEQ ID NOs: 993 and 1770, respectively; SEQ ID NOs: 994 and 1771, respectively; SEQ ID NOs: 995 and 1772, respectively; SEQ ID NOs: 996 and 1773, respectively; SEQ ID NOs: 997 and 1774, respectively; SEQ ID NOs: 998 and 1775, respectively; SEQ ID NOs: 999 and 1776, respectively; SEQ ID NOs: 1000 and 1777, respectively; SEQ ID NOs: 1001 and 1778, respectively; SEQ ID NOs: 1002 and 1779, respectively; SEQ ID NOs: 1003 and 1780, respectively; SEQ ID NOs: 1004 and 1781, respectively; SEQ ID NOs: 1005 and 1782, respectively; SEQ ID NOs: 1006 and 1783, respectively; SEQ ID NOs: 1007 and 1784, respectively; SEQ ID NOs: 1008 and 1785, respectively; SEQ ID NOs: 1009 and 1786, respectively; SEQ ID NOs: 1010 and 1787, respectively; SEQ ID NOs: 1011 and 1788, respectively; SEQ ID NOs: 1012 and 1789, respectively; SEQ ID NOs: 1013 and 1790, respectively; SEQ ID NOs: 1014 and 1791, respectively; SEQ ID NOs: 1015 and 1792, respectively; SEQ ID NOs: 1016 and 1793, respectively; SEQ ID NOs: 1017 and 1794, respectively; SEQ ID NOs: 1018 and 1795, respectively; SEQ ID NOs: 1019 and 1796, respectively; SEQ ID NOs: 1020 and 1797, respectively; SEQ ID NOs: 1021 and 1798, respectively; SEQ ID NOs: 1022 and 1799, respectively; SEQ ID NOs: 1023 and 1800, respectively; SEQ ID NOs: 1024 and 1801, respectively; SEQ ID NOs: 1025 and 1802, respectively; SEQ ID NOs: 1026 and 1803, respectively; SEQ ID NOs: 1027 and 1804, respectively; SEQ ID NOs: 1028 and 1805, respectively; SEQ ID NOs: 1029 and 1806, respectively; SEQ ID NOs: 1030 and 1807, respectively; SEQ ID NOs: 1031 and 1808, respectively; SEQ ID NOs: 1032 and 1809, respectively; SEQ ID NOs: 1033 and 1810, respectively; SEQ ID NOs: 1034 and 1811, respectively; SEQ ID NOs: 1035 and 1812, respectively; SEQ ID NOs: 1036 and 1813,IPTS / 200358788.1Attorney Docket No. JUDO-005WOrespectively; SEQ ID NOs: 1037 and 1814, respectively; SEQ ID NOs: 1038 and 1815 respectively; SEQ ID NOs: 1039 and 1816, respectively; SEQ ID NOs: 1040 and 1817 respectively; SEQ ID NOs: 1041 and 1818, respectively; SEQ ID NOs: 1042 and 1819 respectively; SEQ ID NOs: 1043 and 1820, respectively; SEQ ID NOs: 1044 and 1821 respectively; SEQ ID NOs: 1045 and 1822, respectively; SEQ ID NOs: 1046 and 1823 respectively; SEQ ID NOs: 1047 and 1824, respectively; SEQ ID NOs: 1048 and 1825. respectively; SEQ ID NOs: 1049 and 1826, respectively; SEQ ID NOs: 1050 and 1827 respectively; SEQ ID NOs: 1051 and 1828, respectively; SEQ ID NOs: 1052 and 1829. respectively; SEQ ID NOs: 1053 and 1830, respectively; SEQ ID NOs: 1054 and 1831 respectively; SEQ ID NOs: 1055 and 1832, respectively; SEQ ID NOs: 1056 and 1833, respectively; SEQ ID NOs: 1057 and 1834, respectively; SEQ ID NOs: 1058 and 1835. respectively; SEQ ID NOs: 1059 and 1836, respectively; SEQ ID NOs: 1060 and 1837. respectively; SEQ ID NOs: 1061 and 1838, respectively; SEQ ID NOs: 1062 and 1839. respectively; SEQ ID NOs: 1063 and 1840, respectively; SEQ ID NOs: 1064 and 1841 respectively; SEQ ID NOs: 1065 and 1842, respectively; SEQ ID NOs: 1066 and 1843, respectively; SEQ ID NOs: 1067 and 1844, respectively; SEQ ID NOs: 1068 and 1845. respectively; SEQ ID NOs: 1069 and 1846, respectively; SEQ ID NOs: 1070 and 1847, respectively; SEQ ID NOs: 1071 and 1848, respectively; SEQ ID NOs: 1072 and 1849, respectively; SEQ ID NOs: 1073 and 1850, respectively; SEQ ID NOs: 1074 and 1851. respectively; SEQ ID NOs: 1075 and 1852, respectively; SEQ ID NOs: 1076 and 1853, respectively; SEQ ID NOs: 1077 and 1854, respectively; SEQ ID NOs: 1078 and 1855, respectively; SEQ ID NOs: 1079 and 1856, respectively; SEQ ID NOs: 1080 and 1857 respectively; SEQ ID NOs: 1081 and 1858, respectively; SEQ ID NOs: 1082 and 1859, respectively; SEQ ID NOs: 1083 and 1860, respectively; SEQ ID NOs: 1084 and 1861, respectively; SEQ ID NOs: 1085 and 1862, respectively; SEQ ID NOs: 1086 and 1863, respectively; SEQ ID NOs: 1087 and 1864, respectively; SEQ ID NOs: 1088 and 1865, respectively; SEQ ID NOs: 1089 and 1866, respectively; SEQ ID NOs: 1090 and 1867, respectively; SEQ ID NOs: 1091 and 1868, respectively; SEQ ID NOs: 1092 and 1869, respectively; SEQ ID NOs: 1093 and 1870, respectively; SEQ ID NOs: 1094 and 1871, respectively; SEQ ID NOs: 1095 and 1872, respectively; SEQ ID NOs: 1096 and 1873, respectively; SEQ ID NOs: 1097 and 1874, respectively; SEQ ID NOs: 1098 and 1875,- 26 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOrespectively; SEQ ID NOs: 1099 and 1876, respectively; SEQ ID NOs: 1100 and 1877, respectively; SEQ ID NOs: 1101 and 1878, respectively; SEQ ID NOs: 1102 and 1879. respectively; SEQ ID NOs: 1103 and 1880, respectively; SEQ ID NOs: 1104 and 1881. respectively; SEQ ID NOs: 1105 and 1882, respectively; SEQ ID NOs: 1106 and 1883, respectively; SEQ ID NOs: 1107 and 1884, respectively; SEQ ID NOs: 1108 and 1885. respectively; SEQ ID NOs: 1109 and 1886, respectively; SEQ ID NOs: 1110 and 1887, respectively; SEQ ID NOs: 1111 and 1888, respectively; SEQ ID NOs: 1112 and 1889, respectively; SEQ ID NOs: 1113 and 1890, respectively; SEQ ID NOs: 1114 and 1891. respectively; SEQ ID NOs: 1115 and 1892, respectively; SEQ ID NOs: 1116 and 1893, respectively; SEQ ID NOs: 1117 and 1894, respectively; SEQ ID NOs: 1118 and 1895, respectively; SEQ ID NOs: 1119 and 1896, respectively; SEQ ID NOs: 1120 and 1897. respectively; SEQ ID NOs: 1121 and 1898, respectively; SEQ ID NOs: 1122 and 1899, respectively; SEQ ID NOs: 1123 and 1900, respectively; SEQ ID NOs: 1124 and 1901 respectively; SEQ ID NOs: 1125 and 1902, respectively; SEQ ID NOs: 1126 and 1903. respectively; SEQ ID NOs: 1127 and 1904, respectively; SEQ ID NOs: 1128 and 1905, respectively; SEQ ID NOs: 1129 and 1906, respectively; SEQ ID NOs: 1130 and 1907 respectively; SEQ ID NOs: 1131 and 1908, respectively; SEQ ID NOs: 1132 and 1909, respectively; SEQ ID NOs: 1133 and 1910, respectively; SEQ ID NOs: 1134 and 1911, respectively; SEQ ID NOs: 1135 and 1912, respectively; SEQ ID NOs: 1136 and 1913 respectively; SEQ ID NOs: 1137 and 1914, respectively; SEQ ID NOs: 1138 and 1915, respectively; SEQ ID NOs: 1139 and 1916, respectively; SEQ ID NOs: 1140 and 1917. respectively; SEQ ID NOs: 1141 and 1918, respectively; SEQ ID NOs: 1142 and 1919 respectively; SEQ ID NOs: 1143 and 1920, respectively; SEQ ID NOs: 1144 and 1921, respectively; SEQ ID NOs: 1145 and 1922, respectively; SEQ ID NOs: 1146 and 1923. respectively; SEQ ID NOs: 1147 and 1924, respectively; SEQ ID NOs: 1148 and 1925, respectively; SEQ ID NOs: 1149 and 1926, respectively; SEQ ID NOs: 1150 and 1927, respectively; SEQ ID NOs: 1151 and 1928, respectively; SEQ ID NOs: 1152 and 1929. respectively; SEQ ID NOs: 1153 and 1930, respectively; SEQ ID NOs: 1154 and 1931, respectively; SEQ ID NOs: 1155 and 1932, respectively; SEQ ID NOs: 1156 and 1933, respectively; SEQ ID NOs: 1157 and 1934, respectively; SEQ ID NOs: 1158 and 1935. respectively; SEQ ID NOs: 1159 and 1936, respectively; SEQ ID NOs: 1160 and 1937.- 27 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOrespectively; SEQ ID NOs: 1161 and 1938, respectively; SEQ ID NOs: 1162 and 1939 respectively; SEQ ID NOs: 1163 and 1940, respectively; SEQ ID NOs: 1164 and 1941 respectively; SEQ ID NOs: 1165 and 1942, respectively; SEQ ID NOs: 1166 and 1943 respectively; SEQ ID NOs: 1167 and 1944, respectively; SEQ ID NOs: 1168 and 1945 respectively; SEQ ID NOs: 1169 and 1946, respectively; SEQ ID NOs: 1170 and 1947 respectively; SEQ ID NOs: 1171 and 1948, respectively; SEQ ID NOs: 1172 and 1949, respectively; SEQ ID NOs: 1173 and 1950, respectively; SEQ ID NOs: 1174 and 1951 respectively; SEQ ID NOs: 1175 and 1952, respectively; SEQ ID NOs: 1176 and 1953. respectively; SEQ ID NOs: 1177 and 1954, respectively; SEQ ID NOs: 1178 and 1955, respectively; SEQ ID NOs: 1179 and 1956, respectively; SEQ ID NOs: 1180 and 1957, respectively; SEQ ID NOs: 1181 and 1958, respectively; SEQ ID NOs: 1182 and 1959. respectively; SEQ ID NOs: 1183 and 1960, respectively; SEQ ID NOs: 1184 and 1961, respectively; SEQ ID NOs: 1185 and 1962, respectively; SEQ ID NOs: 1186 and 1963. respectively; SEQ ID NOs: 1187 and 1964, respectively; SEQ ID NOs: 1188 and 1965, respectively; SEQ ID NOs: 1189 and 1966, respectively; SEQ ID NOs: 1190 and 1967, respectively; SEQ ID NOs: 1191 and 1968, respectively; SEQ ID NOs: 1192 and 1969. respectively; SEQ ID NOs: 1193 and 1970, respectively; SEQ ID NOs: 1194 and 1971, respectively; SEQ ID NOs: 1195 and 1972, respectively; SEQ ID NOs: 1196 and 1973, respectively; SEQ ID NOs: 1197 and 1974, respectively; SEQ ID NOs: 1198 and 1975. respectively; SEQ ID NOs: 1199 and 1976, respectively; SEQ ID NOs: 1200 and 1977, respectively; SEQ ID NOs: 1201 and 1978, respectively; SEQ ID NOs: 1202 and 1979, respectively; SEQ ID NOs: 1203 and 1980, respectively; SEQ ID NOs: 1204 and 1981 respectively; SEQ ID NOs: 1205 and 1982, respectively; SEQ ID NOs: 1206 and 1983, respectively; SEQ ID NOs: 1207 and 1984, respectively; SEQ ID NOs: 1208 and 1985, respectively; SEQ ID NOs: 1209 and 1986, respectively; SEQ ID NOs: 1210 and 1987 respectively; SEQ ID NOs: 1211 and 1988, respectively; SEQ ID NOs: 1212 and 1989, respectively; SEQ ID NOs. 1213 and 1990, respectively; SEQ ID NOs: 1214 and 1991, respectively; SEQ ID NOs: 1215 and 1992, respectively; SEQ ID NOs: 1216 and 1993, respectively; SEQ ID NOs: 1217 and 1994, respectively; SEQ ID NOs: 1218 and 1995, respectively; SEQ ID NOs: 1219 and 1996, respectively; SEQ ID NOs: 1220 and 1997, respectively; SEQ ID NOs: 1221 and 1998, respectively; SEQ ID NOs: 1222 and 1999,- 28 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOrespectively; SEQ ID NOs: 1223 and 2000, respectively; SEQ ID NOs: 1224 and 2001, respectively; SEQ ID NOs: 1225 and 2002, respectively; SEQ ID NOs: 1226 and 2003, respectively; SEQ ID NOs: 1227 and 2004, respectively; SEQ ID NOs: 1228 and 2005, respectively; SEQ ID NOs: 1229 and 2006, respectively; SEQ ID NOs: 1230 and 2007, respectively; SEQ ID NOs: 1231 and 2008, respectively; SEQ ID NOs: 1232 and 2009, respectively; SEQ ID NOs: 1233 and 2010, respectively; SEQ ID NOs: 1234 and 2011, respectively; SEQ ID NOs: 1235 and 2012, respectively; SEQ ID NOs: 1236 and 2013, respectively; SEQ ID NOs: 1237 and 2014, respectively; SEQ ID NOs: 1238 and 2015, respectively; SEQ ID NOs: 1239 and 2016, respectively; SEQ ID NOs: 1240 and 2017, respectively; SEQ ID NOs: 1241 and 2018, respectively; SEQ ID NOs: 1242 and 2019, respectively; SEQ ID NOs: 1243 and 2020, respectively; SEQ ID NOs: 1244 and 2021, respectively; SEQ ID NOs: 1245 and 2022, respectively; SEQ ID NOs: 1246 and 2023, respectively; SEQ ID NOs: 1247 and 2024, respectively; SEQ ID NOs: 1248 and 2025, respectively; SEQ ID NOs: 1249 and 2026, respectively; SEQ ID NOs: 1250 and 2027, respectively; SEQ ID NOs: 1251 and 2028, respectively; SEQ ID NOs: 1252 and 2029, respectively; SEQ ID NOs: 1253 and 2030, respectively; SEQ ID NOs: 1254 and 2031, respectively; SEQ ID NOs: 1255 and 2032, respectively; SEQ ID NOs: 1256 and 2033, respectively; SEQ ID NOs: 1257 and 2034, respectively; SEQ ID NOs: 1258 and 2035, respectively; SEQ ID NOs: 1259 and 2036, respectively; SEQ ID NOs: 1260 and 2037, respectively; SEQ ID NOs: 1261 and 2038, respectively; SEQ ID NOs: 1262 and 2039, respectively; SEQ ID NOs: 1263 and 2040, respectively; SEQ ID NOs: 1264 and 2041, respectively; SEQ ID NOs: 1265 and 2042, respectively; SEQ ID NOs: 1266 and 2043, respectively; SEQ ID NOs: 1267 and 2044, respectively; SEQ ID NOs: 1268 and 2045, respectively; SEQ ID NOs: 1269 and 2046, respectively; SEQ ID NOs: 1270 and 2047, respectively; SEQ ID NOs: 1271 and 2048, respectively; SEQ ID NOs: 1272 and 2049, respectively; SEQ ID NOs: 1273 and 2050, respectively; SEQ ID NOs: 1274 and 2051, respectively; SEQ ID NOs: 1275 and 2052, respectively; SEQ ID NOs: 1276 and 2053, respectively; SEQ ID NOs: 1277 and 2054, respectively; SEQ ID NOs: 1278 and 2055, respectively; SEQ ID NOs: 1279 and 2056, respectively; SEQ ID NOs: 1280 and 2057, respectively; SEQ ID NOs: 1281 and 2058, respectively; SEQ ID NOs: 1282 and 2059, respectively; SEQ ID NOs: 1283 and 2060, respectively; SEQ ID NOs: 1284 and 2061,- 29 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOrespectively; SEQ ID NOs: 1285 and 2062, respectively; SEQ ID NOs: 1286 and 2063, respectively; SEQ ID NOs: 1287 and 2064, respectively; SEQ ID NOs: 1288 and 2065, respectively; SEQ ID NOs: 1289 and 2066, respectively; SEQ ID NOs: 1290 and 2067, respectively; SEQ ID NOs: 1291 and 2068, respectively; SEQ ID NOs: 1292 and 2069, respectively; SEQ ID NOs: 1293 and 2070, respectively; SEQ ID NOs: 1294 and 2071, respectively; SEQ ID NOs: 1295 and 2072, respectively; SEQ ID NOs: 1296 and 2073, respectively; SEQ ID NOs: 1297 and 2074, respectively; SEQ ID NOs: 1298 and 2075, respectively; SEQ ID NOs: 1299 and 2076, respectively; SEQ ID NOs: 1300 and 2077, respectively; SEQ ID NOs: 1301 and 2078, respectively; SEQ ID NOs: 1302 and 2079, respectively; SEQ ID NOs: 1303 and 2080, respectively; SEQ ID NOs: 1304 and 2081, respectively; SEQ ID NOs: 1305 and 2082, respectively; SEQ ID NOs: 1306 and 2083, respectively; SEQ ID NOs: 1307 and 2084, respectively; SEQ ID NOs: 1308 and 2085, respectively; SEQ ID NOs: 1309 and 2086, respectively; SEQ ID NOs: 1310 and 2087, respectively; SEQ ID NOs: 1311 and 2088, respectively; SEQ ID NOs: 1312 and 2089, respectively; SEQ ID NOs: 1313 and 2090, respectively; SEQ ID NOs: 1314 and 2091, respectively; SEQ ID NOs: 1315 and 2092, respectively; SEQ ID NOs: 1316 and 2093, respectively; SEQ ID NOs: 1317 and 2094, respectively; SEQ ID NOs: 1318 and 2095, respectively; SEQ ID NOs: 1319 and 2096, respectively; SEQ ID NOs: 1320 and 2097, respectively; SEQ ID NOs: 1321 and 2098, respectively; SEQ ID NOs: 1322 and 2099, respectively; SEQ ID NOs: 1323 and 2100, respectively; SEQ ID NOs: 1324 and 2101, respectively; SEQ ID NOs: 1325 and 2102, respectively; SEQ ID NOs: 1326 and 2103, respectively; SEQ ID NOs: 1327 and 2104, respectively; SEQ ID NOs: 1328 and 2105, respectively; SEQ ID NOs: 1329 and 2106, respectively; SEQ ID NOs: 1330 and 2107, respectively; SEQ ID NOs: 1331 and 2108, respectively; SEQ ID NOs: 1332 and 2109, respectively; SEQ ID NOs: 1333 and 2110, respectively; SEQ ID NOs: 1334 and 2111, respectively; SEQ ID NOs: 1335 and 2112, respectively; SEQ ID NOs: 1336 and 2113, respectively; SEQ ID NOs: 1337 and 2114, respectively; SEQ ID NOs: 1338 and 2115, respectively; SEQ ID NOs: 1339 and 2116, respectively; SEQ ID NOs: 1340 and 2117, respectively; SEQ ID NOs: 1341 and 2118, respectively; SEQ ID NOs: 1342 and 2119, respectively; SEQ ID NOs: 1343 and 2120, respectively; SEQ ID NOs: 1344 and 2121, respectively; SEQ ID NOs: 1345 and 2122, respectively; SEQ ID NOs: 1346 and 2123,- 30 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOrespectively; SEQ ID NOs: 1347 and 2124, respectively; SEQ ID NOs: 1348 and 2125, respectively; SEQ ID NOs: 1349 and 2126, respectively; SEQ ID NOs: 1350 and 2127 respectively; SEQ ID NOs: 1351 and 2128, respectively; SEQ ID NOs: 1352 and 2129 respectively; SEQ ID NOs: 1353 and 2130, respectively; SEQ ID NOs: 1354 and 2131 respectively; SEQ ID NOs: 1355 and 2132, respectively; SEQ ID NOs: 1356 and 2133 respectively; SEQ ID NOs: 1357 and 2134, respectively; SEQ ID NOs: 1358 and 2135, respectively; SEQ ID NOs: 1359 and 2136, respectively; SEQ ID NOs: 1360 and 2137 respectively; SEQ ID NOs: 1361 and 2138, respectively; SEQ ID NOs: 1362 and 2139. respectively; SEQ ID NOs: 1363 and 2140, respectively; SEQ ID NOs: 1364 and 2141, respectively; SEQ ID NOs: 1365 and 2142, respectively; SEQ ID NOs: 1366 and 2143 respectively; SEQ ID NOs: 1367 and 2144, respectively; SEQ ID NOs: 1368 and 2145. respectively; SEQ ID NOs: 1369 and 2146, respectively; SEQ ID NOs: 1370 and 2147, respectively; SEQ ID NOs: 1371 and 2148, respectively; SEQ ID NOs: 1372 and 2149. respectively; SEQ ID NOs: 1373 and 2150, respectively; SEQ ID NOs: 1374 and 2151, respectively; SEQ ID NOs: 1375 and 2152, respectively; SEQ ID NOs: 1376 and 2153, respectively; SEQ ID NOs: 1377 and 2154, respectively; SEQ ID NOs: 1378 and 2155. respectively; SEQ ID NOs: 1379 and 2156, respectively; SEQ ID NOs: 1380 and 2157, respectively; SEQ ID NOs: 1381 and 2158, respectively; SEQ ID NOs: 1382 and 2159, respectively; SEQ ID NOs: 1383 and 2160, respectively; SEQ ID NOs: 1384 and 2161. respectively; SEQ ID NOs: 1385 and 2162, respectively; SEQ ID NOs: 1386 and 2163, respectively; SEQ ID NOs: 1387 and 2164, respectively; SEQ ID NOs: 1388 and 2165, respectively; SEQ ID NOs: 1389 and 2166, respectively; SEQ ID NOs: 1390 and 2167 respectively; SEQ ID NOs: 1391 and 2168, respectively; SEQ ID NOs: 1392 and 2169, respectively; SEQ ID NOs: 1393 and 2170, respectively; SEQ ID NOs: 1394 and 2171, respectively; SEQ ID NOs: 1395 and 2172, respectively; SEQ ID NOs: 1396 and 2173 respectively; SEQ ID NOs: 1397 and 2174, respectively; SEQ ID NOs: 1398 and 2175, respectively; SEQ ID NOs: 1399 and 2176, respectively; SEQ ID NOs: 1400 and 2177, respectively; SEQ ID NOs: 1401 and 2178, respectively; SEQ ID NOs: 1402 and 2179, respectively; SEQ ID NOs: 1403 and 2180, respectively; SEQ ID NOs: 1404 and 2181, respectively; SEQ ID NOs: 1405 and 2182, respectively; SEQ ID NOs: 1406 and 2183, respectively; SEQ ID NOs: 1407 and 2184, respectively; SEQ ID NOs: 1408 and 2185,- 31 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOrespectively; SEQ ID NOs: 1409 and 2186, respectively; SEQ ID NOs: 1410 and 2187, respectively; SEQ ID NOs: 1411 and 2188, respectively; SEQ ID NOs: 1412 and 2189, respectively; SEQ ID NOs: 1413 and 2190, respectively; SEQ ID NOs: 1414 and 2191, respectively; SEQ ID NOs: 1415 and 2192, respectively; SEQ ID NOs: 1416 and 2193, respectively; SEQ ID NOs: 1417 and 2194, respectively; SEQ ID NOs: 1418 and 2195, respectively; SEQ ID NOs: 1419 and 2196, respectively; SEQ ID NOs: 1420 and 2197, respectively; SEQ ID NOs: 1421 and 2198, respectively; SEQ ID NOs: 1422 and 2199, respectively; SEQ ID NOs: 1423 and 2200, respectively; SEQ ID NOs: 1424 and 2201, respectively; SEQ ID NOs: 1425 and 2202, respectively; SEQ ID NOs: 1426 and 2203, respectively; SEQ ID NOs: 1427 and 2204, respectively; SEQ ID NOs: 1428 and 2205, respectively; SEQ ID NOs: 1429 and 2206, respectively; SEQ ID NOs: 1430 and 2207, respectively; SEQ ID NOs: 1431 and 2208, respectively; SEQ ID NOs: 1432 and 2209, respectively; SEQ ID NOs: 1433 and 2210, respectively; SEQ ID NOs: 1434 and 2211, respectively; SEQ ID NOs: 1435 and 2212, respectively; SEQ ID NOs: 1436 and 2213, respectively; SEQ ID NOs: 1437 and 2214, respectively; SEQ ID NOs: 1438 and 2215, respectively; SEQ ID NOs: 1439 and 2216, respectively; SEQ ID NOs: 1440 and 2217, respectively; SEQ ID NOs: 1441 and 2218, respectively; SEQ ID NOs: 1442 and 2219, respectively; SEQ ID NOs: 1443 and 2220, respectively; SEQ ID NOs: 1444 and 2221, respectively; SEQ ID NOs: 1445 and 2222, respectively; SEQ ID NOs: 1446 and 2223, respectively; SEQ ID NOs: 1447 and 2224, respectively; SEQ ID NOs: 1448 and 2225, respectively; SEQ ID NOs: 1449 and 2226, respectively; SEQ ID NOs: 1450 and 2227, respectively; SEQ ID NOs: 1451 and 2228, respectively; SEQ ID NOs: 1452 and 2229, respectively; SEQ ID NOs: 1453 and 2230, respectively; SEQ ID NOs: 1454 and 2231, respectively; SEQ ID NOs: 1455 and 2232, respectively; SEQ ID NOs: 1456 and 2233, respectively; SEQ ID NOs: 1457 and 2234, respectively; SEQ ID NOs: 1458 and 2235, respectively; SEQ ID NOs: 1459 and 2236, respectively; SEQ ID NOs: 1460 and 2237, respectively; SEQ ID NOs: 1461 and 2238, respectively; SEQ ID NOs: 1462 and 2239, respectively; SEQ ID NOs: 1463 and 2240, respectively; SEQ ID NOs: 1464 and 2241, respectively; SEQ ID NOs: 1465 and 2242, respectively; SEQ ID NOs: 1466 and 2243, respectively; SEQ ID NOs: 1467 and 2244, respectively; SEQ ID NOs: 1468 and 2245, respectively; SEQ ID NOs: 1469 and 2246, respectively; SEQ ID NOs: 1470 and 2247,- 32 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOrespectively; SEQ ID NOs: 1471 and 2248, respectively; SEQ ID NOs: 1472 and 2249, respectively; SEQ ID NOs: 1473 and 2250, respectively; SEQ ID NOs: 1474 and 2251 respectively; SEQ ID NOs: 1475 and 2252, respectively; SEQ ID NOs: 1476 and 2253 respectively; SEQ ID NOs: 1477 and 2254, respectively; SEQ ID NOs: 1478 and 2255 respectively; SEQ ID NOs: 1479 and 2256, respectively; SEQ ID NOs: 1480 and 2257 respectively; SEQ ID NOs: 1481 and 2258, respectively; SEQ ID NOs: 1482 and 2259, respectively; SEQ ID NOs: 1483 and 2260, respectively; SEQ ID NOs: 1484 and 2261 respectively; SEQ ID NOs: 1485 and 2262, respectively; SEQ ID NOs: 1486 and 2263. respectively; SEQ ID NOs: 1487 and 2264, respectively; SEQ ID NOs: 1488 and 2265. respectively; SEQ ID NOs: 1489 and 2266, respectively; SEQ ID NOs: 1490 and 2267 respectively; SEQ ID NOs: 1491 and 2268, respectively; SEQ ID NOs: 1492 and 2269. respectively; SEQ ID NOs: 1493 and 2270, respectively; SEQ ID NOs: 1494 and 2271, respectively; SEQ ID NOs: 1495 and 2272, respectively; SEQ ID NOs: 1496 and 2273. respectively; SEQ ID NOs: 1497 and 2274, respectively; SEQ ID NOs: 1498 and 2275, respectively; SEQ ID NOs: 1499 and 2276, respectively; SEQ ID NOs: 1500 and 2277, respectively; SEQ ID NOs: 1501 and 2278, respectively; SEQ ID NOs: 1502 and 2279. respectively; SEQ ID NOs: 1503 and 2280, respectively; SEQ ID NOs: 1504 and 2281, respectively; SEQ ID NOs: 1505 and 2282, respectively; SEQ ID NOs: 1506 and 2283, respectively; SEQ ID NOs: 1507 and 2284, respectively; SEQ ID NOs: 1508 and 2285. respectively; SEQ ID NOs: 1509 and 2286, respectively; SEQ ID NOs: 1510 and 2287, respectively; SEQ ID NOs: 1511 and 2288, respectively; SEQ ID NOs: 1512 and 2289, respectively; SEQ ID NOs: 1513 and 2290, respectively; SEQ ID NOs: 1514 and 2291 respectively; SEQ ID NOs: 1515 and 2292, respectively; SEQ ID NOs: 1516 and 2293, respectively; SEQ ID NOs: 1517 and 2294, respectively; SEQ ID NOs: 1518 and 2295, respectively; SEQ ID NOs: 1519 and 2296, respectively; SEQ ID NOs: 1520 and 2297 respectively; SEQ ID NOs: 1521 and 2298, respectively; SEQ ID NOs: 1522 and 2299, respectively; SEQ ID NOs: 1523 and 2300, respectively; SEQ ID NOs: 1524 and 2301, respectively; SEQ ID NOs: 1525 and 2302, respectively; SEQ ID NOs: 1526 and 2303, respectively; SEQ ID NOs: 1527 and 2304, respectively; SEQ ID NOs: 1528 and 2305, respectively; SEQ ID NOs: 1529 and 2306, respectively; SEQ ID NOs: 1530 and 2307, respectively; SEQ ID NOs: 1531 and 2308, respectively; SEQ ID NOs: 1532 and 2309,- 33 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOrespectively; SEQ ID NOs: 1533 and 2310, respectively; SEQ ID NOs: 1534 and 2311, respectively; SEQ ID NOs: 1535 and 2312, respectively; SEQ ID NOs: 1536 and 2313, respectively; SEQ ID NOs: 1537 and 2314, respectively; SEQ ID NOs: 1538 and 2315, respectively; SEQ ID NOs: 1539 and 2316, respectively; SEQ ID NOs: 1540 and 2317, respectively; SEQ ID NOs: 1541 and 2318, respectively; SEQ ID NOs: 1542 and 2319, respectively; SEQ ID NOs: 1543 and 2320, respectively; SEQ ID NOs: 1544 and 2321, respectively; SEQ ID NOs: 1545 and 2322, respectively; SEQ ID NOs: 1546 and 2323, respectively; SEQ ID NOs: 1547 and 2324, respectively; SEQ ID NOs: 1548 and 2325, respectively; SEQ ID NOs: 1549 and 2326, respectively; SEQ ID NOs: 1550 and 2327, respectively; SEQ ID NOs: 1551 and 2328, respectively; SEQ ID NOs: 1552 and 2329, respectively; SEQ ID NOs: 1553 and 2330, respectively; or SEQ ID NOs: 1554 and 2331, respectively.

[0058] In some embodiments, the sense strand and the antisense strand comprise nucleotide sequences of SEQ ID NOs: 1367 and 2144, respectively; SEQ ID NOs: 1448 and 2225, respectively; SEQ ID NOs: 1527 and 2304, respectively; SEQ ID NOs: 1442 and 2219, respectively; SEQ ID NOs: 1365 and 2142, respectively; SEQ ID NOs: 1390 and 2167, respectively; SEQ ID NOs: 1526 and 2303, respectively; SEQ ID NOs: 1346 and 2123, respectively; SEQ ID NOs: 1348 and 2125, respectively; SEQ ID NOs: 1364 and 2141, respectively; SEQ ID NOs: 1394 and 2171, respectively; SEQ ID NOs: 1449 and 2226, respectively; SEQ ID NOs: 1451 and 2228, respectively; SEQ ID NOs: 1457 and 2234, respectively; SEQ ID NOs: 1459 and 2236, respectively; or SEQ ID NOs: 1531 and 2308, respectively.

[0059] In some embodiments, the nucleic acid A comprises a antisense strand and a sense strand, wherein the sense strand and the antisense strand comprise nucleotide sequences of SEQ ID NOs: 2332 and 3100, respectively; SEQ ID NOs: 2333 and 3101, respectively; SEQ ID NOs: 2334 and 3102, respectively; SEQ ID NOs: 2335 and 3103, respectively; SEQ ID NOs: 2336 and 3104, respectively; SEQ ID NOs: 2337 and 3105, respectively; SEQ ID NOs: 2338 and 3106, respectively; SEQ ID NOs: 2339 and 3107, respectively; SEQ ID NOs: 2340 and 3108, respectively; SEQ ID NOs: 2341 and 3109, respectively; SEQ ID NOs: 2342 and 3110. respectively; SEQ ID NOs: 2343 and 3111, respectively; SEQ ID NOs: 2344 and 3112. respectively; SEQ ID NOs: 2345 and 3113, respectively; SEQ ID NOs: 2346 and 3114- 34 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOrespectively; SEQ ID NOs: 2347 and 3115, respectively; SEQ ID NOs: 2348 and 3116. respectively; SEQ ID NOs: 2349 and 3117, respectively; SEQ ID NOs: 2350 and 3118. respectively; SEQ ID NOs: 2351 and 3119, respectively; SEQ ID NOs: 2352 and 3120. respectively; SEQ ID NOs: 2353 and 3121, respectively; SEQ ID NOs: 2354 and 3122, respectively; SEQ ID NOs: 2355 and 3123, respectively; SEQ ID NOs: 2356 and 3124. respectively; SEQ ID NOs: 2357 and 3125, respectively; SEQ ID NOs: 2358 and 3126, respectively; SEQ ID NOs: 2359 and 3127, respectively; SEQ ID NOs: 2360 and 3128. respectively; SEQ ID NOs: 2361 and 3129, respectively; SEQ ID NOs: 2362 and 3130. respectively; SEQ ID NOs: 2363 and 3131, respectively; SEQ ID NOs: 2364 and 3132. respectively; SEQ ID NOs: 2365 and 3133, respectively; SEQ ID NOs: 2366 and 3134, respectively; SEQ ID NOs: 2367 and 3135, respectively; SEQ ID NOs: 2368 and 3136, respectively; SEQ ID NOs: 2369 and 3137, respectively; SEQ ID NOs: 2370 and 3138, respectively; SEQ ID NOs: 2371 and 3139, respectively; SEQ ID NOs: 2372 and 3140, respectively; SEQ ID NOs: 2373 and 3141, respectively; SEQ ID NOs: 2374 and 3142, respectively; SEQ ID NOs: 2375 and 3143, respectively; SEQ ID NOs: 2376 and 3144, respectively; SEQ ID NOs: 2377 and 3145, respectively; SEQ ID NOs: 2378 and 3146 respectively; SEQ ID NOs: 2379 and 3147, respectively; SEQ ID NOs: 2380 and 3148, respectively; SEQ ID NOs: 2381 and 3149, respectively; SEQ ID NOs: 2382 and 3150, respectively; SEQ ID NOs: 2383 and 3151, respectively; SEQ ID NOs: 2384 and 3152, respectively; SEQ ID NOs: 2385 and 3153, respectively; SEQ ID NOs: 2386 and 3154, respectively; SEQ ID NOs: 2387 and 3155, respectively; SEQ ID NOs: 2388 and 3156, respectively; SEQ ID NOs: 2389 and 3157, respectively; SEQ ID NOs: 2390 and 3158, respectively; SEQ ID NOs: 2391 and 3159, respectively; SEQ ID NOs: 2392 and 3160, respectively; SEQ ID NOs: 2393 and 3161, respectively; SEQ ID NOs: 2394 and 3162, respectively; SEQ ID NOs: 2395 and 3163, respectively; SEQ ID NOs: 2396 and 3164, respectively; SEQ ID NOs: 2397 and 3165, respectively; SEQ ID NOs: 2398 and 3166, respectively; SEQ ID NOs: 2399 and 3167, respectively; SEQ ID NOs: 2400 and 3168, respectively; SEQ ID NOs: 2401 and 3169, respectively; SEQ ID NOs: 2402 and 3170, respectively; SEQ ID NOs: 2403 and 3171, respectively; SEQ ID NOs: 2404 and 3172, respectively; SEQ ID NOs: 2405 and 3173, respectively; SEQ ID NOs: 2406 and 3174, respectively; SEQ ID NOs: 2407 and 3175, respectively; SEQ ID NOs: 2408 and 3176,- 35 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOrespectively; SEQ ID NOs: 2409 and 3177, respectively; SEQ ID NOs: 2410 and 3178, respectively; SEQ ID NOs: 2411 and 3179, respectively; SEQ ID NOs: 2412 and 3180, respectively; SEQ ID NOs: 2413 and 3181, respectively; SEQ ID NOs: 2414 and 3182, respectively; SEQ ID NOs: 2415 and 3183, respectively; SEQ ID NOs: 2416 and 3184, respectively; SEQ ID NOs: 2417 and 3185, respectively; SEQ ID NOs: 2418 and 3186, respectively; SEQ ID NOs: 2419 and 3187, respectively; SEQ ID NOs: 2420 and 3188, respectively; SEQ ID NOs: 2421 and 3189, respectively; SEQ ID NOs: 2422 and 3190, respectively; SEQ ID NOs: 2423 and 3191, respectively; SEQ ID NOs: 2424 and 3192, respectively; SEQ ID NOs: 2425 and 3193, respectively; SEQ ID NOs: 2426 and 3194, respectively; SEQ ID NOs: 2427 and 3195, respectively; SEQ ID NOs: 2428 and 3196, respectively; SEQ ID NOs: 2429 and 3197, respectively; SEQ ID NOs: 2430 and 3198, respectively; SEQ ID NOs: 2431 and 3199, respectively; SEQ ID NOs: 2432 and 3200, respectively; SEQ ID NOs: 2433 and 3201, respectively; SEQ ID NOs: 2434 and 3202, respectively; SEQ ID NOs: 2435 and 3203, respectively; SEQ ID NOs: 2436 and 3204, respectively; SEQ ID NOs: 2437 and 3205, respectively; SEQ ID NOs: 2438 and 3206, respectively; SEQ ID NOs: 2439 and 3207, respectively; SEQ ID NOs: 2440 and 3208, respectively; SEQ ID NOs: 2441 and 3209, respectively; SEQ ID NOs: 2442 and 3210, respectively; SEQ ID NOs: 2443 and 3211, respectively; SEQ ID NOs: 2444 and 3212, respectively; SEQ ID NOs: 2445 and 3213, respectively; SEQ ID NOs: 2446 and 3214, respectively; SEQ ID NOs: 2447 and 3215, respectively; SEQ ID NOs: 2448 and 3216, respectively; SEQ ID NOs: 2449 and 3217, respectively; SEQ ID NOs: 2450 and 3218, respectively; SEQ ID NOs: 2451 and 3219, respectively; SEQ ID NOs: 2452 and 3220, respectively; SEQ ID NOs: 2453 and 3221, respectively; SEQ ID NOs: 2454 and 3222, respectively; SEQ ID NOs: 2455 and 3223, respectively; SEQ ID NOs: 2456 and 3224, respectively; SEQ ID NOs: 2457 and 3225, respectively; SEQ ID NOs: 2458 and 3226, respectively; SEQ ID NOs: 2459 and 3227, respectively; SEQ ID NOs: 2460 and 3228, respectively; SEQ ID NOs: 2461 and 3229, respectively; SEQ ID NOs: 2462 and 3230, respectively; SEQ ID NOs: 2463 and 3231, respectively; SEQ ID NOs: 2464 and 3232, respectively; SEQ ID NOs: 2465 and 3233, respectively; SEQ ID NOs: 2466 and 3234, respectively; SEQ ID NOs: 2467 and 3235, respectively; SEQ ID NOs: 2468 and 3236, respectively; SEQ ID NOs: 2469 and 3237, respectively; SEQ ID NOs: 2470 and 3238,- 36 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOrespectively; SEQ ID NOs: 2471 and 3239, respectively; SEQ ID NOs: 2472 and 3240, respectively; SEQ ID NOs: 2473 and 3241, respectively; SEQ ID NOs: 2474 and 3242. respectively; SEQ ID NOs: 2475 and 3243, respectively; SEQ ID NOs: 2476 and 3244. respectively; SEQ ID NOs: 2477 and 3245, respectively; SEQ ID NOs: 2478 and 3246, respectively; SEQ ID NOs: 2479 and 3247, respectively; SEQ ID NOs: 2480 and 3248. respectively; SEQ ID NOs: 2481 and 3249, respectively; SEQ ID NOs: 2482 and 3250, respectively; SEQ ID NOs: 2483 and 3251, respectively; SEQ ID NOs: 2484 and 3252. respectively; SEQ ID NOs: 2485 and 3253, respectively; SEQ ID NOs: 2486 and 3254, respectively; SEQ ID NOs: 2487 and 3255, respectively; SEQ ID NOs: 2488 and 3256, respectively; SEQ ID NOs: 2489 and 3257, respectively; SEQ ID NOs: 2490 and 3258, respectively; SEQ ID NOs: 2491 and 3259, respectively; SEQ ID NOs: 2492 and 3260, respectively; SEQ ID NOs: 2493 and 3261, respectively; SEQ ID NOs: 2494 and 3262, respectively; SEQ ID NOs: 2495 and 3263, respectively; SEQ ID NOs: 2496 and 3264, respectively; SEQ ID NOs: 2497 and 3265, respectively; SEQ ID NOs: 2498 and 3266, respectively; SEQ ID NOs: 2499 and 3267, respectively; SEQ ID NOs: 2500 and 3268, respectively; SEQ ID NOs: 2501 and 3269, respectively; SEQ ID NOs: 2502 and 3270 respectively; SEQ ID NOs: 2503 and 3271, respectively; SEQ ID NOs: 2504 and 3272, respectively; SEQ ID NOs: 2505 and 3273, respectively; SEQ ID NOs: 2506 and 3274, respectively; SEQ ID NOs: 2507 and 3275, respectively; SEQ ID NOs: 2508 and 3276, respectively; SEQ ID NOs: 2509 and 3277, respectively; SEQ ID NOs: 2510 and 3278, respectively; SEQ ID NOs: 2511 and 3279, respectively; SEQ ID NOs: 2512 and 3280, respectively; SEQ ID NOs: 2513 and 3281, respectively; SEQ ID NOs: 2514 and 3282, respectively; SEQ ID NOs: 2515 and 3283, respectively; SEQ ID NOs: 2516 and 3284, respectively; SEQ ID NOs: 2517 and 3285, respectively; SEQ ID NOs: 2518 and 3286, respectively; SEQ ID NOs: 2519 and 3287, respectively; SEQ ID NOs: 2520 and 3288, respectively; SEQ ID NOs: 2521 and 3289, respectively; SEQ ID NOs: 2522 and 3290, respectively; SEQ ID NOs: 2523 and 3291, respectively; SEQ ID NOs: 2524 and 3292, respectively; SEQ ID NOs: 2525 and 3293, respectively; SEQ ID NOs: 2526 and 3294, respectively; SEQ ID NOs: 2527 and 3295, respectively; SEQ ID NOs: 2528 and 3296, respectively; SEQ ID NOs: 2529 and 3297, respectively; SEQ ID NOs: 2530 and 3298, respectively; SEQ ID NOs: 2531 and 3299, respectively; SEQ ID NOs: 2532 and 3300,- 37 - IPTS / 200358788.1Attomey Docket No. JUDO-005 WOrespectively; SEQ ID NOs: 2533 and 3301, respectively; SEQ ID NOs: 2534 and 3302, respectively; SEQ ID NOs: 2535 and 3303, respectively; SEQ ID NOs: 2536 and 3304 respectively; SEQ ID NOs: 2537 and 3305, respectively; SEQ ID NOs: 2538 and 3306 respectively; SEQ ID NOs: 2539 and 3307, respectively; SEQ ID NOs: 2540 and 3308 respectively; SEQ ID NOs: 2541 and 3309, respectively; SEQ ID NOs: 2542 and 3310 respectively; SEQ ID NOs: 2543 and 3311, respectively; SEQ ID NOs: 2544 and 3312, respectively; SEQ ID NOs: 2545 and 3313, respectively; SEQ ID NOs: 2546 and 3314 respectively; SEQ ID NOs: 2547 and 3315, respectively; SEQ ID NOs: 2548 and 3316. respectively; SEQ ID NOs: 2549 and 3317, respectively; SEQ ID NOs: 2550 and 3318, respectively; SEQ ID NOs: 2551 and 3319, respectively; SEQ ID NOs: 2552 and 3320 respectively; SEQ ID NOs: 2553 and 3321, respectively; SEQ ID NOs: 2554 and 3322. respectively; SEQ ID NOs: 2555 and 3323, respectively; SEQ ID NOs: 2556 and 3324. respectively; SEQ ID NOs: 2557 and 3325, respectively; SEQ ID NOs: 2558 and 3326. respectively; SEQ ID NOs: 2559 and 3327, respectively; SEQ ID NOs: 2560 and 3328, respectively; SEQ ID NOs: 2561 and 3329, respectively; SEQ ID NOs: 2562 and 3330, respectively; SEQ ID NOs: 2563 and 3331, respectively; SEQ ID NOs: 2564 and 3332. respectively; SEQ ID NOs: 2565 and 3333, respectively; SEQ ID NOs: 2566 and 3334, respectively; SEQ ID NOs: 2567 and 3335, respectively; SEQ ID NOs: 2568 and 3336, respectively; SEQ ID NOs: 2569 and 3337, respectively; SEQ ID NOs: 2570 and 3338. respectively; SEQ ID NOs: 2571 and 3339, respectively; SEQ ID NOs: 2572 and 3340, respectively; SEQ ID NOs: 2573 and 3341, respectively; SEQ ID NOs: 2574 and 3342, respectively; SEQ ID NOs: 2575 and 3343, respectively; SEQ ID NOs: 2576 and 3344 respectively; SEQ ID NOs: 2577 and 3345, respectively; SEQ ID NOs: 2578 and 3346, respectively; SEQ ID NOs: 2579 and 3347, respectively; SEQ ID NOs: 2580 and 3348, respectively; SEQ ID NOs: 2581 and 3349, respectively; SEQ ID NOs: 2582 and 3350, respectively; SEQ ID NOs: 2583 and 3351, respectively; SEQ ID NOs: 2584 and 3352, respectively; SEQ ID NOs: 2585 and 3353, respectively; SEQ ID NOs: 2586 and 3354, respectively; SEQ ID NOs: 2587 and 3355, respectively; SEQ ID NOs: 2588 and 3356, respectively; SEQ ID NOs: 2589 and 3357, respectively; SEQ ID NOs: 2590 and 3358, respectively; SEQ ID NOs: 2591 and 3359, respectively; SEQ ID NOs: 2592 and 3360, respectively; SEQ ID NOs: 2593 and 3361, respectively; SEQ ID NOs: 2594 and 3362,- 38 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOrespectively; SEQ ID NOs: 2595 and 3363, respectively; SEQ ID NOs: 2596 and 3364, respectively; SEQ ID NOs: 2597 and 3365, respectively; SEQ ID NOs: 2598 and 3366, respectively; SEQ ID NOs: 2599 and 3367, respectively; SEQ ID NOs: 2600 and 3368, respectively; SEQ ID NOs: 2601 and 3369, respectively; SEQ ID NOs: 2602 and 3370, respectively; SEQ ID NOs: 2603 and 3371, respectively; SEQ ID NOs: 2604 and 3372, respectively; SEQ ID NOs: 2605 and 3373, respectively; SEQ ID NOs: 2606 and 3374, respectively; SEQ ID NOs: 2607 and 3375, respectively; SEQ ID NOs: 2608 and 3376, respectively; SEQ ID NOs: 2609 and 3377, respectively; SEQ ID NOs: 2610 and 3378, respectively; SEQ ID NOs: 2611 and 3379, respectively; SEQ ID NOs: 2612 and 3380, respectively; SEQ ID NOs: 2613 and 3381, respectively; SEQ ID NOs: 2614 and 3382, respectively; SEQ ID NOs: 2615 and 3383, respectively; SEQ ID NOs: 2616 and 3384, respectively; SEQ ID NOs: 2617 and 3385, respectively; SEQ ID NOs: 2618 and 3386, respectively; SEQ ID NOs: 2619 and 3387, respectively; SEQ ID NOs: 2620 and 3388, respectively; SEQ ID NOs: 2621 and 3389, respectively; SEQ ID NOs: 2622 and 3390, respectively; SEQ ID NOs: 2623 and 3391, respectively; SEQ ID NOs: 2624 and 3392, respectively; SEQ ID NOs: 2625 and 3393, respectively; SEQ ID NOs: 2626 and 3394, respectively; SEQ ID NOs: 2627 and 3395, respectively; SEQ ID NOs: 2628 and 3396, respectively; SEQ ID NOs: 2629 and 3397, respectively; SEQ ID NOs: 2630 and 3398, respectively; SEQ ID NOs: 2631 and 3399, respectively; SEQ ID NOs: 2632 and 3400, respectively; SEQ ID NOs: 2633 and 3401, respectively; SEQ ID NOs: 2634 and 3402, respectively; SEQ ID NOs: 2635 and 3403, respectively; SEQ ID NOs: 2636 and 3404, respectively; SEQ ID NOs: 2637 and 3405, respectively; SEQ ID NOs: 2638 and 3406, respectively; SEQ ID NOs: 2639 and 3407, respectively; SEQ ID NOs: 2640 and 3408, respectively; SEQ ID NOs: 2641 and 3409, respectively; SEQ ID NOs: 2642 and 3410, respectively; SEQ ID NOs: 2643 and 3411, respectively; SEQ ID NOs: 2644 and 3412, respectively; SEQ ID NOs: 2645 and 3413, respectively; SEQ ID NOs: 2646 and 3414, respectively; SEQ ID NOs: 2647 and 3415, respectively; SEQ ID NOs: 2648 and 3416, respectively; SEQ ID NOs: 2649 and 3417, respectively; SEQ ID NOs: 2650 and 3418, respectively; SEQ ID NOs: 2651 and 3419, respectively; SEQ ID NOs: 2652 and 3420, respectively; SEQ ID NOs: 2653 and 3421, respectively; SEQ ID NOs: 2654 and 3422, respectively; SEQ ID NOs: 2655 and 3423, respectively; SEQ ID NOs: 2656 and 3424,- 39 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOrespectively; SEQ ID NOs: 2657 and 3425, respectively; SEQ ID NOs: 2658 and 3426, respectively; SEQ ID NOs: 2659 and 3427, respectively; SEQ ID NOs: 2660 and 3428. respectively; SEQ ID NOs: 2661 and 3429, respectively; SEQ ID NOs: 2662 and 3430. respectively; SEQ ID NOs: 2663 and 3431, respectively; SEQ ID NOs: 2664 and 3432, respectively; SEQ ID NOs: 2665 and 3433, respectively; SEQ ID NOs: 2666 and 3434. respectively; SEQ ID NOs: 2667 and 3435, respectively; SEQ ID NOs: 2668 and 3436, respectively; SEQ ID NOs: 2669 and 3437, respectively; SEQ ID NOs: 2670 and 3438. respectively; SEQ ID NOs: 2671 and 3439, respectively; SEQ ID NOs: 2672 and 3440, respectively; SEQ ID NOs: 2673 and 3441, respectively; SEQ ID NOs: 2674 and 3442, respectively; SEQ ID NOs: 2675 and 3443, respectively; SEQ ID NOs: 2676 and 3444, respectively; SEQ ID NOs: 2677 and 3445, respectively; SEQ ID NOs: 2678 and 3446, respectively; SEQ ID NOs: 2679 and 3447, respectively; SEQ ID NOs: 2680 and 3448, respectively; SEQ ID NOs: 2681 and 3449, respectively; SEQ ID NOs: 2682 and 3450, respectively; SEQ ID NOs: 2683 and 3451, respectively; SEQ ID NOs: 2684 and 3452, respectively; SEQ ID NOs: 2685 and 3453, respectively; SEQ ID NOs: 2686 and 3454, respectively; SEQ ID NOs: 2687 and 3455, respectively; SEQ ID NOs: 2688 and 3456 respectively; SEQ ID NOs: 2689 and 3457, respectively; SEQ ID NOs: 2690 and 3458, respectively; SEQ ID NOs: 2691 and 3459, respectively; SEQ ID NOs: 2692 and 3460, respectively; SEQ ID NOs: 2693 and 3461, respectively; SEQ ID NOs: 2694 and 3462, respectively; SEQ ID NOs: 2695 and 3463, respectively; SEQ ID NOs: 2696 and 3464, respectively; SEQ ID NOs: 2697 and 3465, respectively; SEQ ID NOs: 2698 and 3466, respectively; SEQ ID NOs: 2699 and 3467, respectively; SEQ ID NOs: 2700 and 3468, respectively; SEQ ID NOs: 2701 and 3469, respectively; SEQ ID NOs: 2702 and 3470, respectively; SEQ ID NOs: 2703 and 3471, respectively; SEQ ID NOs: 2704 and 3472, respectively; SEQ ID NOs: 2705 and 3473, respectively; SEQ ID NOs: 2706 and 3474, respectively; SEQ ID NOs: 2707 and 3475, respectively; SEQ ID NOs: 2708 and 3476, respectively; SEQ ID NOs: 2709 and 3477, respectively; SEQ ID NOs: 2710 and 3478, respectively; SEQ ID NOs: 2711 and 3479, respectively; SEQ ID NOs: 2712 and 3480, respectively; SEQ ID NOs: 2713 and 3481, respectively; SEQ ID NOs: 2714 and 3482, respectively; SEQ ID NOs: 2715 and 3483, respectively; SEQ ID NOs: 2716 and 3484, respectively; SEQ ID NOs: 2717 and 3485, respectively; SEQ ID NOs: 2718 and 3486,- 40 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOrespectively; SEQ ID NOs: 2719 and 3487, respectively; SEQ ID NOs: 2720 and 3488:respectively; SEQ ID NOs: 2721 and 3489, respectively; SEQ ID NOs: 2722 and 3490. respectively; SEQ ID NOs: 2723 and 3491, respectively; SEQ ID NOs: 2724 and 3492. respectively; SEQ ID NOs: 2725 and 3493, respectively; SEQ ID NOs: 2726 and 3494 respectively; SEQ ID NOs: 2727 and 3495, respectively; SEQ ID NOs: 2728 and 3496. respectively; SEQ ID NOs: 2729 and 3497, respectively; SEQ ID NOs: 2730 and 3498, respectively; SEQ ID NOs: 2731 and 3499, respectively; SEQ ID NOs: 2732 and 3500. respectively; SEQ ID NOs: 2733 and 3501, respectively; SEQ ID NOs: 2734 and 3502, respectively; SEQ ID NOs: 2735 and 3503, respectively; SEQ ID NOs: 2736 and 3504, respectively; SEQ ID NOs: 2737 and 3505, respectively; SEQ ID NOs: 2738 and 3506, respectively; SEQ ID NOs: 2739 and 3507, respectively; SEQ ID NOs: 2740 and 3508, respectively; SEQ ID NOs: 2741 and 3509, respectively; SEQ ID NOs: 2742 and 3510, respectively; SEQ ID NOs: 2743 and 3511, respectively; SEQ ID NOs: 2744 and 3512, respectively; SEQ ID NOs: 2745 and 3513, respectively; SEQ ID NOs: 2746 and 3514, respectively; SEQ ID NOs: 2747 and 3515, respectively; SEQ ID NOs: 2748 and 3516, respectively; SEQ ID NOs: 2749 and 3517, respectively; SEQ ID NOs: 2750 and 3518 respectively; SEQ ID NOs: 2751 and 3519, respectively; SEQ ID NOs: 2752 and 3520, respectively; SEQ ID NOs: 2753 and 3521, respectively; SEQ ID NOs: 2754 and 3522, respectively; SEQ ID NOs: 2755 and 3523, respectively; SEQ ID NOs: 2756 and 3524, respectively; SEQ ID NOs: 2757 and 3525, respectively; SEQ ID NOs: 2758 and 3526, respectively; SEQ ID NOs: 2759 and 3527, respectively; SEQ ID NOs: 2760 and 3528, respectively; SEQ ID NOs: 2761 and 3529, respectively; SEQ ID NOs: 2762 and 3530, respectively; SEQ ID NOs: 2763 and 3531, respectively; SEQ ID NOs: 2764 and 3532, respectively; SEQ ID NOs: 2765 and 3533, respectively; SEQ ID NOs: 2766 and 3534, respectively; SEQ ID NOs: 2767 and 3535, respectively; SEQ ID NOs: 2768 and 3536, respectively; SEQ ID NOs: 2769 and 3537, respectively; SEQ ID NOs: 2770 and 3538, respectively; SEQ ID NOs: 2771 and 3539, respectively; SEQ ID NOs: 2772 and 3540, respectively; SEQ ID NOs: 2773 and 3541, respectively; SEQ ID NOs: 2774 and 3542, respectively; SEQ ID NOs: 2775 and 3543, respectively; SEQ ID NOs: 2776 and 3544, respectively; SEQ ID NOs: 2777 and 3545, respectively; SEQ ID NOs: 2778 and 3546, respectively; SEQ ID NOs: 2779 and 3547, respectively; SEQ ID NOs: 2780 and 3548,- 41 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOrespectively; SEQ ID NOs: 2781 and 3549, respectively; SEQ ID NOs: 2782 and 3550. respectively; SEQ ID NOs: 2783 and 3551, respectively; SEQ ID NOs: 2784 and 3552. respectively; SEQ ID NOs: 2785 and 3553, respectively; SEQ ID NOs: 2786 and 3554. respectively; SEQ ID NOs: 2787 and 3555, respectively; SEQ ID NOs: 2788 and 3556 respectively; SEQ ID NOs: 2789 and 3557, respectively; SEQ ID NOs: 2790 and 3558. respectively; SEQ ID NOs: 2791 and 3559, respectively; SEQ ID NOs: 2792 and 3560. respectively; SEQ ID NOs: 2793 and 3561, respectively; SEQ ID NOs: 2794 and 3562. respectively; SEQ ID NOs: 2795 and 3563, respectively; SEQ ID NOs: 2796 and 3564, respectively; SEQ ID NOs: 2797 and 3565, respectively; SEQ ID NOs: 2798 and 3566. respectively; SEQ ID NOs: 2799 and 3567, respectively; SEQ ID NOs: 2800 and 3568, respectively; SEQ ID NOs: 2801 and 3569, respectively; SEQ ID NOs: 2802 and 3570, respectively; SEQ ID NOs: 2803 and 3571, respectively; SEQ ID NOs: 2804 and 3572, respectively; SEQ ID NOs: 2805 and 3573, respectively; SEQ ID NOs: 2806 and 3574, respectively; SEQ ID NOs: 2807 and 3575, respectively; SEQ ID NOs: 2808 and 3576, respectively; SEQ ID NOs: 2809 and 3577, respectively; SEQ ID NOs: 2810 and 3578, respectively; SEQ ID NOs: 2811 and 3579, respectively; SEQ ID NOs: 2812 and 3580 respectively; SEQ ID NOs: 2813 and 3581, respectively; SEQ ID NOs: 2814 and 3582, respectively; SEQ ID NOs: 2815 and 3583, respectively; SEQ ID NOs: 2816 and 3584, respectively; SEQ ID NOs: 2817 and 3585, respectively; SEQ ID NOs: 2818 and 3586, respectively; SEQ ID NOs: 2819 and 3587, respectively; SEQ ID NOs: 2820 and 3588, respectively; SEQ ID NOs: 2821 and 3589, respectively; SEQ ID NOs: 2822 and 3590, respectively; SEQ ID NOs: 2823 and 3591, respectively; SEQ ID NOs: 2824 and 3592, respectively; SEQ ID NOs: 2825 and 3593, respectively; SEQ ID NOs: 2826 and 3594, respectively; SEQ ID NOs: 2827 and 3595, respectively; SEQ ID NOs: 2828 and 3596, respectively; SEQ ID NOs: 2829 and 3597, respectively; SEQ ID NOs: 2830 and 3598, respectively; SEQ ID NOs: 2831 and 3599, respectively; SEQ ID NOs: 2832 and 3600, respectively; SEQ ID NOs: 2833 and 3601, respectively; SEQ ID NOs: 2834 and 3602, respectively; SEQ ID NOs: 2835 and 3603, respectively; SEQ ID NOs: 2836 and 3604, respectively; SEQ ID NOs: 2837 and 3605, respectively; SEQ ID NOs: 2838 and 3606, respectively; SEQ ID NOs: 2839 and 3607, respectively; SEQ ID NOs: 2840 and 3608, respectively; SEQ ID NOs: 2841 and 3609, respectively; SEQ ID NOs: 2842 and 3610,- 42 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOrespectively; SEQ ID NOs: 2843 and 3611, respectively; SEQ ID NOs: 2844 and 3612 respectively; SEQ ID NOs: 2845 and 3613, respectively; SEQ ID NOs: 2846 and 3614 respectively; SEQ ID NOs: 2847 and 3615, respectively; SEQ ID NOs: 2848 and 3616 respectively; SEQ ID NOs: 2849 and 3617, respectively; SEQ ID NOs: 2850 and 3618 respectively; SEQ ID NOs: 2851 and 3619, respectively; SEQ ID NOs: 2852 and 3620 respectively; SEQ ID NOs: 2853 and 3621, respectively; SEQ ID NOs: 2854 and 3622, respectively; SEQ ID NOs: 2855 and 3623, respectively; SEQ ID NOs: 2856 and 3624, respectively; SEQ ID NOs: 2857 and 3625, respectively; SEQ ID NOs: 2858 and 3626. respectively; SEQ ID NOs: 2859 and 3627, respectively; SEQ ID NOs: 2860 and 3628, respectively; SEQ ID NOs: 2861 and 3629, respectively; SEQ ID NOs: 2862 and 3630, respectively; SEQ ID NOs: 2863 and 3631, respectively; SEQ ID NOs: 2864 and 3632. respectively; SEQ ID NOs: 2865 and 3633, respectively; SEQ ID NOs: 2866 and 3634:respectively; SEQ ID NOs: 2867 and 3635, respectively; SEQ ID NOs: 2868 and 3636. respectively; SEQ ID NOs: 2869 and 3637, respectively; SEQ ID NOs: 2870 and 3638, respectively; SEQ ID NOs: 2871 and 3639, respectively; SEQ ID NOs: 2872 and 3640, respectively; SEQ ID NOs: 2873 and 3641, respectively; SEQ ID NOs: 2874 and 3642. respectively; SEQ ID NOs: 2875 and 3643, respectively; SEQ ID NOs: 2876 and 3644, respectively; SEQ ID NOs: 2877 and 3645, respectively; SEQ ID NOs: 2878 and 3646, respectively; SEQ ID NOs: 2879 and 3647, respectively; SEQ ID NOs: 2880 and 3648. respectively; SEQ ID NOs: 2881 and 3649, respectively; SEQ ID NOs: 2882 and 3650, respectively; SEQ ID NOs: 2883 and 3651, respectively; SEQ ID NOs: 2884 and 3652, respectively; SEQ ID NOs: 2885 and 3653, respectively; SEQ ID NOs: 2886 and 3654 respectively; SEQ ID NOs: 2887 and 3655, respectively; SEQ ID NOs: 2888 and 3656, respectively; SEQ ID NOs: 2889 and 3657, respectively; SEQ ID NOs: 2890 and 3658, respectively; SEQ ID NOs: 2891 and 3659, respectively; SEQ ID NOs: 2892 and 3660 respectively; SEQ ID NOs: 2893 and 3661, respectively; SEQ ID NOs: 2894 and 3662, respectively; SEQ ID NOs: 2895 and 3663, respectively; SEQ ID NOs: 2896 and 3664, respectively; SEQ ID NOs: 2897 and 3665, respectively; SEQ ID NOs: 2898 and 3666, respectively; SEQ ID NOs: 2899 and 3667, respectively; SEQ ID NOs: 2900 and 3668, respectively; SEQ ID NOs: 2901 and 3669, respectively; SEQ ID NOs: 2902 and 3670, respectively; SEQ ID NOs: 2903 and 3671, respectively; SEQ ID NOs: 2904 and 3672,- 43 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOrespectively; SEQ ID NOs: 2905 and 3673, respectively; SEQ ID NOs: 2906 and 3674:respectively; SEQ ID NOs: 2907 and 3675, respectively; SEQ ID NOs: 2908 and 3676. respectively; SEQ ID NOs: 2909 and 3677, respectively; SEQ ID NOs: 2910 and 3678. respectively; SEQ ID NOs: 2911 and 3679, respectively; SEQ ID NOs: 2912 and 3680, respectively; SEQ ID NOs: 2913 and 3681, respectively; SEQ ID NOs: 2914 and 3682. respectively; SEQ ID NOs: 2915 and 3683, respectively; SEQ ID NOs: 2916 and 3684, respectively; SEQ ID NOs: 2917 and 3685, respectively; SEQ ID NOs: 2918 and 3686. respectively; SEQ ID NOs: 2919 and 3687, respectively; SEQ ID NOs: 2920 and 3688, respectively; SEQ ID NOs: 2921 and 3689, respectively; SEQ ID NOs: 2922 and 3690, respectively; SEQ ID NOs: 2923 and 3691, respectively; SEQ ID NOs: 2924 and 3692, respectively; SEQ ID NOs: 2925 and 3693, respectively; SEQ ID NOs: 2926 and 3694, respectively; SEQ ID NOs: 2927 and 3695, respectively; SEQ ID NOs: 2928 and 3696, respectively; SEQ ID NOs: 2929 and 3697, respectively; SEQ ID NOs: 2930 and 3698, respectively; SEQ ID NOs: 2931 and 3699, respectively; SEQ ID NOs: 2932 and 3700, respectively; SEQ ID NOs: 2933 and 3701, respectively; SEQ ID NOs: 2934 and 3702, respectively; SEQ ID NOs: 2935 and 3703, respectively; SEQ ID NOs: 2936 and 3704 respectively; SEQ ID NOs: 2937 and 3705, respectively; SEQ ID NOs: 2938 and 3706, respectively; SEQ ID NOs: 2939 and 3707, respectively; SEQ ID NOs: 2940 and 3708, respectively; SEQ ID NOs: 2941 and 3709, respectively; SEQ ID NOs: 2942 and 3710, respectively; SEQ ID NOs: 2943 and 3711, respectively; SEQ ID NOs: 2944 and 3712, respectively; SEQ ID NOs: 2945 and 3713, respectively; SEQ ID NOs: 2946 and 3714, respectively; SEQ ID NOs: 2947 and 3715, respectively; SEQ ID NOs: 2948 and 3716, respectively; SEQ ID NOs: 2949 and 3717, respectively; SEQ ID NOs: 2950 and 3718, respectively; SEQ ID NOs: 2951 and 3719, respectively; SEQ ID NOs: 2952 and 3720, respectively; SEQ ID NOs: 2953 and 3721, respectively; SEQ ID NOs: 2954 and 3722, respectively; SEQ ID NOs: 2955 and 3723, respectively; SEQ ID NOs: 2956 and 3724, respectively; SEQ ID NOs: 2957 and 3725, respectively; SEQ ID NOs: 2958 and 3726, respectively; SEQ ID NOs: 2959 and 3727, respectively; SEQ ID NOs: 2960 and 3728, respectively; SEQ ID NOs: 2961 and 3729, respectively; SEQ ID NOs: 2962 and 3730, respectively; SEQ ID NOs: 2963 and 3731, respectively; SEQ ID NOs: 2964 and 3732, respectively; SEQ ID NOs: 2965 and 3733, respectively; SEQ ID NOs: 2966 and 3734,- 44 - IPTS / 200358788.1Attorney Docket No. JUDO-005 WOrespectively; SEQ ID NOs: 2967 and 3735, respectively; SEQ ID NOs: 2968 and 3736:respectively; SEQ ID NOs: 2969 and 3737, respectively; SEQ ID NOs: 2970 and 3738. respectively; SEQ ID NOs: 2971 and 3739, respectively; SEQ ID NOs: 2972 and 3740. respectively; SEQ ID NOs: 2973 and 3741, respectively; SEQ ID NOs: 2974 and 3742, respectively; SEQ ID NOs: 2975 and 3743, respectively; SEQ ID NOs: 2976 and 3744. respectively; SEQ ID NOs: 2977 and 3745, respectively; SEQ ID NOs: 2978 and 3746, respectively; SEQ ID NOs: 2979 and 3747, respectively; SEQ ID NOs: 2980 and 3748. respectively; SEQ ID NOs: 2981 and 3749, respectively; SEQ ID NOs: 2982 and 3750, respectively; SEQ ID NOs: 2983 and 3751, respectively; SEQ ID NOs: 2984 and 3752, respectively; SEQ ID NOs: 2985 and 3753, respectively; SEQ ID NOs: 2986 and 3754, respectively; SEQ ID NOs: 2987 and 3755, respectively; SEQ ID NOs: 2988 and 3756, respectively; SEQ ID NOs: 2989 and 3757, respectively; SEQ ID NOs: 2990 and 3758, respectively; SEQ ID NOs: 2991 and 3759, respectively; SEQ ID NOs: 2992 and 3760, respectively; SEQ ID NOs: 2993 and 3761, respectively; SEQ ID NOs: 2994 and 3762, respectively; SEQ ID NOs: 2995 and 3763, respectively; SEQ ID NOs: 2996 and 3764, respectively; SEQ ID NOs: 2997 and 3765, respectively; SEQ ID NOs: 2998 and 3766 respectively; SEQ ID NOs: 2999 and 3767, respectively; SEQ ID NOs: 3000 and 3768, respectively; SEQ ID NOs: 3001 and 3769, respectively; SEQ ID NOs: 3002 and 3770, respectively; SEQ ID NOs: 3003 and 3771, respectively; SEQ ID NOs: 3004 and 3772, respectively; SEQ ID NOs: 3005 and 3773, respectively; SEQ ID NOs: 3006 and 3774, respectively; SEQ ID NOs: 3007 and 3775, respectively; SEQ ID NOs: 3008 and 3776, respectively; SEQ ID NOs: 3009 and 3777, respectively; SEQ ID NOs: 3010 and 3778, respectively; SEQ ID NOs: 3011 and 3779, respectively; SEQ ID NOs: 3012 and 3780, respectively; SEQ ID NOs: 3013 and 3781, respectively; SEQ ID NOs: 3014 and 3782, respectively; SEQ ID NOs: 3015 and 3783, respectively; SEQ ID NOs: 3016 and 3784, respectively; SEQ ID NOs: 3017 and 3785, respectively; SEQ ID NOs: 3018 and 3786, respectively; SEQ ID NOs: 3019 and 3787, respectively; SEQ ID NOs: 3020 and 3788, respectively; SEQ ID NOs: 3021 and 3789, respectively; SEQ ID NOs: 3022 and 3790, respectively; SEQ ID NOs: 3023 and 3791, respectively; SEQ ID NOs: 3024 and 3792, respectively; SEQ ID NOs: 3025 and 3793, respectively; SEQ ID NOs: 3026 and 3794, respectively; SEQ ID NOs: 3027 and 3795, respectively; SEQ ID NOs: 3028 and 3796,- 45 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOrespectively; SEQ ID NOs: 3029 and 3797, respectively; SEQ ID NOs: 3030 and 3798. respectively; SEQ ID NOs: 3031 and 3799, respectively; SEQ ID NOs: 3032 and 3800. respectively; SEQ ID NOs: 3033 and 3801, respectively; SEQ ID NOs: 3034 and 3802. respectively; SEQ ID NOs: 3035 and 3803, respectively; SEQ ID NOs: 3036 and 3804 respectively; SEQ ID NOs: 3037 and 3805, respectively; SEQ ID NOs: 3038 and 3806. respectively; SEQ ID NOs: 3039 and 3807, respectively; SEQ ID NOs: 3040 and 3808. respectively; SEQ ID NOs: 3041 and 3809, respectively; SEQ ID NOs: 3042 and 3810. respectively; SEQ ID NOs: 3043 and 3811, respectively; SEQ ID NOs: 3044 and 3812. respectively; SEQ ID NOs: 3045 and 3813, respectively; SEQ ID NOs: 3046 and 3814. respectively; SEQ ID NOs: 3047 and 3815, respectively; SEQ ID NOs: 3048 and 3816. respectively; SEQ ID NOs: 3049 and 3817, respectively; SEQ ID NOs: 3050 and 3818. respectively; SEQ ID NOs: 3051 and 3819, respectively; SEQ ID NOs: 3052 and 3820, respectively; SEQ ID NOs: 3053 and 3821, respectively; SEQ ID NOs: 3054 and 3822, respectively; SEQ ID NOs: 3055 and 3823, respectively; SEQ ID NOs: 3056 and 3824, respectively; SEQ ID NOs: 3057 and 3825, respectively; SEQ ID NOs: 3058 and 3826, respectively; SEQ ID NOs: 3059 and 3827, respectively; SEQ ID NOs: 3060 and 3828 respectively; SEQ ID NOs: 3061 and 3829, respectively; SEQ ID NOs: 3062 and 3830, respectively; SEQ ID NOs: 3063 and 3831, respectively; SEQ ID NOs: 3064 and 3832, respectively; SEQ ID NOs: 3065 and 3833, respectively; SEQ ID NOs: 3066 and 3834, respectively; SEQ ID NOs: 3067 and 3835, respectively; SEQ ID NOs: 3068 and 3836, respectively; SEQ ID NOs: 3069 and 3837, respectively; SEQ ID NOs: 3070 and 3838, respectively; SEQ ID NOs: 3071 and 3839, respectively; SEQ ID NOs: 3072 and 3840, respectively; SEQ ID NOs: 3073 and 3841, respectively; SEQ ID NOs: 3074 and 3842, respectively; SEQ ID NOs: 3075 and 3843, respectively; SEQ ID NOs: 3076 and 3844, respectively; SEQ ID NOs: 3077 and 3845, respectively; SEQ ID NOs: 3078 and 3846, respectively; SEQ ID NOs: 3079 and 3847, respectively; SEQ ID NOs: 3080 and 3848, respectively; SEQ ID NOs: 3081 and 3849, respectively; SEQ ID NOs: 3082 and 3850, respectively; SEQ ID NOs: 3083 and 3851, respectively; SEQ ID NOs: 3084 and 3852, respectively; SEQ ID NOs: 3085 and 3853, respectively; SEQ ID NOs: 3086 and 3854, respectively; SEQ ID NOs: 3087 and 3855, respectively; SEQ ID NOs: 3088 and 3856, respectively; SEQ ID NOs: 3089 and 3857, respectively; SEQ ID NOs: 3090 and 3858,- 46 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOrespectively; SEQ ID NOs: 3091 and 3859, respectively; SEQ ID NOs: 3092 and 3860. respectively; SEQ ID NOs: 3093 and 3861, respectively; SEQ ID NOs: 3094 and 3862. respectively; SEQ ID NOs: 3095 and 3863, respectively; SEQ ID NOs: 3096 and 3864. respectively; SEQ ID NOs: 3097 and 3865, respectively; SEQ ID NOs: 3098 and 3866 respectively; or SEQ ID NOs: 3099 and 3867, respectively.

[0060] In some embodiments, the a nucleic acid A comprises a double stranded region that is 17-30 (e.g., 17-25 or 17-23) nucleotide pairs in length.

[0061] In some embodiments, each of the antisense strand and the sense strand is independently no more than 30 nucleotides in length (e.g., the sense strand is 21 nucleotides in length and the antisense strand is 23 nucleotides in length).

[0062] In some embodiments, the a nucleic acid A comprises a region of complementarity to the SLC6A19 RNA that is at least 17 (e.g., 19, 20, 21, 22, or 23) nucleotides in length. In some embodiments, In some embodiments, at least one of the antisense strand and the sense strand comprises a 3’ overhang of at least 2 nucleotides.

[0063] In some embodiments, the nucleic acid A comprises at least one modified internucleoside linkage, sugar moiety, or nucleobase.

[0064] In some embodiments, the modified internucleoside linkage, sugar moiety, or nucleobase comprises a modification selected from the group consisting of a deoxy-nucleoside, a 3 ’-terminal deoxy-thymine (dT) nucleoside, a 2’-O-methyl (2’-OMe) modified nucleoside, a 2’-fluoro (2’-F) modified nucleoside, a 2’-deoxy-modified nucleoside, a locked nucleotide (LNA), an unlocked nucleoside, a conformationally restricted nucleoside, a constrained ethyl nucleoside, an abasic nucleoside, a 2’-O,4’-C-ethylene-bridged nucleic acid (ENA), a 2’-amino-modified nucleoside, a 2’-O-allyl-modified nucleoside, 2’-C-alkyl-modified nucleoside, 2’-hydroxly-modified nucleoside, a 2’ -methoxy ethyl (2’-MOE) modified nucleoside, a 2’-O-alkylmodified nucleoside, a 5-methylcytosine, a morpholino nucleoside, a phosphoramidate, a non-natural base comprising nucleoside, a tetrahydropyran modified nucleoside, a 1,5-anhydrohexitol modified nucleoside, a cyclohexenyl modified nucleoside, a nucleotide comprising a 5’-phosphorothioate group, a nucleotide comprising a 5’-methylphosphonate group, a nucleotide comprising a 5’ phosphate or 5’ phosphate mimic, a nucleotide comprising vinyl phosphonate, a nucleoside comprising adenosine-glycol nucleic acid (GNA), a nucleoside comprising thymidine-glycol nucleic acid (GNA) S-Isomer, a nucleotide comprising 2-hydroxymethyl-tetrahydrofurane-5 -phosphate, a -47 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOnucleotide comprising 2’deoxythymidine-3 ’phosphate, a nucleotide comprising 2’-deoxy guanosine-3 ’ -phosphate, and a terminal nucleoside linked to a cholesteryl derivative and a dodecanoic acid bisdecylamide group; and combinations thereof. In some embodiments, the modified internucleoside linkage comprises a phosphorothioate linkage, and / or the modified nucleobase comprises 5-methylcytosine.

[0065] In some embodiments, the antisense strand comprises one or more 2’-M0E modified nucleotides, optionally wherein all nucleotides of the antisense strand are 2’ -MOE modified nucleotides.

[0066] In some embodiments, the antisense strand and / or the sense strand comprise one or more modified nucleotides. In some embodiments, substantially all nucleotides of the antisense strand, sense strand, or dsRNA comprise a modification. In some embodiments, all nucleotides of the antisense strand, sense strand, or dsRNA comprise a modification.

[0067] In some embodiments, the one or more modified nucleotides is selected from the group consisting of a deoxy-nucleotide, a 3 ’-terminal deoxy -thymine (dT) nucleotide, a 2'-O-methyl modified nucleotide, a 2' -fluoro modified nucleotide, a 2'-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2’-amino-modified nucleotide, a 2’ -O-allyl -modified nucleotide, 2’ -C-alkyl -modified nucleotide, 2’-hydroxly-modified nucleotide, a 2’ -methoxy ethyl modified nucleotide, a 2’-O-alkyl-modified nucleotide, a morpholino nucleotide (e.g., a phosphorodiamidate morpholino nucleic acid (PMO)), a phosphoramidate, a non-natural base comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a phosphoryl guanidine-based backbone, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5’-phosphate, a nucleotide comprising a 5 ’-phosphate mimic, a thermally destabilizing nucleotide, a glycol modified nucleotide (GNA), and a 2-O-(N-methylacetamide) modified nucleotide; and combinations thereof.

[0068] In some embodiments, the one or more modified nucleotides is selected from the group consisting of a deoxy-nucleotide, a 2'-O-methyl modified nucleotide, a 2'-fluoro modified nucleotide, a 2'-deoxy-modified nucleotide, a glycol modified nucleotide (GNA), and a vinyl-phosphonate nucleotide; and combinations thereof.- 48 - IPTS / 200358788.1Attorney Docket No. JUDO-005WO

[0069] In some embodiments, the one or more modified nucleotides is selected from the group consisting of a deoxy-nucleotide, a 2'-O-methyl modified nucleotide, and a 2'-fluoro modified nucleotide; and combinations thereof.

[0070] In some embodiments, the one or more modified nucleotides is selected from the group consisting of LNA, HNA, CeNA, 2'-methoxyethyl, 2'-O-alkyl, 2’-O-allyl, 2'-C- allyl, 2'-fluoro, 2'-deoxy, 2’ -hydroxyl, and glycol; and combinations thereof.

[0071] In some embodiments, the one or more modified nucleotides is selected from the group consisting of a C7-modified deaza-adenine, a C7-modified deaza-guanosine, a C5-modified cytosine, a C5-modified uridine, Nl-methyl-pseudouridine (ml\| / ), 1-ethyl-pseudouridine (el y), 5-methoxy-uridine (mo5U), 5-methyl-cytidine (m5C), pseudouridine (\| / ), 5-methoxymethyl uridine, 5-methylthio uridine, 1 -methoxymethyl pseudouridine, 5-methyl cytidine, 5-methoxy cytidine, or any combination thereof.

[0072] In some embodiments, the one or more modified nucleotides is selected from the group consisting of a phosphorothioate (PS) modification, a phosphoryl guanidine (PN) modification, a mesyl phosphoramidate modification, a borano-phosphate modification, an alkyl phosphonate nucleic acid (phNA), a peptide nucleic acid (PNA), or any combination thereof.

[0073] In some embodiments, the one or more modified nucleotides is selected from the group consisting of a deoxyribonucleic acid (DNA), optionally wherein the DNA is or comprises a DNA analog, optionally wherein the DNA analog comprises one or more morpholino subunits linked together by phosphorus-containing linkage(s), optionally wherein the DNA analog is or comprises a phosphorodiamidate morpholino nucleic acid (PMO), optionally wherein the PMO comprises about 12-40 nucleotides.

[0074] In some embodiments, the one or more modified nucleotides is a peptide nucleic acid (PNA) modification.

[0075] In some embodiments, the one or more modified nucleotides is one or more modification to a 5’ end of the antisense compound or dsRNA agent. In some embodiments, the modification to the 5' end is a 5’ amino modification.

[0076] As described herein, in some embodiments, a provided nucleic acid (e.g., ASO or siRNA) sequence may comprise one or more modified residues or nucleotides. In some embodiments, a modified residue is an abasic residue or nucleotide, which may be denoted as “abasic,” “(abasic),” or like terms within a provided sequence. For purposes of comparing the sequence of a molecule -49 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOhaving an abasic residue at a particular position with a reference sequence that includes a specified base or nucleotide at the same relative position in the reference sequence, the abasic residue shall be considered to not interrupt the sequence for purposes of determining contiguous base parameters, e.g., the number of contiguous bases the abasic-containing molecule has in common with the reference sequence; i.e., the abasic residue or nucleotide will be considered, for these purposes, to be a “wild card.” For example, for a sequence of UUUUCACACCCAAUAUCACAA, a sequence having at least 5 contiguous bases of said reference sequence may comprise CAAU(abasic), CAA(abasic)A, CA(abasic)UA, C(abasic)AUA, (abasic)AAUA, and so forth.

[0077] In some embodiments, the compound further comprises a lipid or lipid-based moiety.

[0078] In some embodiments, the compound is capable of inhibiting expression of SLC6A19.

[0079] In some embodiments, the compound is capable of delivering the nucleic acid A to a cell, tissue, or subject. In some embodiments, the delivery is enhanced compared to a reference. In some embodiments, the reference is an unconjugated nucleic acid A.

[0080] In some embodiments, the compound is capable of decreasing the level of a target gene in a cell, tissue, or subject. In some embodiments, the decrease is enhanced compared to a reference, optionally wherein the reference is an unconjugated nucleic acid A.

[0081] In some embodiments, the compound is capable of reducing the expression and / or activity of the target in a cell, tissue, or subject.

[0082] Also provided herein are pharmaceutical compositions comprising a compound described herein, and a pharmaceutically acceptable carrier.

[0083] Also provided are methods of treating a disease or condition in a subject suffering from or susceptible to the disease or condition, comprising administering to the subject a compound or pharmaceutical composition described herein.

[0084] In some embodiments, the disease or condition is associated with expression of a cell surface receptor. In some embodiments, the disease or condition comprises a cell in which both a cell surface receptor and a target recognized by the payload moiety are present. In some embodiments, the disease or condition is a kidney disease or condition. In some embodiments, the kidney disease or condition is a glomerular disorder, a renal tubular disorder, chronic kidney disease, other renal disorders, an inborn error of metabolism, a systemic metabolic disorder, a disorder of the thyroid, a disorder of the parathyroid, a disorder of the inner ear, a neurological - 50 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOdisorder, or a viral infection, or any combination thereof; or optionally wherein the kidney disease or condition is urea cycle disorder or autosomal dominant polycystic kidney disease (ADPKD). In some embodiments, the disease or condition is a systemic disease or condition, optionally wherein the systemic disease or condition is phenylketonuria (PKU).

[0085] Also provided are methods of treating a systemic disease in a subject suffering from or susceptible to the systemic disease, comprising contacting a compound or pharmaceutical composition described herein with a target protein present on the surface of a kidney cell.

[0086] Also provided are methods of delivering to a cell, tissue, or organism, comprising administering to the cell, tissue, or organism a compound or pharmaceutical composition described herein. In some embodiments, the cell is chosen from: kidney cells, thyroid cells, parathyroid cells, cells of the inner ear or nervous system cells, or a combination thereof. In some embodiments, the kidney cell is chosen from a proximal tubular epithelial cell and / or a podocyte.

[0087] In some embodiments, administering the compound to the subject, cell, tissue, or organism delivers the nucleic acid A to at least 5% more target cells compared to: (i) an otherwise similar cell, tissue or organism delivered an unconjugated nucleic acid A; (ii) a non-target cell; or (iii) both (i) and (ii).

[0088] In some embodiments, the target cell is or comprises a kidney cell. In some embodiments, the target cell is or comprises a cell that has expression of a kidney cell surface factor chosen from Megalin or Cubilin.BRIEF DESCRIPTION OF THE DRAWINGS

[0089] The following detailed description, given by way of example, but not intended to limit the disclosure solely to the specific embodiments described, may best be understood in conjunction with the accompanying drawing(s).

[0090] FIG. 1 shows results of screening human SLC6A19-targeting siRNAs for knockdown of huSLC6A19 expression in HEP3B217 cells in culture. Significant knockdown of SLC6A19 expression (>50%, dashed line) was observed for S003 and S005-S014 siRNAs, with doseresponse also observed for many of these siRNAs when comparing between 10 nM and 1 nM administrations of respective siRNAs.

[0091] FIG. 2 shows the relative location of the indicated siRNA against the SLC6A19 mRNA transcript (NM_1003841.3).- 51 - IPTS / 200358788.1Attorney Docket No. JUDO-005WO

[0092] FTG.3 shows the murine SLC6A19 mRNA expression in kidney cells in mice treated with two unconjugated exemplary siRNA duplexes or two exemplary siRNA duplexes conjugated to a triantennary aminoglycoside moiety.

[0093] FIG.4 shows the murine SLC6A19 mRNA expression in kidney cells in mice treated with two unconjugated exemplary siRNA duplexes or two exemplary siRNA duplexes conjugated to a triantennary polymyxin B moiety.DETAILED DESCRIPTION

[0094] In various embodiments, provided are compounds, comprising a targeting moiety and a payload moiety, and modulatory nucleic acid agents, e.g., antisense oligonucleotides (ASOs) and / or inhibitory RNAs (iRNAs, e.g., siRNAs) capable of modulating (in certain embodiments, inhibiting) expression of a target gene (e.g., SLC6A19 gene), and methods of using the compounds and modulatory nucleic acid agents for modulating (e.g., inhibiting) a target gene, e.g., SLC6A19 gene, in mammals. Also provided, in various embodiments, are methods and compositions including the compounds and modulatory nucleic acid agents for treating a subject having a SLC6A19-associated diseases or disorders, e g., a glomerular disorder, a renal tubular disorder, other renal disorders, an inborn error of metabolism, a (systemic) metabolic disorder, a disorder of the thyroid, a disorder of the parathyroid, a disorder of the inner ear, a neurological disorder, or a viral infection, or any combination thereof.Definitions

[0095] As used herein, all numerical values or numerical ranges include endpoints of such ranges, and include whole integers within or encompassing such ranges and fractions of the values or the integers within or encompassing ranges, unless the context clearly indicates otherwise. Thus, for example, reference to a range of 90-100%, includes 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, etc., as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so forth, including 100%. In another example, reference to a range of 1-5,000 fold includes, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, fold, etc., as well as 1.1, 1.2, 1.3, 1.4, 1.5, fold, etc., 2.1, 2.2, 2.3, 2.4, 2.5, fold, etc., and so forth, including 5,000-fold.- 52 - IPTS / 200358788.1Attorney Docket No. JUDO-005WO

[0096] As used herein, the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element, e.g., a plurality of elements.

[0097] As used herein, the term “about” refers to within the typical ranges of tolerances in the art. For example, “about” can be understood as about 2 standard deviations from the mean. In certain embodiments, “about” means ±10% variation from the recited quantitative value (and includes the recited quantitative value itself). In certain embodiments, “about” means ±5% variation from the recited quantitative value (and includes the recited quantitative value itself). When “about” is present before a series of numbers or a range, it is understood that “about” can modify each of the numbers in the series or range.

[0098] As used herein, the term “at least” prior to a number or series of numbers is understood to include the number adjacent to the term “at least,” and all subsequent numbers or integers that could logically be included, as clear from context. For example, the number of nucleotides in a nucleic acid molecule must be an integer, and “at least 18 nucleotides of a 21 nucleotide nucleic acid molecule” means that 18, 19, 20, or 21 nucleotides have the indicated property. When “at least” is present before a series of numbers or a range, it is understood that “at least” can modify each of the numbers in the series or range.

[0099] A composition or method described herein as “comprising” one or more named elements or steps is open-ended, meaning that the named elements or steps are essential, but other elements or steps may be added within the scope of the composition or method. To avoid prolixity, it is also understood that any composition or method described as “comprising” (or which “comprises”) one or more named elements or steps also describes the corresponding, more limited composition or method “consisting essentially of’ (or which “consists essentially of’) the same named elements or steps, meaning that the composition or method includes the named essential elements or steps and may also include additional elements or steps that do not materially affect the basic and novel characteristic(s) of the composition or method. It is also understood that any composition or method described herein as “comprising” or “consisting essentially of’ one or more named elements or steps also describes the corresponding, more limited, and closed-ended composition or method “consisting of’ (or “consists of’) the named elements or steps to the exclusion of any other unnamed element or step. In any composition or method disclosed herein, known or- 53 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOdisclosed equivalents of any named essential element or step may be substituted for that element or step.

[0100] As used herein, the term “including” refers to, and is used interchangeably with, the phrase “including but not limited to.”

[0101] As used herein, “no more than” or “less than” is understood as the value adjacent to the phrase and logical lower values or integers, as logical from context, to zero. For example, a duplex with an overhang of “no more than 2 nucleotides” has a 2, 1, or 0 nucleotide overhang. When “no more than” is present before a series of numbers or a range, it is understood that “no more than” can modify each of the numbers in the series or range. As used herein, ranges include both the upper and lower limit.

[0102] As used herein, the term “or” refers to, and is used interchangeably with, the term “and / or,” unless context clearly indicates otherwise.

[0103] In the event of a conflict between an indicated target site and the nucleotide sequence for a sense or antisense strand, the indicated sequence takes precedence.

[0104] As used herein, “active target segments” refer to the locations on the target nucleic acid (e g., an SLC6A19 mRNA) defined by having one or more active modulatory RNA compounds targeted thereto. There may be substantial variation in activity (e.g., as defined by percent inhibition) of the modulatory RNA compounds within an active target segment. Active modulatory RNA compounds are those that are determined to modulate the expression of their target RNA. In some embodiments, active modulatory RNA compounds are inhibitory, optionally inhibiting expression of their target RNA at least about 50%, optionally at least about 70% and optionally at least about 80%, or more. In some embodiments, the level of inhibition required to define an active inhibitory RNA compound is defined based on the results from a screen used to define the active target segments. Those skilled in the art understand that the percent inhibition by an inhibitory RNA compound on a target mRNA will vary between assays due to factors relating to assay conditions.

[0105] As used herein, the term “agent,” may refer to a physical entity or phenomenon. In some embodiments, an agent may be characterized by a particular feature and / or effect. In some embodiments, an agent may be a compound, molecule, or entity of any chemical class including, for example, a small molecule, polypeptide, nucleic acid, saccharide, lipid, metal, or a combination or complex thereof. In some embodiments, the term “agent” may refer to a compound, molecule,- 54 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOor entity that comprises a polymer. In some embodiments, the term may refer to a compound or entity that comprises one or more polymeric moieties. In some embodiments, the term “agent” may refer to a compound, molecule, or entity that is substantially free of a particular polymer or polymeric moiety. In some embodiments, the term may refer to a compound, molecule, or entity that lacks or is substantially free of any polymer or polymeric moiety.

[0106] As used herein, the term “amino acid” in its broadest sense, as used herein, refers to any compound and / or substance that can be incorporated into a polypeptide chain, e.g., through formation of one or more peptide bonds. In some embodiments, an amino acid has the general structure H2N-C(H)(R)-COOH. In some embodiments, an amino acid is a naturally-occurring amino acid. In some embodiments, an amino acid is a non-natural amino acid; in some embodiments, an amino acid is a D-amino acid; in some embodiments, an amino acid is an L-amino acid. “Standard amino acid” refers to any of the twenty standard L-amino acids commonly found in naturally occurring peptides. “Nonstandard amino acid” refers to any amino acid, other than the standard amino acids, regardless of whether it is prepared synthetically or obtained from a natural source. In some embodiments, an amino acid, including a carboxy- and / or aminoterminal amino acid in a polypeptide, can contain a structural modification as compared with the general structure above. For example, in some embodiments, an amino acid may be modified by methylation, amidation, acetylation, pegylation, glycosylation, phosphorylation, and / or substitution (e.g., of the amino group, the carboxylic acid group, one or more protons, and / or the hydroxyl group) as compared with the general structure. In some embodiments, such modification may, for example, alter the circulating half-life of a polypeptide containing the modified amino acid as compared with one containing an otherwise identical unmodified amino acid. In some embodiments, such modification does not significantly alter a relevant activity of a polypeptide containing the modified amino acid, as compared with one containing an otherwise identical unmodified amino acid. As will be clear from context, in some embodiments, the term “amino acid” may be used to refer to a free amino acid; in some embodiments it may be used to refer to an amino acid residue of a polypeptide.

[0107] As used herein, the term “antisense oligonucleotide” or “ASO” refers to an oligonucleotide that is capable of interacting with and / or hybridizing to a pre-mRNA or an mRNA having a complementary nucleotide sequence thereby modifying gene expression. In some embodiments, the terms “antisense oligonucleotide” and “antisense polynucleotide” are used - 55 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOinterchangeably. As used herein, the term “exon skipping” refers to the modification of pre-mRNA splicing by the targeting of splice donor and / or acceptor and branch sites within a pre-mRNA with one or more complementary ASO(s). By blocking access of a spliceosome to one or more splice donor, acceptor or branch site, an ASO can prevent a splicing reaction thereby causing the exclusion of one or more exons from a fully-processed mRNA. Exon skipping is achieved in the nucleus during the maturation process of pre-mRNAs. It includes the masking of key sequences involved in the splicing of targeted exons by using ASOs that are complementary to splice donor / acceptor, branch-point sequences and / or by overlapping ESE (in exon) / ISE (in intron) within a pre-mRNA.

[0108] As used herein, the term “antisense strand” or “guide strand” refers to a strand of an iRNA (e.g., a dsRNA), which includes a region that is substantially complementary to a target sequence (e g., a SLC6A19 mRNA). As used herein, the term “sense strand” or “passenger strand” refers to a strand of an iRNA (e.g., a dsRNA) that includes a region that is substantially complementary to a region of the antisense strand.

[0109] As used herein, the term “blunt” or “blunt end” refers to that there are no unpaired nucleotides at that end of a double stranded RNA agent, i.e., no nucleotide overhang. A “blunt ended” double stranded RNA agent is double stranded over its entire length, i.e., no nucleotide overhang at either end of the molecule. RNAi agents of the present disclosure include RNAi agents with no nucleotide overhang at one end (i.e., agents with one overhang and one blunt end) or with no nucleotide overhangs at either end. Most often such a molecule will be double-stranded over its entire length.

[0110] As used herein, the term “cell associated with a kidney” refers to a cell that is or can be found in a kidney (e.g., during development, during tissue homeostasis, or in the course of a disease or disorder). In some embodiments, a cell associated with a kidney is also referred to as a "kidney cell" herein. In some embodiments, a cell associated with a kidney includes any one or all of the following cell types: a proximal tubule epithelial cell, a podocyte, a parietal epithelial cell, a mesangial cell, a renal stem cell, an epithelial progenitor cell, a fibroblast, a myo-fibroblast, a pericyte, an ascending loop of Henle cell, a descending loop of Henle cell, a distal tubule cell, a connecting tubule cell, an intercalated cell, a principal cell. Exemplary renal cell populations are provided in Schumacher etal., (2021) npj Regen Med 6, 45, the entire contents of which are hereby- 56 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOincorporated by reference. In some embodiments, a kidney cell is or comprises a cell derived from a kidney, e.g., a kidney tumor cell and / or a metastatic kidney tumor cell.

[0111] As used herein, the term “cell surface factor” refers to a factor (e.g., that is or comprises a polypeptide) that is present on the surface of cell(s) of interest (e.g., target cell(s) as described herein which, in many embodiments, may be kidney cell(s)).

[0112] As used herein, the term “cleavage region” refers to a region that is located immediately adjacent to the cleavage site. The “cleavage site” is the site on a target sequence (e.g., a target mRNA sequence) at which cleavage occurs. In some embodiments, the cleavage region comprises three bases on either end of, and immediately adjacent to, the cleavage site. In some embodiments, the cleavage region comprises two bases on either end of, and immediately adjacent to, the cleavage site. In some embodiments, the cleavage site specifically occurs at the site bound by nucleotides 10 and 11 of an antisense strand, and the cleavage region comprises nucleotides 11, 12 and 13.

[0113] As used herein, the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents). In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition, or even in a combination compound (e.g., as part of a single chemical complex or covalent entity).

[0114] As used herein, “complementary” refers to a nucleic acid molecule that can form hydrogen bond(s) with another nucleic acid molecule by either traditional Watson-Crick base pairing or other non-traditional types of pairing (e.g., Hoogsteen or reversed Hoogsteen hydrogen bonding) between complementary nucleosides or nucleotides. In reference to the oligonucleotides of the present disclosure, the binding free energy for an antisense oligonucleotide / antisense strand - 57 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOwith its complementary sequence is sufficient to allow the relevant function of the oligonucleotide agent to proceed and there is a sufficient degree of complementarity to avoid non-specific binding of the antisense oligonucleotide / antisense strand to non-target sequences under conditions in which specific binding is desired, i.e., under physiological conditions in the case of in vivo therapeutic treatment. Determination of binding free energies for nucleic acid molecules is well known in the art (see, e.g., Turner et ah, CSH Symp. Quant. Biol. 1 / 7:123-133 (1987); Frier et al, Proc. Nat. Acad. Sci. USA 83:9373-77 (1986); and Turner et al, J. Am. Chem. Soc. 109:3783-3785 (1987)). Thus, “complementary” (or “specifically hybridizable”) is a term that indicate a sufficient degree of complementarity or precise pairing such that stable and specific binding occurs between an antisense oligonucleotide / antisense strand and a pre-mRNA or mRNA target. It is understood in the art that a nucleic acid molecule need not be 100% complementary to a target nucleic acid sequence to be specifically hybridizable. That is, two or more nucleic acid molecules may be less than fully complementary.

[0115] Complementarity is indicated by a percentage of contiguous residues in a nucleic acid molecule that can form hydrogen bonds with a second nucleic acid molecule. For example, if a first nucleic acid molecule has 10 nucleotides and a second nucleic acid molecule has 10 nucleotides, then base pairing of 5, 6, 7, 8, 9, or 10 nucleotides between the first and second nucleic acid molecules represents 50%, 60%, 70%, 80%, 90%, and 100% complementarity, respectively. “Perfectly” or “fully” complementary nucleic acid molecules means those in which all the contiguous residues of a first nucleic acid molecule will hydrogen bond with the same number of contiguous residues in a second nucleic acid molecule, wherein the nucleic acid molecules either both have the same number of nucleotides (i.e., have the same length) or the two molecules have different lengths.

[0116] In some embodiments, the term “complementary,” when used to describe a first nucleotide sequence in relation to a second nucleotide sequence, refers to the ability of an oligonucleotide or polynucleotide comprising the first nucleotide sequence to hybridize and form a duplex structure under certain conditions with an oligonucleotide or polynucleotide comprising the second nucleotide sequence, as will be understood by the skilled person. Such conditions can, for example, be stringent conditions, where stringent conditions can include: 400 mM NaCl, 40 mM PIPES pH 6.4, 1 mM EDTA, 50°C or 70°C for 12-16 hours followed by washing (see, e.g., “Molecular Cloning: A Laboratory Manual, Sambrook, et al. (1989) Cold Spring Harbor Laboratory Press).- 58 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOOther conditions, such as physiologically relevant conditions as can be encountered inside an organism, can apply. The skilled person will be able to determine the set of conditions most appropriate for a test of complementarity of two sequences in accordance with the ultimate application of the hybridized nucleotides.

[0117] “Complementary” sequences, as used herein, can also include, or be formed entirely from, non-Watson-Crick base pairs or base pairs formed from non-natural and modified nucleotides, in so far as the above requirements with respect to their ability to hybridize are fulfilled. Such non-Watson-Crick base pairs include, but are not limited to, G: U Wobble or Hoogstein base pairing.

[0118] In some embodiments, complementary sequences within an iRNA, e.g., within a dsRNA as described herein, include base-pairing of an oligonucleotide or polynucleotide comprising a first nucleotide sequence to an oligonucleotide or polynucleotide comprising a second nucleotide sequence over the entire length of one or both nucleotide sequences. Such sequences can be referred to as “fully complementary” with respect to each other herein. However, where a first sequence is referred to as “substantially complementary” with respect to a second sequence herein, the two sequences can be fully complementary, or they can form one or more, but generally not more than 5, 4, 3, or 2 mismatched base pairs upon hybridization for a duplex up to 30 base pairs, while retaining the ability to hybridize under the conditions most relevant to their ultimate application, e.g., inhibition of gene expression via a RISC pathway. However, where two oligonucleotides are designed to form, upon hybridization, one or more single stranded overhangs, such overhangs shall not be regarded as mismatches with regard to the determination of complementarity. For example, a dsRNA comprising one oligonucleotide 21 nucleotides in length and another oligonucleotide 23 nucleotides in length, wherein the longer oligonucleotide comprises a sequence of 21 nucleotides that is fully complementary to the shorter oligonucleotide, can yet be referred to as “fully complementary” for the purposes described herein.

[0119] In various embodiments, the terms “complementary,” “fully complementary” and “substantially complementary” can be used with respect to the base matching between the sense strand and the antisense strand of a dsRNA, or between the antisense strand of a double stranded RNA agent and a target sequence, as will be understood from the context of their use.

[0120] As used herein, an oligonucleotide or polynucleotide that is “substantially complementary to at least part of’ a messenger RNA (mRNA) refers to an oligonucleotide or polynucleotide that is substantially complementary to a contiguous portion of the mRNA of - 59 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOinterest (e.g., an mRNA encoding a B°AT1 polypeptide). For example, a polynucleotide is complementary to at least a part of a SLC6A19 mRNA if the sequence is substantially complementary to a non-interrupted portion of an mRNA encoding a B°AT1 polypeptide.

[0121] As used herein, the term “Cubilin” refers to a receptor encoded by the CUBN gene. Amino acid sequences for full length Cubilin, and / or for nucleic acids that encode it can be found in a public database such as GenBank, UniProt and Swiss-Prot. For example, the amino acid sequence of human Cubilin (SEQ ID NO: 6, for which residues 1-23 represent a signal peptide; residues 24-35 represent a propeptide which can be removed in the mature form, and residues 36-3623 represent a mature Cubilin polypeptide) can be found as UniProt / Swiss-Prot Accession No.060494 and the nucleic acid sequence encoding human Cubilin can be found at Accession No. NM_001081.3. Cubilin is also known, for example, as IFCR, Gp280, Intrinsic Factor- Vitamin B 12 Receptor, MGA1, or IGS1. Those skilled in the art will appreciate that the Cubilin sequence of SEQ ID NO: 6 is exemplary, and certain variations (including, for example, conservative substitutions in SEQ ID NO: 6, codon-optimized variants of Cubilin-encoding nucleic acid sequences, etc.) are understood to also be or encode human Cubilin. Additionally, those skilled in the art will appreciate that homologs and orthologs of human Cubilin are known and / or knowable through the exercise or ordinary skill, for example, based on degree of sequence identity, presence of one or more characteristic sequence elements, and / or one or more shared activities. In some embodiments, Cubilin comprises full-length Cubilin, or a variant or a fragment thereof. In some embodiments, Cubilin that is targeted in accordance with the present disclosure is a Cubilin expressed by particular target cell(s) and / or tissue(s) of interest (e.g., in an organism of interest). In some embodiments, a Cubilin that is targeted in accordance with the present disclosure is an engineered Cubilin. In many embodiments, a Cubilin that is targeted in accordance with the present disclosure is present on the surface of target cell(s) of interest (e.g., in target tissue(s) of interest) and that becomes internalized by such cell upon binding of a Cubilin binding moiety as described herein. Cubilin has been reported to be expressed in one or more of the following tissues and / or cells: immune cells (e.g., bone marrow cells, lymph node cells, thymic cells, peripheral blood mononuclear cells [e.g., myeloid and / or lymphoid cells], erythrocytes, eosinophils, neutrophils, and / or platelets); nervous system (e.g., brain tissue, cortex, cerebellum, retinal cells, spinal cord cells, nerve cells, neurons, and / or supporting cells; endothelial cells; muscle (e.g., heart muscle, smooth muscle, and / or skeletal muscle); small instetine; colon; adipocytes; kidney; liver; lung;- 60 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOspleen; stomach; esophagus; bladder; pancreas; thyroid; salivary gland; adrenal gland; pituitary gland; breast; skin; ovary; uterus; placenta; prostate; and testis. Cubilin expression is reported to be enriched (e.g., high relative to one or more other tissues) in the following tissues and / or cells in particular: renal tissue, thyroid tissue, parathyroid tissue, cells of the inner ear, and nervous system tissue. Cubilin has been specifically reported to be expressed (e.g., at relatively high level(s)) on surfaces of kidney cells such a proximal tubular epithelial cells and podocytes. See Nielsen R. et al. (2016), Kidney hit. 89(l):58-67.

[0122] As used herein, the term “Cubilin-binding moiety” refers to a moiety that binds to Cubilin when contacted therewith. Typically, a Cubilin-binding moiety useful in accordance with the present disclosure binds specifically to Cubilin under the circumstances of the contacting. In some embodiments, a Cubilin-binding moiety is or comprises a ligand provided in Table 4. In some embodiments, a Cubilin-binding moiety is internalized upon binding to Cubilin on a cell surface.

[0123] As used herein, the terms “double stranded RNA agent,” “double stranded RNA molecule,” “dsRNA agent,” and “dsRNA” are used interchangeably and refer to a complex of nucleic acid molecules (optionally including modified nucleotides, as defined herein, in substitution at one, multiple, or all such ribonucleic acids of one or both strands of such dsRNA agent), having a duplex structure comprising two anti-parallel and substantially complementary nucleic acid strands, referred to as having “sense” and “antisense” orientations with respect to a target RNA, e.g., a SLC6A19 gene. In general, the majority of nucleotides of each strand of a dsRNA molecule are ribonucleotides, but as described in detail herein, each or both strands can also include one or more non-ribonucleotides, e g., a deoxyribonucleotide or a modified nucleotide.

[0124] As used herein, an “effective amount” is an amount sufficient to effect beneficial or desired results.

[0125] As used herein, “hybridization” refers to the pairing of complementary strands of antisense compounds to their target sequence or the pairing of complementary strands of doublestranded nucleic acid molecules with one another. While not limited to a particular mechanism, the most common mechanism of pairing involves hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleoside or nucleotide bases (nucleobases). For example, the natural base adenine is complementary to the natural nucleobases thymidine and uracil which pair through the formation of hydrogen bonds.- 61 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOThe natural base guanine is complementary to the natural base 5-methyl cytosine and the artificial base known as a G-clamp. Hybridization can occur under varying circumstances.

[0126] A modulatory nucleic acid described herein is “specifically hybridizable” when there is a sufficient degree of complementarity to avoid non-specific binding of the modulatory nucleic acid to non-target nucleic acid sequences under conditions in which specific binding is desired, i.e., under physiological conditions in the case of in vivo assays or therapeutic treatment, and under conditions in which assays are performed in the case of in vitro assays.

[0127] As used herein, “stringent hybridization conditions” or “stringent conditions” refers to conditions under which a modulatory nucleic acid will hybridize to its target sequence, but to a minimal number of other sequences. Stringent conditions are sequence-dependent and will be different in different circumstances, and “stringent conditions” under which modulatory nucleic acids hybridize to a target sequence are determined by the nature and composition of the modulatory RNA compounds and the assays in which they are being investigated.

[0128] As used herein, the term “inhibiting” is used interchangeably with “reducing,” “silencing,” “downregulating”, “suppressing”, and other similar terms, and includes any level of inhibition. As used herein, the phrase “inhibiting expression of a SLC6A19” refers to inhibition of expression of any SLC6A19 gene (e.g., a mouse SLC6A19 gene, a rat SLC6A19 gene, a monkey SLC6A19 gene, or a human SLC6A19 gene) as well as variants or mutants of a SLC6A19 gene. Thus, the SLC6A19 gene may be a wild-type SLC6A19 gene, a mutant SLC6A19 gene, or a transgenic SLC6A19 gene in the context of a genetically manipulated cell, group of cells, or organism.

[0129] As used herein, the terms “iRNA,” “RNAi agent,” “iRNA agent,”, “RNA interference agent” are used interchangeably and refer to an agent that contains RNA as that term is defined herein, and which mediates the targeted cleavage of an RNA transcript via an RNA-induced silencing complex (RISC) pathway. iRNA directs the sequence-specific degradation of mRNA through a process known as RNA interference (RNAi). In some embodiments, the iRNA modulates, e.g., inhibits, the expression of a SLC6A19 gene in a cell, e g., a cell within a subject, such as a mammalian subject.

[0130] In some embodiments, an “iRNA” of the present disclosure includes a single stranded RNA that interacts with a target RNA sequence, e.g., a SLC6A19 target mRNA sequence. In some embodiments, an “iRNA” of the present disclosure is a double stranded RNA.- 62 - IPTS / 200358788.1Attorney Docket No. JUDO-005WO

[0131] As used herein, the term “Megalin” refers to a receptor which is a member of the low-density lipoprotein receptor (LDLR) family. Megalin is encoded by the LRP2 gene. Amino acid sequences for full length Megalin, and / or for nucleic acids that encode it can be found in a public database such as GenBank, UniProt and Swiss-Prot. For example, the amino acid sequence of human Megalin (SEQ ID NO: 5, for which residues 27-4411 represent an extracellular domain comprising LDL Receptor Class A domains, LDL Receptor Class B domains, and EGF-like domains; residues 4589-4602 represent a DAB2 interaction domain; and residues 4453-4622 represent a cytoplasmic domain comprising NPXY motifs, SH2 binding domains, SH3 binding domains, and proline-rich domains) can be found as UniProt / Swiss-Prot Accession No. P98164 and the nucleic acid sequence encoding human Megalin can be found at Accession No. NM_ 004525.3. Megalin is also known, for example, as Low-density lipoprotein receptor-related protein 2 (LRP2), Glycoprotein 330 (Gp330), Calcium Sensor Protein, or Heymann Nephritis Antigen Homolog. Those skilled in the art will appreciate that the sequence of SEQ ID NO: 5 is exemplary, and certain variations (including, for example, conservative substitutions in SEQ ID NO: 5, as well as codon-optimized variants of associated nucleic acid sequences, etc.) are understood to also be or encode human Megalin. Additionally, those skilled in the art will appreciate that homologs and orthologs of human Megalin are known and / or knowable through the exercise or ordinary skill, for example, based on degree of sequence identity, presence of one or more characteristic sequence elements, and / or one or more shared activities. In some embodiments, Megalin comprises full-length Megalin, or a variant or a fragment thereof. In some embodiments, Megalin that is targeted in accordance with the present disclosure is a Megalin expressed by particular target cell(s) and / or tissue(s) of interest (e.g., in an organism of interest). In some embodiments, a Megalin that is targeted in accordance with the present disclosure is an engineered Megalin. In many embodiments, a Megalin that is targeted in accordance with the present disclosure is present on the surface of target cell(s) of interest (e.g., in target tissue(s) of interest, such as kidney) and that becomes internalized by such cell upon binding of a Megalin binding moiety as described herein. Megalin has been reported to be expressed in one or more of the following tissues and / or cells: immune cells (e.g., bone marrow cells, lymph node cells, thymic cells, peripheral blood mononuclear cells [e.g., myeloid and / or lymphoid cells], erythrocytes, eosinophils, neutrophils, and / or platelets); nervous system cells (e.g., brain tissue, cortex, cerebellum, retinal cells, spinal cord cells, nerve cells, neurons, and / or supporting cells); endothelial cells; muscle (e.g., heart - 63 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOmuscle, smooth muscle, and / or skeletal muscle); small intestine; colon; adipocytes; kidney; liver; lung; spleen; stomach; esophagus; bladder; pancreas; thyroid; salivary gland; adrenal gland; pituitary gland; breast; skin; ovary; uterus; placenta; prostate; and testis. Megalin expression is reported to be enriched (e.g., high relative to one or more other tissues) in the following tissues and / or cells in particular: renal tissue, thyroid tissue, parathyroid tissue, cells of the inner ear, and nervous system tissue. Megalin has been specifically reported to be expressed (e.g., at relatively high level(s)) on surfaces of kidney cells such a proximal tubular epithelial cells and podocytes. See Nielsen R. et al. (2016), Kidney hit. 89(1): 58-67.

[0132] As used herein, the term “Megalin-binding moiety” refers to a moiety that binds to Megalin when contacted therewith. Typically, a Megalin-binding moiety useful in accordance with the present disclosure binds specifically to Megalin under the circumstances of the contacting. In some embodiments, a Megalin-binding moiety is or comprises: a peptide, an aminoglycoside, an endogenous ligand (e.g., a ligand disclosed in Table 3 or an analog or variant thereof), a xenobiotic, an antibody or a fragment thereof, or any combination thereof. In some embodiments, a Megalin-binding moiety is internalized upon binding to Megalin on a cell surface.

[0133] As used herein, the term “modulatory nucleic acid” or “modulatory nucleic acid agent” refers to a nucleic acid capable of modulating the expression of a target gene (e.g., a SLC6A19 mRNA). In some embodiments, a modulatory nucleic acid is a modulatory RNA. In some embodiments, a modulatory nucleic acid comprises an antisense oligonucleotide (ASO), double stranded RNA (dsRNA), exon skipping agent, exon inclusion agent, other splicing modulator, or a combination thereof.

[0134] As used herein, the term “modified nucleotide” refers to a nucleotide having, independently, a modified sugar moiety, a modified internucleotide linkage, or modified nucleobase, or any combination thereof. Thus, the term modified nucleotide encompasses substitutions, additions or removal of, e.g., a functional group or atom, to intemucleoside linkages, sugar moieties, or nucleobases. The modifications suitable for use in the agents of the present disclosure include all types of modifications disclosed herein or known in the art. Any such modifications, as used in a siRNA type molecule, are encompassed by “iRNA” or “RNAi agent,” or as used in an ASO type molecule, are encompassed by “antisense oligonucleotide" or “ASO,” for the purposes of this specification and claims.- 64 - IPTS / 200358788.1Attorney Docket No. JUDO-005WO

[0135] In certain embodiments, inclusion of a deoxy-nucleotide within an RNAi agent, or within an ASO or other modulatory nucleic acid agent, can be considered to constitute a modified nucleotide. In addition, as used in this specification, an “iRNA”, or an ASO, may include ribonucleotides with chemical modifications; an iRNA, or an ASO, may include substantial modifications at multiple nucleotides.

[0136] As used herein, “substantially all of the nucleotides are modified” refers to largely but not wholly modified and can include not more than 5, 4, 3, 2, or 1 unmodified nucleotides.

[0137] As used herein, the term “moiety” refers to a portion or fragment of a molecule that retains one or more functionalities of said molecule and can be included as a part of other molecules. For example, a “aminoglycoside moiety” may be any portion of an aminoglycoside that retains Megalin-binding ability and can be included as a part of an aminoglycoside-nucleic acid conjugate. In some embodiments, a moiety may be functionalized to comprise a reactive group (e g., a reactive group for conjugation with other moieties or molecules).

[0138] As used herein, the term “nucleotide overhang” or “overhang” refers to at least one unpaired nucleotide that protrudes from the duplex structure of a double stranded iRNA. For example, when a 3'-end of one strand of a dsRNA extends beyond the 5'-end of the other strand, or vice versa, there is a nucleotide overhang. A dsRNA can comprise an overhang of at least one nucleotide; alternatively, the overhang can comprise at least two nucleotides, at least three nucleotides, at least four nucleotides, at least five nucleotides or more. A nucleotide overhang can comprise or consist of a nucleotide / nucleoside analog, including a deoxynucleotide / nucleoside. The overhang(s) can be on the sense strand, the antisense strand, or any combination thereof. Furthermore, the nucleotide(s) of an overhang can be present on the 5'-end, 3'-end, or both ends of either an antisense or sense strand of a dsRNA.

[0139] As used herein, “percent (%) identity” refers to the extent to which two sequences (nucleotide or amino acid) have the same residue at the same positions in an alignment. Generally, a double-stranded RNA (dsRNA) or antisense oligonucleotide (ASO) disclosed herein, or a portion thereof, may have a defined percent identity to a target sequence and / or complement thereof. Percent identity is calculated according to the number of bases that have identical base pairing corresponding to the reference sequence (e.g., a target sequence, a complementary strand of a dsRNA, an antisense oligonucleotide, or antisense strand sequence) to which it is being compared. As used herein, a sequence is identical to the reference sequence if it has the same nucleobase - 65 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOpairing ability. For example, an RNA which contains uracil in place of thymidine in the disclosed sequences would be considered identical as they both pair with adenine. The percent identity may be over the entire length of the oligomeric compound or in a portion of a given strand (e.g., nucleobases 1-20 of a 27-mer may be compared to a 20-mer, or to a defined 20 nucleotide sequence within a target nucleic acid (e.g., an SLC6A19 mRNA), to determine percent identity of the 27-mer across residues 1-20 to the comparator 20-mer). For example, a 16-mer having the same sequence as nucleobases 2-17 of a 20-mer is 80% identical to the 20-mer across the entire length of the 20-mer; a 30-mer comprising the full sequence of the complement of a 20-mer has a portion of 100% identity with the 20-mer.

[0140] It is understood by those skilled in the art that a nucleic acid (e.g., iRNA or ASO) needs not have an identical sequence to one described herein (e.g., a modulatory nucleic acid described herein) to function similarly. It is also well known by those skilled in the art that it is possible to increase or decrease the length of a nucleic acid (e.g., iRNA or ASO) and / or introduce mismatch bases (with either target sequence, complementary strand(s) of a double-stranded RNA, or both) without eliminating activity. Accordingly, shortened or extended versions - on one or both strands where a dsRNA - of modulatory nucleic acids described herein, or non-identical versions of the modulatory nucleic acids described herein, fall within the scope of this disclosure. In some embodiments, non-identical versions are those wherein each base does not have the same pairing activity as the modulatory nucleic acids described herein. In other embodiments, a non-identical version includes at least one mismatch or at least one base replaced with a different base with different pairing activity (e.g., G can be replaced by C, A, or T). The non-identical bases may be adjacent to each other, dispersed throughout the oligonucleotide, or both.

[0141] As used herein, the term “peptide” refers to a polypeptide that is typically relatively short, for example having a length of less than about 100 amino acids, less than about 50 amino acids, less than about 40 amino acids less than about 30 amino acids, less than about 25 amino acids, less than about 20 amino acids, less than about 15 amino acids, or less than 10 amino acids. As used herein, the term “polypeptide” refers to a polymeric chain of amino acids. In some embodiments, a polypeptide has an amino acid sequence that occurs in nature. In some embodiments, a polypeptide has an amino acid sequence that does not occur in nature. In some embodiments, a polypeptide has an amino acid sequence that is engineered in that it is designed and / or produced- 66 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOthrough action of the hand of man. Tn some embodiments, a polypeptide may comprise or consist of natural amino acids, non-natural amino acids, or both.

[0142] As used herein, the term “pharmaceutical composition” refers to a composition in which an active agent (e.g., a modulatory nucleic acid agent as disclosed herein) is formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, a pharmaceutical composition may be specially formulated for administration in a particular form (e.g., in a solid form or a liquid form), and / or may be specifically adapted for, for example: oral administration (for example, as a drenche [aqueous or non-aqueous solutions or suspensions], tablet, capsule, bolus, powder, granule, paste, etc, which may be formulated specifically for example for buccal, sublingual, or systemic absorption); parenteral administration (for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation, etc); topical application (for example, as a cream, ointment, patch or spray applied for example to skin, lungs, or oral cavity); intravaginal or intrarectal administration (for example, as a pessary, suppository, cream, or foam); ocular administration; nasal or pulmonary administration, etc.

[0143] As used herein, “prevention” or “preventing,” when used in reference to a disease, disorder or condition thereof, may be treated or ameliorated by a reduction in expression of a SLC6A19 gene, refers to a reduction in the likelihood that a subject will develop a symptom associated with such a disease, disorder, or condition, e.g., a symptom of unwanted or excessive SLC6A19 and / or B°AT1 expression, such as a metabolic disorder and / or a kidney disease or condition, such as a glomerular disorder, a renal tubular disorder, other renal disorders, an inborn error of metabolism, a systemic metabolic disorder, a disorder of the thyroid, a disorder of the parathyroid, a disorder of the inner ear, a neurological disorder, a viral infection, etc. The likelihood of developing, e.g., a kidney disease or condition, is reduced, for example, when an individual having one or more risk factors for a kidney disease or condition either fails to develop the kidney disease or condition or develops the a kidney disease or condition with less severity relative to a population having the same risk factors and not receiving treatment as described herein. The failure to develop a disease, disorder or condition, or the reduction in the development -67 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOof a symptom associated with such a disease, disorder or condition (e.g., by at least about 10% on a clinically accepted scale for that disease or disorder), or the exhibition of delayed symptoms delayed (e.g., by days, weeks, months or years) is considered effective prevention.

[0144] As used herein, “reference” refers to a standard or control relative to which a comparison is performed. For example, in some embodiments, an agent, animal, individual, population, sample, sequence or value of interest is compared with a reference or control agent, animal, individual, population, sample, sequence or value. In some embodiments, a reference or control is tested and / or determined substantially simultaneously with the testing or determination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as would be understood by those skilled in the art, a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment. Those skilled in the art will appreciate when sufficient similarities are present to justify reliance on and / or comparison to a particular possible reference or control.

[0145] As used herein, the term “sample” as used herein, includes a collection of similar fluids, cells, or tissues isolated from a subject, as well as fluids, cells, or tissues present within a subject. Examples of biological fluids include blood, serum and serosal fluids, plasma, cerebrospinal fluid, ocular fluids, lymph, urine, saliva, and the like. Tissue samples may include samples from tissues, organs, or localized regions. For example, samples may be derived from particular organs, parts of organs, or fluids or cells within those organs. In certain embodiments, samples may be derived from the kidney (e.g., whole kidney or certain segments of kidney or certain types of cells in the kidney, such as, e.g., proximal tubular epithelial cells, podocytes, etc.). In some embodiments, a “sample derived from a subject” refers to urine obtained from the subject. A “sample derived from a subject” can refer to blood or blood derived serum or plasma from the subject.

[0146] As used herein, the term “SLC6A19” refers to a gene encoding a system B° transmembrane protein that actively transports most neutral amino acids across the apical membrane of epithelial cells, as well as the B°AT1 proteins encoded by that gene. The human SLC6A19 gene region covers approximately 25 kb. The SLC6A19 transcript contains 12 exons, and at least one mRNA isoform (XM_054352501.1) has been identified or otherwise predicted as produced. Nucleotide and amino acid sequences of SLC6A19 may be found, for example, at GenBank Accession No. NM_001003841.3, noting that SLC6A19 variants (abbreviated elsewhere herein to " NM 1003841.3"), including a predicted transcript variant XI found, e.g., at accession number - 68 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOXM_054352501.1, have also been described. XM_045393498.1 is further noted as the \4acaca fascicularis SLC6A19 reference sequence.

[0147] As used herein, the term “SLC6A19-associated disease” or “SLC6A19-associated disease” is a disease, disorder, or a condition that is caused by, or is associated with, unwanted or excessive SLC6A19 expression. The term " SLC6A19-associated disease” includes a disease, disorder or condition that may be treated or ameliorated by a reduction in SLC6A19 expression. The term SLC6A19-associated disease” includes metabolic disorders, including nephropathy and various other kidney diseases or conditions, such as glomerular disorders, renal tubular disorders, other renal disorders, inborn errors of metabolism, systemic metabolic disorders, disorders of the thyroid, disorders of the parathyroid, disorders of the inner ear, neurological disorders, viral infections, phenylketonuria (PKU) and related aminoacidopathies, etc.

[0148] As used herein, the term “specific” with reference to an agent having an activity is understood by those skilled in the art to mean that the agent discriminates between potential target entities or states. For example, an in some embodiments, an agent is said to bind “specifically” to its target if it binds preferentially with that target in the presence of one or more competing alternative targets. In many embodiments, specific interaction is dependent upon the presence of a particular structural feature of the target entity (e.g., an epitope, a cleft, a binding site). It is to be understood that specificity need not be absolute. In some embodiments, specificity may be evaluated relative to that of the binding agent for one or more other potential target entities (e.g., competitors). In some embodiments, specificity is evaluated relative to that of a reference specific binding agent. In some embodiments specificity is evaluated relative to that of a reference nonspecific binding agent. In some embodiments, the agent or entity does not detectably bind to the competing alternative target under conditions of binding to its target entity. In some embodiments, binding agent binds with higher on-rate, lower off-rate, increased affinity, decreased dissociation, and / or increased stability to its target entity as compared with the competing alternative target(s).

[0149] As used herein, the term “specific binding” refers to an ability to discriminate between possible binding partners in the environment in which binding is to occur. A binding agent that interacts with one particular target when other potential targets are present is said to “bind specifically” to the target with which it interacts. In some embodiments, specific binding is assessed by detecting or determining degree of association between the binding agent and its partner; in some embodiments, specific binding is assessed by detecting or determining degree of - 69 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOdissociation of a binding agent-partner complex; in some embodiments, specific binding is assessed by detecting or determining ability of the binding agent to compete an alternative interaction between its partner and another entity. In some embodiments, specific binding is assessed by performing such detections or determinations across a range of concentrations.[01501 As used herein, “specificity” is a measure of the ability of a particular ligand to distinguish its binding partner from other potential binding partners.

[0151] As used herein, the term “subject” refers to an organism, for example, a mammal (e.g., a human, a non-human mammal, a non-human primate, a primate, a laboratory animal, a mouse, a rat, a hamster, a gerbil, a cat, a dog). In some embodiments, a human subject is an adult, adolescent, or pediatric subject. In some embodiments, a subject is suffering from a disease, disorder or condition, e.g., a disease, disorder or condition that can be treated as provided herein. In some embodiments, a subject is susceptible to a disease, disorder, or condition; in some embodiments, a susceptible subject is predisposed to and / or shows an increased risk (as compared to the average risk observed in a reference subject or population) of developing the disease, disorder or condition. In some embodiments, a subject displays one or more symptoms of a disease, disorder or condition. In some embodiments, a subject does not display a particular symptom (e.g., clinical manifestation of disease) or characteristic of a disease, disorder, or condition. In some embodiments, a subject does not display any symptom or characteristic of a disease, disorder, or condition. In some embodiments, a subject is a patient. In some embodiments, a subject is an individual to whom diagnosis and / or therapy is and / or has been administered.

[0152] As used herein, the term “targeting moiety” as used herein, refers to a moiety that, when contacted with a system that includes one or more target cells of interest (e.g., in culture, in a tissue, and / or in an organism) binds specifically with such target cells. In many embodiments, a targeting moiety binds to a cell surface factor (e g., to a factor that is preferentially or specifically found on surface(s) of such target cells of interest). In some embodiments, binding of a targeting moiety to a cell surface factor results in internalization of a targeting moiety. Typically, a targeting moiety useful in accordance with the present disclosure retains its specific binding character when included in a conjugate agent as described herein; in some embodiments, binding of such a conjugate agent to a relevant cell surface factor results in internalization of a conjugate agent. In some embodiments, a targeting moiety binds specifically to a factor on the surface of kidney cells.- 70 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOIn some embodiments, a targeting moiety binds specifically to Cubilin. In some embodiments, a targeting moiety binds specifically to Megalin.

[0153] As used herein, the terms “target nucleic acid,” “nucleic acid molecule encoding SLC6A19,” and “nucleic acid molecule encoding B°AT1” encompass RNA (including pre-mRNA and mRNA or portions thereof) transcribed from DNA encoding SLC6A 19 and / or B°AT1, and also cDNA derived from such RNA. In a preferred embodiment, the target nucleic acid is an mRNA encoding for human B°AT1.

[0154] As used herein, the term “target region” of a RNA refers either to: (1) for an ASO-targeted RNA, the sequence within the ASO-targeted RNA that is complementary to the ASO sequence or (2) for an RNAi agent -targeted RNA, the sequence within the RNAi agent-targeted RNA that is complementary to the antisense strand of the RNAi agent.

[0155] As used herein, the term "target RNA-associated disease” is a disease, disorder or a condition that is caused by, or is associated with, unwanted or excessive target RNA levels and / or expression. The term "target RNA-associated disease” includes a disease, disorder or condition that may be treated or ameliorated by a reduction in target RNA expression. The term "target RNA-associated disease” includes metabolic disorders, including nephropathy and various other kidney diseases or conditions, such as glomerular disorders, renal tubular disorders, other renal disorders, inborn errors of metabolism, systemic metabolic disorders, disorders of the thyroid, disorders of the parathyroid, disorders of the inner ear, neurological disorders, viral infections, phenylketonuria (PKU) and related aminoacidopathies, etc.

[0156] As used herein, “therapeutically effective amount” is intended to include the amount of a modulatory nucleic acid agent that, when administered to a subject having a SLC6A19-associated disease, is sufficient to effect treatment of the disease (e.g., by diminishing, ameliorating, or maintaining the existing disease or one or more symptoms of disease). The "therapeutically effective amount" may vary depending on the modulatory nucleic acid agent, how the agent is administered, the disease and its severity and the history, age, weight, family history, genetic makeup, the types of preceding or concomitant treatments, if any, and other individual characteristics of the subject to be treated. “Prophylactically effective amount,” as used herein, is intended to include the amount of a modulatory nucleic acid agent that, when administered to a subject having a SLC6A19-associated disorder, is sufficient to prevent or ameliorate the disease or one or more symptoms of the disease. Ameliorating the disease includes slowing the course of - 71 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOthe disease or reducing the severity of later-developing disease. The "prophylactically effective amount" may vary depending on the modulatory nucleic acid agent, how the agent is administered, the degree of risk of disease, and the history, age, weight, family history, genetic makeup, the types of preceding or concomitant treatments, if any, and other individual characteristics of the patient to be treated.

[0157] A “therapeutically effective amount” or “prophylactically effective amount” also includes an amount of a modulatory nucleic acid agent that produces some desired effect at a reasonable benefit / risk ratio applicable to any treatment. The iRNA employed in the methods of the present disclosure may be administered in a sufficient amount to produce a reasonable benefit / risk ratio applicable to such treatment.

[0158] As used herein, the term “treating” or “treatment” refers to a beneficial or desired result, such as reducing at least one sign or symptom of a SLC6A19-associated disorder in a subject. Treatment also includes a reduction of one or more sign or symptoms associated with unwanted SLC6A19 and / or B°AT1 expression; diminishing the extent of unwanted SLC6A19 and / or B°AT1 activation or stabilization; amelioration or palliation of unwanted SLC6A19 and / or B°AT1 activation or stabilization. “Treatment” can also mean prolonging survival as compared to expected survival in the absence of treatment. The term “lower” in the context of the level of SLC6A19 and / or B°AT1 in a subject or a disease marker or symptom refers to a statistically significant decrease in such level. The decrease can be, for example, at least 10%, 15%, 20%, 25%, 30%, %, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more. In certain embodiments, a decrease is at least 20%. In certain embodiments, the decrease is at least 50% in a disease marker, e.g., protein or gene expression level. “Lower” in the context of the level of SLC6A19 and / or B°AT1 in a subject is preferably down to a level accepted as within the range of normal for an individual without such disorder. In certain embodiments, “lower” is the decrease in the difference between the level of a marker or symptom for a subject suffering from a disease and a level accepted within the range of normal for an individual, e.g., the level of decrease in bodyweight between an obese individual and an individual having a weight accepted within the range of normal.

[0159] As used herein, the term “variant” refers to a molecule or entity (e.g., that are or comprise a nucleic acid, protein, or small molecule) that shows significant structural identity with a reference molecule or entity but differs structurally from the reference molecule or entity, e.g., in the - 72 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOpresence or absence or in the level of one or more chemical moi eties as compared to the reference molecule or entity. In some embodiments, a “variant” may be referred to as a “derivative” or “analog.” In some embodiments, a variant differs functionally from its reference molecule or entity. In many embodiments, whether a particular molecule or entity is properly considered to be a “variant” of a reference is based on its degree of structural identity with the reference molecule. As will be appreciated by those skilled in the art, a biological or chemical reference molecule in typically characterized by certain characteristic structural elements. A variant, by definition, is a distinct molecule or entity that shares one or more such characteristic structural elements but differs in at least one aspect from the reference molecule or entity. To give but a few examples, a polypeptide may have a characteristic sequence element comprised of a plurality of amino acids having designated positions relative to one another in linear or three-dimensional space and / or contributing to a particular structural motif and / or biological function; a nucleic acid may have a characteristic sequence element comprised of a plurality of nucleotide residues having designated positions relative to on another in linear or three-dimensional space. In some embodiments, a variant polypeptide or nucleic acid may differ from a reference polypeptide or nucleic acid as a result of one or more differences in amino acid or nucleotide sequence and / or one or more differences in chemical moi eties (e.g., carbohydrates, lipids, phosphate groups) that are covalently components of the polypeptide or nucleic acid (e.g., that are attached to the polypeptide or nucleic acid backbone). In some embodiments, a variant polypeptide or nucleic acid shows an overall sequence identity with a reference polypeptide or nucleic acid that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, or 99%. In some embodiments, a variant polypeptide or nucleic acid does not share at least one characteristic sequence element with a reference polypeptide or nucleic acid. In some embodiments, a reference polypeptide or nucleic acid has one or more biological activities. In some embodiments, a variant polypeptide or nucleic acid shares one or more of the biological activities of the reference polypeptide or nucleic acid. In some embodiments, a variant polypeptide or nucleic acid lacks one or more of the biological activities of the reference polypeptide or nucleic acid. In some embodiments, a variant polypeptide or nucleic acid shows a reduced level of one or more biological activities as compared to the reference polypeptide or nucleic acid. In some embodiments, a polypeptide or nucleic acid of interest is considered to be a “variant” of a reference polypeptide or nucleic acid if it has an amino acid or nucleotide sequence that is identical to that of the reference but for a small number of - 73 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOsequence alterations at particular positions. Typically, fewer than about 20%, about 15%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, or about 2% of the residues in a variant are substituted, inserted, or deleted, as compared to the reference. In some embodiments, a variant polypeptide or nucleic acid comprises about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, or about 1 substituted residues as compared to a reference. Often, a variant polypeptide or nucleic acid comprises a very small number (e.g., fewer than about 5, about 4, about 3, about 2, or about 1) number of substituted, inserted, or deleted, functional residues (i.e., residues that participate in a particular biological activity) relative to the reference. In some embodiments, a variant polypeptide or nucleic acid comprises not more than about 5, about 4, about 3, about 2, or about 1 addition or deletion, and, in some embodiments, comprises no additions or deletions, as compared to the reference. In some embodiments, a variant polypeptide or nucleic acid comprises fewer than about 25, about 20, about 19, about 18, about 17, about 16, about 15, about 14, about 13, about 10, about 9, about 8, about 7, about 6, and commonly fewer than about 5, about 4, about 3, or about 2 additions or deletions as compared to the reference. In some embodiments, a reference polypeptide or nucleic acid is one found in nature. In some embodiments, a reference polypeptide or nucleic acid is a human polypeptide or nucleic acid.Chemical Definitions

[0160] In the event of a conflict between a chemical structure and a chemical name, the chemical structure takes precedence.

[0161] As used herein, the definition of each expression, e.g., alkyl, m, p, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

[0162] As used herein, the term “aminoglycoside” refers to a compound having a core structure that comprises 2-deoxystreptamine:HOc <y ''OHOHIt will be understood that 2-deoxystreptamine can be attached to other moieties via any available position, as valency rules permit. For example, gentamicin (as specifically exemplified herein) is- 74 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOa compound that comprises a 2-deoxystreptamine core. Various other examples of aminoglycosides, including derivatives thereof, are disclosed herein.

[0163] As used herein, the term “linker,” “linkage,” and “spacer” are used interchangeably and refer to an organic moiety that connects two parts of a compound, e.g., covalently attaches two parts of a compound. Linkers typically comprise a direct bond or an atom such as oxygen or sulfur, a unit such as NH, C(O), C(O)NH, SO, SO2, SO2NH or a chain of atoms, such as substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl, alkylheteroaiylalkenyl, alkylheteroarylalkynyl, alkenylheteroaiylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl, alkynylheteroarylalkyl alkynylheteroarylalkenyl, alkynylheteroarylalkynyl, alky lheterocyclyl alkyl alkylheterocyclylalkenyl, alkylhererocyclylalkynyl, alkenylheterocyclylalkyl alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl, alkynylhereroaryl, where one or more methylenes can be interrupted or terminated by O, S, S(O), SO2, NH, C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic.

[0164] In certain embodiments, a linker may be a covalent bond that connects two groups or a chain of between 1 and 100 atoms in length, for example a chain of 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20 or more carbon atoms in length, where the linker may be linear, branched, cyclic or a single atom. In some cases, the linker is a branched linker that refers to a linking moiety that connects three or more groups. In certain cases, one, two, three, four or five or more carbon atoms of a linker backbone may be optionally substituted with a sulfur, nitrogen or oxygen heteroatom. In some cases, the linker backbone includes a linking functional group, such as an ether, thioether, amino, amide, sulfonamide, carbamate, thiocarbamate, urea, thiourea, ester, thioester or imine. The bonds between backbone atoms may be saturated or unsaturated, and in some cases not more than one, two, or three unsaturated bonds are present in a linker backbone. The linker may include one or more substituent groups, for example with an alkyl, aryl or alkenyl group. A linker may -75 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOinclude, without limitations, polyethylene glycol; ethers, thioethers, tertiary amines, alkyls, which may be straight or branched, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1 -dimethylethyl (t-butyl), and the like. The linker backbone may include a cyclic group, for example, an aryl, a heterocycle or a cycloalkyl group, where 2 or more atoms, e.g., 2, 3, or 4 atoms, of the cyclic group are included in the backbone. A linker may be cleavable or non-cleavable. In some cases, the linker is a branched linker, such as a branched linker as described herein (e.g., a linker that branches to allow for multi-valent targeting moiety, multi-valent payload moiety, or both, within a single conjugate).

[0165] Certain compositions of the disclosure provide compounds having aliphatic hydrocarbons. An aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below.

[0166] A straight aliphatic chain is limited to unbranched carbon chain moieties. As used herein, the term “aliphatic group” refers to a straight chain, branched-chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group.

[0167] As used herein, “alkyl” refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the number of carbon atoms specified, or up to 30 carbon atoms if no specification is made. For example, alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those moieties which are positional isomers of these moieties. Alkyl of 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl and tetracosyl. In certain embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), and optionally 20 or fewer. Alkyl groups may be substituted or unsubstituted.

[0168] As used herein, “alkylene” refers to an alkyl group having the specified number of carbons, for example from 2 to 12 carbon atoms, that contains two points of attachment to the rest of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene -(CH2)-, ethylene -(CH2CH2)-, n-propylene (CH2CH2CH2)-, isopropylene -(CH2CH(CH3))-, and the like. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents.

[0169] As used herein, “alkenyl” refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having the number of carbon atoms specified, or up to 26 carbon -76 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOatoms if no limitation on the number of carbon atoms is specified; and having one or more double bonds in the moiety. Alkenyl of 6 to 26 carbon atoms is exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosoenyl, docosenyl, tricosenyl, and tetracosenyl, in their various isomeric forms, where the unsaturated bond(s) can be located anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s).

[0170] As used herein, “alkynyl” refers to hydrocarbyl moieties of the scope of alkenyl, but having one or more triple bonds in the moiety.

[0171] Unless the number of carbons is otherwise specified, “lower alkyl,” as used herein, means an alkyl group, as defined above, but having from one to ten carbons, optionally from one to six carbon atoms in its backbone structure such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Throughout the disclosure, certain alkyl groups are lower alkyls. In certain embodiments, a substituent designated herein as alkyl is a lower alkyl.

[0172] As used herein, “aryl” includes 3- to 12-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon (z.e., carbocyclic aryl) or where one or more atoms are heteroatoms (z.e., heteroaryl). Optionally, aryl groups include 5- to 12-membered rings, optionally 6- to 10-membered rings. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Exemplary aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. Aryl can be monocyclic, bicyclic, or polycyclic.

[0173] As used herein, “cycloalkyl” refers to monocyclic, bicyclic, bridged, spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Certain cycloalkyls have from 3-10 carbon atoms in the ring structure, and optionally have 3-6 carbons in the ring structure. Cycloalkyl groups may be substituted or unsubstituted.

[0174] As used herein, “heteroalkyl” refers to an alkyl moiety as hereinbefore defined which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms.- 77 - IPTS / 200358788.1Attorney Docket No. JUDO-005WO

[0175] As used herein, “heteroaryl” includes substituted or unsubstituted aromatic 3- to 12-membered ring structures, optionally 5- to 12-membered rings, optionally 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Heteroaryl can be monocyclic, bicyclic, or polycyclic.

[0176] As used herein, the term “heterocyclyl” or “heterocyclic group” refers to 3- to 12-membered ring structures, optionally 5- to 12-membered rings, optionally 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, and the like.

[0177] As used herein, the term “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human subjects and animal subjects without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0178] As used herein, the term “pharmaceutically acceptable carrier” refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject -78 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOcompound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject being treated. Such carriers are known in the art. Pharmaceutically acceptable carriers include carriers for administration by injection.

[0179] As used herein, “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.

[0180] The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. In certain embodiments, the substituents on substituted alkyls are selected from Ci-6 alkyl, C3-6 cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In certain embodiments, the substituents on substituted alkyls are selected from fluoro, carbonyl, cyano, or hydroxyl. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants.Compounds- 79 - IPTS / 200358788.1Attorney Docket No. JUDO-005WO

[0181] Disclosed herein, inter alia, are compounds comprising a targeting moiety (e.g., an aminoglycoside or a variant or derivative thereof, a glucosamine or a variant or derivative thereof, or other targeting moieties disclosed herein) and a payload moiety. In some embodiments, the compound comprises one payload moiety and one or more targeting moieties. In some embodiments, a compound comprises one or more payload moieties and one targeting moiety. In some embodiments, the compound comprises one or more payload moieties and one or more targeting moieties.

[0182] In some embodiments, the compound further comprises a linker. In some embodiments, the linker links the targeting moiety and the payload moiety. In some embodiments, the targeting moiety specifically binds to a target protein. In some embodiments, the target protein is a cell surface factor on target cells of interest (e.g., kidney cells). In some embodiments, the payload moiety is or comprises a nucleic acid agent. In some embodiments, a payload moiety is or comprises a therapeutic agent (e.g., a therapeutic oligonucleotide).

[0183] In some embodiments, compounds of the disclosure have a structure represented by the following formula: (Bnl - Ln2 - An3), wherein B is a targeting moiety and nl is an integer (i.e., 1 or greater, typically less than 6); L is a linker (optionally a branched linker, e.g., to allow for conjugate structures that include multiple targeting moieties associated with one or more payload moieties within a single structure) and n2 is 0 or an integer (i.e., 1 or greater, typically less than 6); and A is a modulatory nucleic acid and n3 is an integer (i.e., 1 or greater, typically less than 6). In some embodiments, n2 = nl and / or n2 = n3. In some embodiments, nl and / or n3 is / are 1. In some embodiments, a provided compound has a structure represented by the formula (B-L-A). In some embodiments, a provided compound has a structure represented by a formula of: (B-L)n-A, wherein n is an integer greater than 1, and the compound comprises more than one targeting moiety. In some embodiments, a provided compound has structure represented by a formula of: B-(L-A)n, wherein n is an integer greater than 1, and the compound comprises more than one modulatory nucleic acid.

[0184] In some embodiments, provided compounds may be particularly useful or effective for the delivery of nucleic acid agents to kidney cells and / or to other cells that express or otherwise comprise a surface factor (e.g., Megalin or Cubilin) specifically bound by a targeting moiety as described herein.- 80 - IPTS / 200358788.1Attorney Docket No. JUDO-005WO

[0185] Without wishing to be bound by theory, certain embodiments of the present disclosure provide for binding of a targeting moiety linked to a modulatory nucleic acid to a cell surface factor present on the surface of a relevant (e.g., kidney) cell, e.g., of a tissue, to achieve internalization of the cell surface factor, along with the bound targeting moiety (as part of a compound described herein that includes the modulatory nucleic acid). In some embodiments, such internalization may mean that the relevant cell surface factor is no longer (at least for a period of time) available at the surface of the cell, e.g., of a tissue, for, e.g., signaling and / or binding to a ligand.

[0186] In some embodiments, a kidney cell surface factor is present on, e.g., can be detected on, a surface of a tissue associated with a kidney, e.g., a tissue that is part of or can be found in a kidney, e.g., during development, during tissue homeostasis, and / or in the course of a disease or disorder. In some embodiments, a kidney cell surface factor is present on, e.g., can be detected on, a proximal tubule epithelial cell and / or a podocyte. In some embodiments, an internalized compound or a portion thereof (e.g., a payload moiety comprised in the compound) is delivered to a vesicle in a cell (e.g., a lysosome, an endosome, a clathrin coated pit, or an intracellular membranous organelle, or any combination thereof). In some embodiments, an internalized compound or a portion thereof (e.g., a payload moiety comprised in the compound) is delivered to a compartment in a cell, e.g., a cytoplasm, a mitochondria, a ribosome, a nucleus, a nucleolus, or any other compartment in a cell, or any combination thereof.

[0187] In some embodiments, an internalized compound or a portion thereof (e g., a payload moiety comprised in the compound) in a cell (e.g., in a vesicle or a compartment in a cell) can reduce the expression and / or activity of a target of a payload moiety. In some embodiments, an internalized compound or a portion thereof (e.g., a modulatory nucleic acid comprised in the compound) in a cell (e.g., in a vesicle or a compartment in a cell) can reduce the expression and / or activity of a target of the modulatory nucleic acid.

[0188] In some embodiments, internalization of a compound or a portion thereof (e.g., a payload moiety) into a cell (e.g., into a vesicle or a compartment in a cell) uncouples, e.g., separates, a targeting moiety from a payload moiety. In some embodiments, internalization of a compound or a portion thereof (e.g., a modulatory nucleic acid comprised in the compound) into a cell (e.g., into a vesicle or a compartment in a cell) uncouples, e.g., separates, a targeting moiety from a modulatory nucleic acid.- 81 - IPTS / 200358788.1Attorney Docket No. JUDO-005WO

[0189] In some embodiments, a targeting moiety is uncoupled, e.g., separated, from a payload moiety by a chemical reaction and / or mechanical separation. In some embodiments, a targeting moiety is uncoupled, e.g., separated, from a modulatory nucleic acid by a chemical reaction and / or mechanical separation. In some embodiments, a chemical reaction comprises an enzymatic reaction to cleave a linker linking a targeting moiety to a modulatory nucleic acid.

[0190] In some embodiments, a compound disclosed herein can be filtered by a glomerular capillary, e.g., into a Bowman’s capsule. In some embodiments, a compound disclosed herein has a size, charge, conformation, and / or other properties that allows it to be filtered by a glomerular capillary. In some embodiments, a threshold for glomerular filtration is in the range of 30-50 kDa.I. Target Proteins

[0191] In various embodiments, target proteins of the present disclosure are cell surface factors. In some embodiments, a cell surface factor is preferentially present on the surface of target cell(s) as compared with cells of one or more other tissues. In some embodiments, the target cell(s) is kidney cell(s). In some embodiments, a cell surface factor is present on certain non-target cells in addition to target cells. In some embodiments, a cell surface factor is not preferentially or specifically present on relevant target cells of interest. In some embodiments, a cell surface factor is internalized when bound by one or more particular ligands (e.g., a targeting moiety as described herein). In some embodiments, a cell surface factor may interact with (e.g., bind to, form a complex with, etc.) one or more other components of a cell (e.g., with one or more cell membrane components and / or one or more cell surface components and / or one or more cell-internal components) on whose surface it is found. In some embodiments, a cell surface factor, and / or a particular form or variant thereof, may be associated with a particular cell state or condition (e.g., stage of development, disease state, etc.).

[0192] In some embodiments, a cell surface factor is or comprises a polypeptide which is present (e.g., can be detected on) on a surface of a cell, e.g., of a tissue. In some embodiments, a cell surface factor is present on (e.g., can be detected on) a surface of a cell expressing Megalin, e.g., as described herein. In some embodiments, a cell surface factor is or comprises a receptor.

[0193] In some embodiments, a cell surface factor is or comprises a kidney cell surface factor. In some embodiments, a kidney cell surface factor is present on (e.g., can be detected on) a surface of a cell associated with a kidney, e.g., a cell that is or can be found in a kidney, e g., during - 82 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOdevelopment, during tissue homeostasis, or in the course of a disease or disorder. In some embodiments, a kidney cell surface factor is present on, e.g., can be detected on, a proximal tubule epithelial cell, a podocyte and / or a kidney cyst cell.

[0194] In some embodiments, a kidney cell surface factor is present on, e.g., can be detected on, a surface of a tissue associated with a kidney, e.g., a tissue that is part of or can be found in a kidney, e.g., during development, during tissue homeostasis, and / or in the course of a disease or disorder.

[0195] In some embodiments, a kidney cell surface factor is or comprises a receptor which is present, e.g., can be detected on, a surface of a cell, e.g., a cell associated with a kidney as described herein, or a tissue associated with a kidney as described herein.

[0196] In some embodiments, a kidney cell surface factor can bind to one or more co-receptors on the surface of a cell, e.g., of a tissue. In some embodiments, a kidney cell surface factor can be internalized upon binding of a kidney-specific targeting moiety (e.g., comprised in a provided compound) to a kidney cell surface factor. In some embodiments, internalization of a kidney cell surface factor as a result of binding to a kidney-specific targeting moiety comprised in a provided compound also internalizes the compound or a portion thereof (e.g., a comprised payload moiety) into a cell. In some embodiments, an internalized compound or a portion thereof (e.g., a comprised payload moiety) is delivered to a vesicle in a cell (e.g., a lysosome, an endosome, a clathrin coated pit, or an intracellular membranous organelle, or a combination thereof). In some embodiments, an internalized compound or a portion thereof (e.g., a comprised payload moiety) is delivered to a compartment in a cell, e.g., a cytoplasm, a mitochondrion, a ribosome, a nucleus, a nucleolus, or any other compartment in a cell, or a combination thereof.

[0197] In some embodiments, a cell surface factor (e.g., a kidney cell surface factor) is or comprises a receptor chosen from Megalin, Cubilin, or both.a. Megalin

[0198] In some embodiments, a targeted kidney cell surface factor for delivery of a targeting moiety-associated modulatory nucleic acid agent of the instant disclosure is Megalin, or a fragment, or a variant thereof.

[0199] Megalin is a receptor of about 600kDa (about 4655 amino acids) and belongs to the low-density lipoprotein receptor family (as disclosed in Nielsen R. et al. (2016), Kidney Int. 89(1): 58- - 83 - IPTS / 200358788.1Attorney Docket No. JUDO-005WO67). Megalin is also known as LDL Receptor Related Protein 2 (LRP2), Glycoprotein 330 (Gp33O), Calcium Sensor Protein, or Heymann Nephritis Antigen Homolog.

[0200] Human Megalin protein sequence:MDRGPAAVACTLLLALVACLAPASGQECDSAHFRCGSGHCIPADWRCDGTKDCSDDADEIGCAV VTCQQGYFKCQSEGQCIPNSWVCDQDQDCDDGSDERQDCSQSTCSSHQITCSNGQCIPSEYRCD HVRDCPDGADENDCQYPTCEQLTCDNGACYNTSQKCDWKVDCRDSSDEINCTEICLHNEFSCGN GECIPRAYVCDHDNDCQDGSDEHACNYPTCGGYQFTCPSGRCIYQNWVCDGEDDCKDNGDEDGC ESGPHDVHKCSPREWSCPESGRCISIYKVCDGILDCPGREDENNTSTGKYCSMTLCSALNCQYQ CHETPYGGACFCPPGYI INHNDSRTCVEFDDCQIWGICDQKCESRPGRHLCHCEEGYILERGQY CKANDS FGEAS 11 FSNGRDLL I GD I HGRS FRI LVE S QNRGVAVGVAFHYHLQRVFWTDTVQNKV FSVDINGLNIQEVLNVSVETPENLAVDWVNNKIYLVETKVNRIDMVNLDGSYRVTLITENLGHP RGIAVDPTVGYLFFSDWESLSGEPKLERAFMDGSNRKDLVKTKLGWPAGVTLDMISKRVYWVDS RFDYIETVTYDGIQRKTWHGGSLIPHPFGVSLFEGQVFFTDWTKMAVLKANKFTETNPQVYYQ ASLRPYGVTVYHSLRQPYATNPCKDNNGGCEQVCVLSHRTDNDGLGFRCKCTFGFQLDTDERHC IAVQNFLIFSSQVAIRGIPFTLSTQEDVMVPVSGNPSFFVGIDFDAQDSTIFFSDMSKHMIFKQ KIDGTGREILAANRVENVESLAFDWISKNLYWTDSHYKSISVMRLADKTRRTWQYLNNPRSW VHPFAGYLFFTDWFRPAKIMRAWSDGSHLLPVINTTLGWPNGLAIDWAASRLYWVDAYFDKIEH STFDGLDRRRLGHIEQMTHPFGLAI FGEHLFFTDWRLGAI IRVRKADGGEMTVIRSGIAYILHL KSYDVNIQTGSNACNQPTHPNGDCSHFCFPVPNFQRVCGCPYGMRLASNHLTCEGDPTNEPPTE QCGLFSFPCKNGRCVPNYYLCDGVDDCHDNSDEQLCGTLNNTCSSSAFTCGHGECIPAHWRCDK RNDCVDGSDEHNCPTHAPASCLDTQYTCDNHQCISKNWVCDTDNDCGDGSDEKNCNSTETCQPS QFNCPNHRCIDLSFVCDGDKDCVDGSDEVGCVLNCTASQFKCASGDKCIGVTNRCDGVFDCSDN SDEAGCPTRPPGMCHSDEFQCQEDGICIPNFWECDGHPDCLYGSDEHNACVPKTCPSSYFHCDN GNCIHRAWLCDRDNDCGDMSDEKDCPTQPFRCPSWQWQCLGHNICVNLSWCDGIFDCPNGTDE SPLCNGNSCSDFNGGCTHECVQEPFGAKCLCPLGFLLANDSKTCEDIDECDILGSCSQHCYNMR GSFRCSCDTGYMLESDGRTCKVTASESLLLLVASQNKIIADSVTSQVHNIYSLVENGSYIVAVD FDSISGRIFWSDATQGKTWSAFQNGTDRRWFDSSIILTETIAIDWVGRNLYWTDYALETIEVS KIDGSHRTVLISKNLTNPRGLALDPRMNEHLLFWSDWGHHPRIERASMDGSMRTVIVQDKIFWP CGLTIDYPNRLLYFMDSYLDYMDFCDYNGHHRRQVIASDLI IRHPYALTLFEDSVYWTDRATRR VMRANKWHGGNQSWMYNIQWPLGIVAVHPSKQPNSVNPCAFSRCSHLCLLSSQGPHFYSCVCP SGWSLSPDLLNCLRDDQPFLITVRQHIIFGISLNPEVKSNDAMVPIAGIQNGLDVEFDDAEQYI YWVENPGEIHRVKTDGTNRTVFASISMVGPSMNLALDWISRNLYSTNPRTQSIEVLTLHGDIRY RKTLIANDGTALGVGFPIGITVDPARGKLYWSDQGTDSGVPAKIASANMDGTSVKTLFTGNLEH LECVTLDIEEQKLYWAVTGRGVIERGNVDGTDRMILVHQLSHPWGIAVHDSFLYYTDEQYEVIE RVDKATGANKIVLRDNVPNLRGLQVYHRRNAAESSNGCSNNMNACQQICLPVPGGLFSCACATG FKLNPDNRSCSPYNSFIWSMLSAIRGFSLELSDHSETMVPVAGQGRNALHVDVDVSSGFIYWC DFSSSVASDNAIRRIKPDGSSLMNIVTHGIGENGVRGIAVDWVAGNLYFTNAFVSETLIEVLRI NTTYRRVLLKVTVDMPRHIWDPKNRYLFWADYGQRPKIERSFLDCTNRTVLVSEGIVTPRGLA VDRSDGYVYWVDDSLDIIARIRINGENSEVIRYGSRYPTPYGITVFENSIIWVDRNLKKIFQAS KEPENTEPPTVIRDNINWLRDVTIFDKQVQPRSPAEVNNNPCLENNGGCSHLCFALPGLHTPKC DCAFGTLQSDGKNCAISTENFLIFALSNSLRSLHLDPENHSPPFQTINVERTVMSLDYDSVSDR IYFTQNLASGVGQISYATLSSGIHTPTVIASGIGTADGIAFDWITRRIYYSDYLNQMINSMAED GSNRTVIARVPKPRAIVLDPCQGYLYWADWDTHAKIERATLGGNFRVPIVNSSLVMPSGLTLDY EEDLLYWVDASLQRIERSTLTGVDREVIVNAAVHAFGLTLYGQYI YWTDLYTQRI YRANKYDGS GQIAMTTNLLSQPRGINTWKNQKQQCNNPCEQFNGGCSHICAPGPNGAECQCPHEGNWYLANN- 84 - IPTS / 200358788.1Attorney Docket No. JUDO-005WORKHCIVDNGERCGASSFTCSNGRCISEEWKCDNDNDCGDGSDEMESVCALHTCSPTAFTCANGR CVQYS YRCDYYNDCGDGS DEAGCL FRDCNAT TE FMCNNRRC I PRE FI CNGVDNCHDNNT SDEKN CPDRTCQSGYTKCHNSNICIPRVYLCDGDNDCGDNSDENPTYCTTHTCSSSEFQCASGRCIPQH WYCDQETDCFDASDEPASCGHSERTCLADEFKCDGGRCIPSEWICDGDNDCGDMSDEDKRHQCQ NQNCSDSEFLCVNDRPPDRRCIPQSWVCDGDVDCTDGYDENQNCTRRTCSENEFTCGYGLCIPK IFRCDRHNDCGDYSDERGCLYQTCQQNQFTCQNGRCISKTFVCDEDNDCGDGSDELMHLCHTPE PTCPPHEFKCDNGRCIEMMKLCNHLDDCLDNSDEKGCGINECHDPSISGCDHNCTDTLTSFYCS CRPGYKLMSDKRTCVDIDECTEMPFVCSQKCENVIGSYICKCAPGYLREPDGKTCRQNSNIEPY LIFSNRYYLRNLTIDGYFYSLILEGLDNWALDFDRVEKRLYWIDTQRQVIERMFLNKTNKETI INHRLPAAESLAVDWVSRKLYWLDARLDGLFVSDLNGGHRRMLAQHCVDANNTFCFDNPRGLAL HPQYGYLYWADWGHRAYIGRVGMDGTNKSVI ISTKLEWPNGITIDYTNDLLYWADAHLGYIEYS DLEGHHRHTVYDGALPHPFAITIFEDTIYWTDWNTRTVEKGNKYDGSNRQTLVNTTHRPFDIHV YHPYRQPIVSNPCGTNNGGCSHLCLIKPGGKGFTCECPDDFRTLQLSGSTYCMPMCSSTQFLCA NNEKCIPIWWKCDGQKDCSDGSDELALCPQRFCRLGQFQCSDGNCTSPQTLCNAHQNCPDGSDE DRLLCENHHCDSNEWQCANKRCIPESWQCDTFNDCEDNSDEDSSHCASRTCRPGQFRCANGRCI PQAWKCDVDNDCGDHSDEPIEECMSSAHLCDNFTEFSCKTNYRCIPKWAVCNGVDDCRDNSDEQ GCEERTCHPVGDFRCKNHHCIPLRWQCDGQNDCGDNSDEENCAPRECTESEFRCVNQQCIPSRW ICDHYNDCGDNSDERDCEMRTCHPEYFQCTSGHCVHSELKCDGSADCLDASDEADCPTRFPDGA YCQATMFECKNHVCIPPYWKCDGDDDCGDGSDEELHLCLDVPCNSPNRFRCDNNRCI YSHEVCN GVDDCGDGTDETEEHCRKPTPKPCTEYEYKCGNGHCIPHDNVCDDADDCGDWSDELGCNKGKER TCAENICEQNCTQLNEGGFICSCTAGFETNVFDRTSCLDINECEQFGTCPQHCRNTKGSYECVC ADGFTSMSDRPGKRCAAEGSSPLLLLPDNVRIRKYNLSSERFSEYLQDEEYIQAVDYDWDPKDI GLSWYYTVRGEGSRFGAIKRAYIPNFESGRNNLVQEVDLKLKYVMQPDGIAVDWVGRHIYWSD VKNKRIEVAKLDGRYRKWLISTDLDQPAAIAVNPKLGLMFWTDWGKEPKIESAWMNGEDRNILV FEDLGWPTGLSIDYLNNDRIYWSDFKEDVIETIKYDGTDRRVIAKEAMNPYSLDIFEDQLYWIS KEKGEVWKQNKFGQGKKEKTLWNPWLTQVRIFHQLRYNKSVPNLCKQICSHLCLLRPGGYSCA CPQGSSFIEGSTTECDAAIELPINLPPPCRCMHGGNCYFDETDLPKCKCPSGYTGKYCEMAFSK GISPGTTAVAVLLTILLIWIGALAIAGFFHYRRTGSLLPALPKLPSLSSLVKPSENGNGVTFR S GADLNMD I GVS GFGPE TAI DRSMAMSEDFVMEMGKQP I 1 FENPMYSARDSAVKWQP I QVTVS ENVDNKNYGSPINPSEIVPETNPTSPAADGTQVTKWNLFKRKSKQTTNFENPI YAQMENEQKES VAATPPPSPSLPAKPKPPSRRDPTPTYSATEDTFKDTANLVKEDSEV (SEQ ID NO: 5)

[0201] The extracellular domain of Megalin includes clusters of cysteine-rich complement-type repeats. The repeats are separated by beta-propeller domains comprising YWTD motifs and EGF-type repeats. Megalin has one transmembrane domain which positions it in parts of the cell membrane that includes cholesterol and / or glycosphingolipids. Megalin also has an intracellular C-terminal cytoplasmic domain which can regulate receptor trafficking and / or endocytosis. The cytoplasmic domain of Megalin comprises NPXY motifs and several other domains such as proline-rich sequences and PDZ motifs. Megalin’ s cytoplasmic domain has been linked to receptor internalization. A typical structure of Megalin is disclosed in Figure 1 of Marzolo and Farfan (2011), Biol Res 44: 89-105, the entire contents of which are hereby incorporated by reference.- 85 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOThe extracellular domain of Megalin may also include one or more post-translational modifications, such as glycosylation.

[0202] Megalin has been described to interact, at least in certain cases, with a co-receptor, Cubilin. Megalin has been identified on surfaces of one or more of the following tissues and / or cells: immune cells (e.g., bone marrow cells, lymph node cells, thymic cells, peripheral blood mononuclear cells [e.g., myeloid and / or lymphoid cells], erythrocytes, eosinophils, neutrophils, and / or platelets); nervous system (e.g., brain tissue, cortex, cerebellum, retinal cells, spinal cord cells, nerve cells, neurons, and / or supporting cells; endothelial cells; muscle (e.g., heart muscle, smooth muscle, and / or skeletal muscle); small intestine; colon; adipocytes; kidney; liver; lung; spleen; stomach; esophagus; bladder; pancreas; thyroid; salivary gland; adrenal gland; pituitary gland; breast; skin; ovary; uterus; placenta; prostate; and testis.. In kidney tissue, Megalin has been reported to be found on the surface of proximal tubular epithelial cells and podocytes. In proximal tubule epithelia cells of the kidney, Megalin expression has been observed in the brush border, in endocytic vesicles, dense apical tubules and / or lysosomes.b. Cubilin

[0203] In some embodiments, a kidney cell surface factor is Cubilin, or a fragment, or a variant thereof.

[0204] Cubilin is a receptor of about 460kDa. Cubilin is also known as IFCR, Gp280, Intrinsic Factor- Vitamin B12 Receptor, MGA1, or IGS1. As an extracellular protein, Cubilin can interact with other membrane proteins, e.g., Megalin. One of the functions of Cubilin is as a receptor for intrinsic factor-vitamin B12 complexes.

[0205] Human Cubilin protein sequence:MMNMSLPFLWSLLTLLI FAEVNGEAGELELQRQKRS INLQQPRMATERGNLVFLTGSAQNIEFR TGSLGKIKLNDEDLSECLHQIQKNKEDI IELKGSAIGLPQNISSQIYQLNSKLVDLERKFQGLQ QTVDKKVCSSNPCQNGGTCLNLHDSFFCICPPQWKGPLCSADVNECEIYSGTPLSCQNGGTCVN TMGSYSCHCPPETYGPQCASKYDDCEGGSVARCVHGICEDLMREQAGEPKYSCVCDAGWMFSPN SPACTLDRDECSFQPGPCSTLVQCFNTQGSFYCGACPTGWQGNGYICEDINECEINNGGCSVAP PVECVNTPGSSHCQACPPGYQGDGRVCTLTDICSVSNGGCHPDASCSSTLGSLPLCTCLPGYTG NGYGPNGCVQLSNICLSHPCLNGQCIDTVSGYFCKCDSGWTGVNCTENINECLSNPCLNGGTCV DGVDSFSCECTRLWTGALCQVPQQVCGESLSGINGSFSYRSPDVGYVHDVNCFWVIKTEMGKVL RITFTFFRLESMDNCPHEFLQVYDGDSSSAFQLGRFCGSSLPHELLSSDNALYFHLYSEHLRNG RGFTVRWETQQPECGGILTGPYGS IKSPGYPGNYPPGRDCVWIWTSPDLLVTFTFGTLSLEHH DDCNKDYLEIRDGPLYQDPLLGKFCTTFSVPPLQTTGPFARIHFHSDSQISDQGFHITYLTSPS DLRCGGNYTDPEGELFLPELSGPFTHTRQCVYMMKQPQGEQIQINFTHVELQCQSDSSQNYIEV- 86 - IPTS / 200358788.1Attorney Docket No. JUDO-005WORDGETLLGKVCGNGTISHIKSITNSVWIRFKIDASVEKASFRAVYQVACGDELTGEGVIRSPFF PNVYPGERTCRWTIHQPQSQVILLNFTVFEIGSSAHCETDYVEIGSSSILGSPENKKYCGTDIP SFITSVYNFLYVTFVKSSSTENHGFMAKFSAEDLACGEILTESTGTIQSPGHPNVYPHGINCTW HILVQPNHLIHLMFETFHLEFHYNCTNDYLEVYDTDSETSLGRYCGKS IPPSLTSSGNSLMLVF VTDSDLAYEGFLINYEAISAATACLQDYTDDLGTFTSPNFPNNYPNNWECIYRITVRTGQLIAV HFTNFSLEEAIGNYYTDFLEIRDGGYEKSPLLGIFYGSNLPPTIISHSNKLWLKFKSDQIDTRS GFSAYWDGSSTGCGGNLTTSSGTFISPNYPMPYYHSSECYWWLKSSHGSAFELEFKDFHLEHHP NCTLDYLAVYDGPSSNSHLLTQLCGDEKPPLIRSSGDSMFIKLRTDEGQQGRGFKAEYRQTCEN WIVNQTYGILESIGYPNPYSENQHCNWTIRATTGNTVNYTFLAFDLEHHINCSTDYLELYDGP RQMGRYCGVDLPPPGSTTSSKLQVLLLTDGVGRREKGFQMQWFVYGCGGELSGATGSFSSPGFP NRYPPNKECIWYIRTDPGSSIQLTIHDFDVEYHSRCNFDVLEIYGGPDFHSPRIAQLCTQRSPE NPMQVSSTGNELAIRFKTDLSINGRGFNASWQAVTGGCGGIFQAPSGEIHSPNYPSPYRSNTDC SWVIRVDRNHRVLLNFTDFDLEPQDSCIMAYDGLSSTMSRLARTCGREQLANPIVSSGNSLFLR FQSGPSRQNRGFRAQFRQACGGHILTSSFDTVSSPRFPANYPNNQNCSWIIQAQPPLNHITLSF THFELERSTTCARDFVEILDGGHEDAPLRGRYCGTDMPHPITSFSSALTLRFVSDSSISAGGFH TTVTASVSACGGTFYMAEGIFNSPGYPDIYPPNVECVWNIVSSPGNRLQLSFISFQLEDSQDCS RDFVEIREGNATGHLVGRYCGNSFPLNYSSIVGHTLWVRFISDGSGSGTGFQATFMKIFGNDNI VGTHGKVASPFWPENYPHNSNYQWTVNVNASHWHGRILEMDIEEIQNCYYDKLRIYDGPSIHA RLIGAYCGTQTESFSSTGNSLTFHFYSDSSISGKGFLLEWFAVDAPDGVLPTIAPGACGGFLRT GDAPVFLFSPGWPDSYSNRVDCTWLIQAPDSTVELNILSLDIESHRTCAYDSLVIRDGDNNLAQ QLAVLCGREIPGPIRSTGEYMFIRFTSDSSVTRAGFNASFHKSCGGYLHADRGI ITSPKYPETY PSNLNCSWHVLVQSGLTIAVHFEQPFQIPNGDSSCNQGDYLVLRNGPDICSPPLGPPGGNGHFC GSHASSTLFTSDNQMFVQFISDHSNEGQGFKIKYEAKSLACGGNVYIHDADSAGYVTSPNHPHN YPPHADCIWILAAPPETRIQLQFEDRFDIEVTPNCTSNYLELRDGVDSDAPILSKFCGTSLPSS QWSSGEVMYLRFRSDNSPTHVGFKAKYS IAQCGGRVPGQSGWES IGHPTLPYRDNLFCEWHLQ GLSGHYLTISFEDFNLQNSSGCEKDFVEIWDNHTSGNILGRYCGNTIPDSIDTSSNTAWRFVT DGSVTASGFRLRFESSMEECGGDLQGSIGTFTSPNYPNPNPHGRICEWRITAPEGRRITLMFNN LRLATHPSCNNEHVIVFNGIRSNSPQLEKLCSSVNVSNEIKSSGNTMKVIFFTDGSRPYGGFTA SYTSSEDAVCGGSLPNTPEGNFTSPGYDGVRNYSRNLNCEWTLSNPNQGNSSISIHFEDFYLES HQDCQFDVLEFRVGDADGPLMWRLCGPSKPTLPLVIPYSQVWIHFVTNERVEHIGFHAKYSFTD CGGIQIGDSGVITSPNYPNAYDSLTHCSSLLEAPQGHTITLTFSDFDIEPHTTCAWDSVTVRNG GSPESPIIGQYCGNSNPRTIQSGSNQLWTFNSDHSLQGGGFYATWNTQTLGCGGIFHSDNGTI RS PHWPQNFPENSRCSWTAI THKSKHLE I S FDNNFL I PSGDGQCQNS FVKVWAGTEEVDKALLA TGCGNVAPGPVITPSNTFTAVFQSQEAPAQGFSASFVSRCGSNFTGPSGYI ISPNYPKQYDNNM NCTYVIEANPLSWLLTFVSFHLEARSAVTGSCVNDGVHI IRGYSVMSTPFATVCGDEMPAPLT IAGPVLLNFYSNEQITDFGFKFSYRIISCGGVFNFSSGIITSPAYSYADYPNDMHCLYTITVSD DKVIELKFSDFDWPSTSCSHDYLAIYDGANTSDPLLGKFCGSKRPPNVKSSNNSMLLVFKTDS FQTAKGWKMSFRQTLGPQQGCGGYLTGSNNTFASPDSDSNGMYDKNLNCVWI I IAPVNKVIHLT FNTFALEAASTRQRCLYDYVKLYDGDSENANLAGTFCGSTVPAPFISSGNFLTVQFISDLTLER EGFNATYTIMDMPCGGTYNATWTPQNISSPNSSDPDVPFSICTWVIDSPPHQQVKITVWALQLT SQDCTQNYLQLQDSPQGHGNSRFQFCGRNASAVPVFYSSMSTAMVIFKSGWNRNSRMSFTYQI ADCNRDYHKAFGNLRSPGWPDNYDNDKDCTVTLTAPQNHTISLFFHSLGIENSVECRNDFLEVR NGSNSNSPLLGKYCGTLLPNPVFSQNNELYLRFKSDSVTSDRGYEI IWTSSPSGCGGTLYGDRG SFTSPGYPGTYPNNTYCEWVLVAPAGRLVTINFYFISIDDPGDCVQNYLTLYDGPNASSPSSGP YCGGDTS IAPFVASSNQVFIKFHADYARRPSAFRLTWDS (SEQ IDNO: 6)- 87 - IPTS / 200358788.1Attorney Docket No. JUDO-005WO

[0206] The extracellular domain of Cubilin includes repeats of CUB domains (complement Clr / Cls, Uegf [epidermal growth factor-related sea urchin protein], and bone morphogenic protein 1) and EGF-type repeats. A typical structure of Cubilin is disclosed in Figure 1 of Marzolo and Farfan (2011), Biol Res 44: 89-105, the entire contents of which are hereby incorporated by reference. The extracellular domain of Cubilin may also include one or more post-translational modifications, such as glycosylation.

[0207] Cubilin has been reported to be found on surfaces of one or more of the following tissues and / or cells: immune cells (e.g., bone marrow cells, lymph node cells, thymic cells, peripheral blood mononuclear cells [e.g., myeloid and / or lymphoid cells], erythrocytes, eosinophils, neutrophils, and / or platelets); nervous system (e.g., brain tissue, cortex, cerebellum, retinal cells, spinal cord cells, nerve cells, neurons, and / or supporting cells; endothelial cells; muscle (e.g., heart muscle, smooth muscle, and / or skeletal muscle); small intestine; colon; adipocytes; kidney; liver; lung; splenic; stomach; esophagus; bladder; pancreas; thyroid; salivary gland; adrenal gland; pituitary gland; breast; skin; ovary; uterus; placenta; prostate; and testis. In kidney tissue, Cubilin has been reported to be found on the surface of proximal tubular epithelial cells and podocytes.II. Targeting Moiety

[0208] Targeting moieties include any molecule or any part of a molecule that is capable of binding (e.g., capable of specifically binding) to a given target. Such molecules may be, but are not limited to, small molecules, aptamers, polypeptides or proteins, etc. In some embodiments, a targeting moiety of the present disclosure comprises a small molecule.

[0209] In some embodiments, a targeting moiety of the present disclosure is not a therapeutic moiety, i.e., the targeting moiety by itself does not confer a therapeutic benefit.

[0210] In some embodiments, targeting moieties disclosed herein are capable of binding to, e.g., selectively binding to, a surface factor (or a moiety or portion thereof, and / or to a particular form such as a disease-associated form thereof) present on surfaces of target cell(s) of interest (e.g., kidney cells). In some embodiments, the cell surface factor is a kidney cell surface factor. In some embodiments, the cell surface receptor is or comprises a receptor chosen from Megalin, Cubilin, or both.

[0211] Without wishing to be bound by theory, the present disclosure proposes that binding of a targeting moiety (e.g., gentamine, gentamicin, neamine, paromomycin, kanamycin, neomycin,- 88 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOetc., or other related compound) to a cell surface factor present on the surface of a relevant (e.g., kidney) cell, e.g., of a tissue, can achieve internalization of the cell surface factor, along with the bound targeting moiety (which may, for example, be part of a compound as described herein). In some embodiments, such internalization may mean that the relevant cell surface factor is no longer (at least for a period of time) available at the surface of the cell, e.g., of a tissue, for, e.g., signaling and / or binding to a ligand.

[0212] Among other things, the present disclosure provides an insight that triggering internalization of a surface factor may usefully achieve delivery of a targeting moiety (and / or an agent, such as a compound as described herein, that includes it), e.g., into an internal compartment such as a vesicle and / or an organelle, and / or the cytoplasm of the cell. The present disclosure further provides an insight that such internalization may be particularly useful for delivering a compound described herein and / or a portion thereof (e.g., a payload moiety thereof), into the cell. The present disclosure provides a specific insight that such internalization may be particularly useful for delivery of payload moieties (e.g., nucleic acid agents as described herein), including specifically in the context of a conjugate agent as described herein.

[0213] In some embodiments, at least 5% of a cell surface factor (for example, at least 10% of a cell surface factor, at least 20% of a cell surface factor, at least 30% of a cell surface factor, at least 40% of a cell surface factor, at least 50% of a cell surface factor, at least 60% of a cell surface factor, at least 75% of a cell surface factor, at least 90% of a cell surface factor, or at least 95% of a cell surface factor) is internalized upon binding to a targeting moiety. In some embodiments, substantially all or all of a cell surface factor is internalized upon binding to a targeting moiety.

[0214] In some embodiments, binding of a targeting moiety to a cell surface factor on the surface of a cell, e.g., of a tissue, does not internalize the cell surface factor.a. Aminoglycosides and Aminoglycoside-Related Targeting Moieties

[0215] In certain aspects, a targeting moiety of the present disclosure comprises or has an aminoglycoside or aminoglycoside-related structure, or other such compound.

[0216] Aminoglycosides comprise the following 2-deoxystreptamine core structure:2H2N NH2HO OHOH- 89 - IPTS / 200358788.1Attorney Docket No. JUDO-005WO

[0217] Among aminoglycosides, the total number of rings can vary from two to four. Rings I and II (2-deoxystreptamine) are the most common moieties of aminoglycosides, with different substitution patterns. The N1 and N3 amino groups of ring II are common to all aminoglycosides, as are hydrogen-bond donors at the 2’ and 6’ positions of ring I. The linkage of ring III to 2-deoxystreptamine can vary. In the neomycin class, including paromomycin, ring III is connected to position 5 of ring II (4,5-disubstituted ring II), whereas in the kanamycin class, including the gentamicins, ring III is linked to position 6 of ring II (4,6-disubstituted ring II). Rings III of the kanamycin class aminoglycosides share common chemical groups at the 2” and 3” positions.IPTS / 200358788.1Attorney Docket No. JUDO-005WO

[0218] Among the aminoglycosides (e.g., gentamine, gentamicin, neamine, paromomycin, kanamycin, neomycin, etc.), gentamicin was identified in the art to bind Megalin with low affinity, but can promote internalization of such compounds within the kidneys (Dagil R et al., (2013) Journal of Biological Chemistry, 288(6); 4424-4435). Certain aspects of the disclosure relate to identification and use of a genus of aminoglycoside compounds including and related to gentamine, gentamicin, neamine, paromomycin, kanamycin, neomycin, etc., as a targeting moiety for conjugation with a payload moiety (e.g., a modulatory nucleic acid), via a linker moiety.

[0219] In some embodiments, a targeting moiety is or comprises an aminoglycoside. In some embodiments, the aminoglycoside is selected from: streptomycin, neomycin, kanamycin, paromomycin, gentamicin, G-418 (geneticin), ELX-02, tobramycin, amikacin, netilmicin, spectinomycin, sisomicin, dibekacin, isepamicin, framycetin, paromomycin, apramycin, fradiomycin, arbekacin, and plazomicin, or a derivative or a variant thereof.

[0220] In some embodiments, an aminoglycoside disclosed herein has minimal bactericidal activity and / or toxicity, e.g., nephrotoxicity.

[0221] In some embodiments, an aminoglycoside comprises a variant having reduced toxicity, e.g., reduced nephrotoxicity as compared to an aminoglycoside without a variant. In some embodiments, an aminoglycoside comprises a variant having reduced bactericidal activity as compared to an aminoglycoside without a variant. In some embodiments, an aminoglycoside comprises a variant which retains activity, e.g., readthrough activity of premature termination codons, as compared to an aminoglycoside without a variant. In some embodiments, a variant of an aminoglycoside has reduced overall cationic charge as compared to an aminoglycoside without - 91 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOa variant. Exemplary aminoglycosides and variants thereof are disclosed in: Popadynec M. et al., (2021) ACS Med. Chem. Lett. 12( 9), 1486-1492; and in Brasell EJ et al., (2019), PLoS ONE 14(12): e0223954; the entire contents of each of which is hereby incorporated by reference.

[0222] In some embodiments, an aminoglycoside comprises an analog of an aminoglycoside having reduced antimicrobial activity (e g., an aminoglycoside produced by resistance mutations in bacteria), and / or reduced endosomal or lysosomal stability, or both.

[0223] In some embodiments, an aminoglycoside has one or more, or all of the following characteristics: (i) high potency for binding to a cell surface factor, e.g., Megalin, Cubilin, or both; (ii) low nephrotoxicity; (iii) low ototoxicity; (iv) reduced endosomal or lysosomal stability; (v) reduced antimicrobial activity; or (vi) a combination of any one or all of (i) to (v).

[0224] In some embodiments, an aminoglycoside disclosed herein binds to one or more extracellular domains of a cell surface factor (e g., Megalin, Cubilin, or both). In some embodiments, an aminoglycoside disclosed herein binds a cell surface receptor at or near one or more complement type repeats. Exemplary binding of an aminoglycoside to human Megalin is disclosed in Dagil R et al., (2013) Journal of Biological Chemistry; 288(6); 4424-4435; the entire contents of which are hereby incorporated by reference.

[0225] In various embodiments, targeting moieties of the present disclosure comprise or have the following structure of Formula (XI) or (XE):RN4N-RN3RN6M_ON5OlR10(xr)wherein:RN9R1is hydrogen orR2is hydrogen or -G-RG;R3is -OH or-NRN7RN8;IPTS / 200358788.1Attorney Docket No. JUDO-005WOR4and R5are each independently hydrogen or -OH;R6is hydrogen, -G-RG, -C(O)-Ci-Ce alkyl optionally substituted with one or more halogen, or Rc, wherein Recombines with RN1° to form a heterocycle;R7is hydrogen, -OH, or -ORC, wherein -ORCcombines with RN1° to form a heterocycle; R8is -CH3 or -OH;R9is hydrogen, -CH2OH, -CH2O-G-RG, or -CH2S-G-RG;R10is Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, or-G-RG, wherein the Ci-Ce alkyl or-C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen;RGis the attachment point to the rest of the molecule;RN1is hydrogen, Ci-Ce alkyl optionally substituted with one or more halogen, HO-Ci-Ce alkylene, RNA-C(O)-, RNAO-C(O)-, N(RNA)2-C(O)-, (H2N)(HN=)C-, RNA-S(O)2- or -GX-G;RN2is hydrogen, Ci-Ce alkyl, or -C(O)-Ci-Ce alkyl, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN1and RN2together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN3and RN4are each independently hydrogen, C1-C6 alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-Ce alkyl, -C(=NH)NH2, wherein the Ci-Ce alkyl or-C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN3and RN4together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN5and RN6are each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-Ce alkyl, Ci-Ce alkyl ene-OC(O)-Ci-Ce alkyl, -C(=NH)NH2, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN5and RN6together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN7and RN8are each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-Ce alkyl, -C(=NH)NH2, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN7and RN8together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN9is hydrogen, -CH3, or -C(0)CH3;- 93 - IPTS / 200358788.1Attorney Docket No. JUDO-005WORN1° is hydrogen, -C(O)-RNA, -C(O)-ORNA, -C(O)-N(RNA)2, -S(O)2-RNA, optionally substituted phenyl, or combines with R6being Rcor R7being -OReto form a heterocycle;RNAis each independently Ci-Ce alkyl optionally substituted with one or more halogen, C2-Ce heteroalkyl, optionally substituted aryl, or optionally substituted heteroaryl;Raand Rbare each independently hydrogen or -CH3;Rcis -C(O)-, -S(O)-, -S(O)2- or-C(=NH)-;G is -(CH2)t-*, -(CH2)t-(CH2OCH2)s-(CH2)t-*, -(CH2-C(O)NH-(CH2)t-*, or-(CH2)t-NHC(O)-(CH2)t-*, whereinindicates the attachment point to the oxygen atom;GNis -(CH2-NHC(O)-*, -(CH2)t-C(O)-*, -(CH2)t-(CH2OCH2)s-(CH2)t-C(O)-*, or -(CH2)t-(CH2OCH2)s-(CH2)t-*, wherein indicates the attachment point to the nitrogen atom;each s is independently an integer from 1 to 10; andeach t is independently an integer from 0 to 20.

[0226] In some embodiments, the targeting moiety does not comprise or have a structure selected from:Ry, and Rz are each independently hydrogen or -CH3. In certain embodiments, the targeting NH2H2N 7 NH2moiety B does not comprise of have a structureof OH2. In certain embodiments,IPTS / 200358788.1Attorney Docket No. JUDO-005WOthe targeting moiety B does not comprise of have a structureofembodiments, the targeting moiety B does not comprise of have a structureof In certain embodiments, the targeting moiety B does not comprise of have a structure ofIn certain embodiments, the targeting moiety B does not comprise of have aIn certain embodiments, the targeting moiety B does not compriseof have a structureof In certain embodiments, the targeting moiety B does not- 95 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOcomprise of have a structureof In certain embodiments, the targeting moiety Bdoes not comprise of have a structureof In certain embodiments, the NHotargeting moiety B does not comprise of have a structureof certain embodiments, the targeting moiety B does not comprise of have a structure ofOH NH2 In certain embodiments, the targeting moiety B does not compriseof have a structureof, wherein Rx, Ry, and Rz are each independently hydrogen or -CH3.

[0227] In some embodiments,- 96 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOR2is RG-(CH2)t-*, RG-(CH2)t-(CH2OCH2)s-(CH2)t-*, or RG-(CH2)t-NHC(O)-(CH2)t-*, wherein indicates the attachment point to the oxygen atom;R6is hydrogen;R9is hydrogen or -CH2OH; andRN1and RN2are each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)- Ci-Ce alkyl, or -C(=NH)NH2; orRN1and RN2together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring.

[0228] In some embodiments,R2is hydrogen;R6is RG-(CH2)t-*, RG-(CH2)t-(CH2OCH2)s-(CH2)t-*, or RG-(CH2)t-NHC(O)-(CH2)t-*, wherein indicates the attachment point to the oxygen atom;R9is hydrogen or -CH2OH; andRN1is hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-Ce alkyl, or -C(=NH)NH2, and RN1is hydrogen or Ci-Ce alkyl, or RN1and RN2together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring.

[0229] In some embodiments,R2is hydrogen;R6is hydrogen;R9is -CH2S-(CH2)t-RG; andRN1is hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-Ce alkyl, or -C(=NH)NH2, and RN1is hydrogen or Ci-Ce alkyl, or RN1and RN2together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring.

[0230] In some embodiments,R2is hydrogen;R6is hydrogen;R9is hydrogen or -CH2OH;RN1is RG-(CH2)t-C(O)-* or RG-(CH2)t-(CH2OCH2)s-(CH2)t-C(O)-*, whereinindicates the attachment point to the nitrogen atom; andRN2is hydrogen or Ci-Ce alkyl.- 97 - IPTS / 200358788.1Attorney Docket No. JUDO-005WORN,'NZ

[0231] In some embodiments, R1is hydrogen. In some embodiments,R1isR

[0232] In some embodiments, R2is hydrogen. In some embodiments, R2is-G-RG.

[0233] In some embodiments, R3is -OH. In some embodiments, R3is — NRN7RN8.

[0234] In some embodiments, R4and R5are each independently hydrogen. In some embodiments, R4and R5are each independently -OH.

[0235] In some embodiments, R6is hydrogen. In some embodiments, R6is In some embodiments, R6is -G-RG. In some embodiments, R6is -C(O)-Ci-Ce alkyl optionally substituted with one or more halogen. In some embodiments, R6is Rc, wherein Rccombines with RN1° to form a heterocycle.

[0236] In some embodiments, R7is hydrogen. In some embodiments, R7is -OH. In some embodiments, R7is -ORe, wherein -ORCcombines with R1° to form a heterocycle.

[0237] In some embodiments, R8is -CH3. In some embodiments, R8is -OH.

[0238] In some embodiments, R9is hydrogen. In some embodiments, R9is -CH2OH. In some embodiments, R9is -CH2O-G-RG. In some embodiments, R9is -CH2S-G-RG.

[0239] In some embodiments, R10is Ci-Ce alkyl, wherein the Ci-Ce alkyl is optionally substituted with one or more halogen. In some embodiments, R10is -C(O)-Ci-Ce alkyl, wherein the C(O) Ci-Ce alkyl is optionally substituted with one or more halogen. In some embodiments, R10is-G-RG.

[0240] In some embodiments, when RN1is not RG-GN-, at least one of RN3, RN4, RN3, RN6, RN7, and RN8is not hydrogen, and / or -NRN1RN2is not -NH2 or -NHCH3.

[0241] In some embodiments, when RN1is RG-G -, at least one of RN3, RN4, RN5, RN6, RN7, and RN8is not hydrogen, and / or RN2is not hydrogen or -CH3.

[0242] In some embodiments, RN1is hydrogen. In some embodiments, RN1is Ci-Ce alkyl optionally substituted with one or more halogen. In some embodiments, RN1is HO-Ci-Ce alkylene. In some embodiments, RN1is RNA-C(O)-. In some embodiments, RN1is RNAO-C(O)-. In some embodiments, RN1is N(RNA)2-C(O)-. In some embodiments, RN1is (H2N)(HN=)C- In some embodiments, RN1is RNA-S(O)2- In some embodiments, RN1is -GN-RG.- 98 - IPTS / 200358788.1Attorney Docket No. JUDO-005WO

[0243] In some embodiments, RN2is hydrogen. Tn some embodiments, RN2is Ci-Ce alkyl, wherein the Ci-Ce alkyl is optionally substituted with one more halogen. In some embodiments, RN2is -C(O)-Ci-C6 alkyl, wherein the -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen. In some embodiments, RN1and RN2together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring. In some embodiments, RN1and RN2together with the atom to which they are attached form an optionally substituted 5-membered heterocyclyl ring. In some embodiments, RN1and RN2together with the atom to which they are attached form an optionally substituted 6-membered heterocyclyl ring. In some embodiments, RN1and RN2together with the atom to which they are attached form an optionally substituted 7-membered heterocyclyl ring.

[0244] In some embodiments, RN1is hydrogen, -CH3, -C(O)CHs, -C(O)CF3, -CH2CH2OH, -C(=NH)NH2. In some embodiments, RN1is hydrogen. In some embodiments, RN1is-CHa. In some embodiments, RN1is -C(O)CHa. In some embodiments, RN1is -C(O)CFa. In some embodiments, RN1is -CH2CH2OH. In some embodiments, RN1is -C(=NH)NH2.

[0245] In some embodiments, RN2is hydrogen or -CH3. In some embodiments, RN2is hydrogen. In some embodiments, RN2is -CH3. In some embodiments, RN1and RN2together with the atom to which they are attached form a morpholine ring.

[0246] In some embodiments, RN3and RN4are each independently hydrogen. In some embodiments, RN3and RN4are each independently Ci-Ce alkyl, wherein the Ci-Ce alkyl is optionally substituted with one or more halogen. In some embodiments, RN3and RN4are each independently Ci-Ce alkylene-OH. In some embodiments, RN3and RN4are each independently -C(O)-Ci-Ce alkyl, wherein the -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen. In some embodiments, RN3and RN4are each independently -C(=NH)NH2. In some embodiments, RN3and RN4together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring. RN3and R4together with the atom to which they are attached form an optionally substituted 5-membered heterocyclyl ring. RN3and RN4together with the atom to which they are attached form an optionally substituted 6-membered heterocyclyl ring. RN3and RN4together with the atom to which they are attached form an optionally substituted 7-membered heterocyclyl ring.

[0247] In some embodiments, RN3is hydrogen or -CH3. In some embodiments, RN3is hydrogen. In some embodiments, RN3is-CHa. In some embodiments, RN4is hydrogen, -CH3, - -99 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOCH2CH3, -C(O)CH3, -C(O)CF3-CH2CH2OH, or -C(=NH)NH2. In some embodiments, RN4is hydrogen. In some embodiments, RN4is -CH3. In some embodiments, R4is -CH2CH3. In some embodiments, RN4is -C(O)CH3. In some embodiments, RN4is -C(O)CF3. In some embodiments, RN4is,-CH2CH2OH. In some embodiments, RN4is -C(=NH)NH2. In some embodiments, RN3and RN4together with the atom to which they are attached form a morpholine ring.

[0248] In some embodiments, RN5and RN6are each independently hydrogen. In some embodiments, RN5and RN6are each independently Ci-Ce alkyl, wherein the Ci-Ce alkyl is optionally substituted with one or more halogen. In some embodiments, RN5and RN6are each independently C1-C6 alkylene-OH. In some embodiments, RN5and RN6are each independently -C(O)-Ci-C6 alkyl, wherein the -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen. In some embodiments, RN5and RN6are each independently Ci-Ce alkylene-OC(O)-Ci-G> alkyl. In some embodiments, RN5and RN6are each independently -C(=NH)NH2. In some embodiments, RN5and RN6together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring. In some embodiments, R?and RN6together with the atom to which they are attached form an optionally substituted 5-membered heterocyclyl ring. In some embodiments, RN5and RN6together with the atom to which they are attached form an optionally substituted 6-membered heterocyclyl ring. In some embodiments, RN5and RN6together with the atom to which they are attached form an optionally substituted 7-membered heterocyclyl ring.

[0249] In some embodiments, RN?is hydrogen or -CH3. In some embodiments, RN5is hydrogen. In some embodiments, RN5is -CH3. In some embodiments, RN6is hydrogen, -CH3, -CH2CH3, -C(O)CH3, -C(O)CF3, -CH2CH2OH, or -C(=NH)NH2. In some embodiments, RN6is hydrogen. In some embodiments, RN6is -CH3. In some embodiments, RN6is -CH2CH3. In some embodiments, RN6is -C(O)CH3. In some embodiments, RN6is -C(O)CF3. In some embodiments, RN6is,-CH2CH2OH. In some embodiments, RN6is -C(=NH)NH2. In some embodiments, R?and RN6together with the atom to which they are attached form a morpholine ring.

[0250] In some embodiments, RN7and RN8are each independently hydrogen. In some embodiments, RN7and RN8are each independently Ci-Ce alkyl, wherein the Ci-Ce alkyl is optionally substituted with one or more halogen. In some embodiments, RN7and RN8are each independently Ci-Ce alkylene-OH. In some embodiments, RN7and RN8are each independently -C(O)-Ci-Ce alkyl, wherein the -C(O)-Ci-Ce alkyl is optionally substituted with one or more - too - IPTS / 200358788.1Attorney Docket No. JUDO-005WOhalogen. In some embodiments, RN7and RN8are each independently -C(=NH)NH2. In some embodiments, RN7and RN8together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring. RN7and R8together with the atom to which they are attached form an optionally substituted 5-membered heterocyclyl ring. RN7and RN8together with the atom to which they are attached form an optionally substituted 6-membered heterocyclyl ring. RN7and RN8together with the atom to which they are attached form an optionally substituted 7-membered heterocyclyl ring.

[0251] In some embodiments, RN7is hydrogen or -CH3. In some embodiments, RN7is hydrogen. In some embodiments, RN7is -CH3. In some embodiments, RN8is hydrogen, -CH3, -CH2CH3, -C(O)CH3, -C(O)CF3,-CH2CH2OH, or-C(=NH)NH2. In some embodiments, RN8is hydrogen. In some embodiments, RN8is -CH3. In some embodiments, RN8is -CH2CH3. In some embodiments, RN8is -C(O)CH3. In some embodiments, RN8is -C(O)CF3. In some embodiments, RN8is -CH2CH2OH. In some embodiments, RN8is -C(=NH)NH2. In some embodiments, RN7and RN8together with the atom to which they are attached form a morpholine ring.

[0252] In some embodiments, RN9is hydrogen. In some embodiments, RN9is -CH3. In some embodiments, RN9is -C(O)CH3.

[0253] In some embodiments, RN1° is hydrogen. In some embodiments, RN1° is -C(O)-RNA. In some embodiments, RN1° is -C(O)-ORNA. In some embodiments, RN1° is -C(O)-N(RNA)2.

[0254] In some embodiments, RN1° is -S(O)2-RNA. In some embodiments, RN1° is optionally substituted phenyl. In some embodiments, RN1° combines with R6being Rcor R7being -ORCto form a heterocycle.

[0255] In some embodiments, RNAis each independently Ci-Ce alkyl optionally substituted with one or more halogen. In some embodiments, RNAis each independently C2-C6 heteroalkyl. In some embodiments, RNAis each independently optionally substituted aryl. In some embodiments, RNAis each independently optionally substituted heteroaryl.

[0256] In some embodiments, Raand Rbare each independently hydrogen. In some embodiments, Raand Rbare each independently -CH3.

[0257] In some embodiments, Rcis -C(O)-. In some embodiments, Rcis — S(O)-. In some embodiments, Rcis -S(O)2- In some embodiments, Rcis C(=NH).

[0258] In some embodiments, G is -(CH2)t-*, wherein indicates the attachment point to the oxygen atom. In some embodiments, G is -(CH2)t-(CH2OCH2)s-(CFl2)t-*, wherein indicates - 101 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOthe attachment point to the oxygen atom. Tn some embodiments, G is -(CH2)t-C(O)NH-(CH2)t-*, wherein indicates the attachment point to the oxygen atom. In some embodiments, G is -(CH2)t-NHC(O)-(CH2)t-*, whereinindicates the attachment point to the oxygen atom.

[0259] In some embodiments, GNis -(CH2)t-NHC(O)-*, whereinindicates the attachment point to the nitrogen atom. In some embodiments, GNis -(CH2)t-C(O)-*, whereinindicates the attachment point to the nitrogen atom. In some embodiments, GNis -(CH2)t-(CH2OCH2)s-(CH2)t-C(O)-*, whereinindicates the attachment point to the nitrogen atom. In some embodiments, GNis -(CH2)t-(CH2OCH2)s-(CH2)t-*, whereinindicates the attachment point to the nitrogen atom.

[0260] In some embodiments, each s is independently an integer of 1. In some embodiments, each s is independently an integer of 2. In some embodiments, each s is independently an integer of 3. In some embodiments, each s is independently an integer of 4. In some embodiments, each s is independently an integer of 5. In some embodiments, each s is independently an integer of 6. In some embodiments, each s is independently an integer of 7. In some embodiments, each s is independently an integer of 8. In some embodiments, each s is independently an integer of 9. In some embodiments, each s is independently an integer of 10.In some embodiments, each t is independently an integer of 0. In some embodiments, each t is independently an integer of 1. In some embodiments, each t is independently an integer of 2. In some embodiments, each t is independently an integer of 3. In some embodiments, each t is independently an integer of 4. In some embodiments, each t is independently an integer of 5. In some embodiments, each t is independently an integer of 6. In some embodiments, each t is independently an integer of 7. In some embodiments, each t is independently an integer of 8. In some embodiments, each t is independently an integer of 9. In some embodiments, each t is independently an integer of 10. In some embodiments, each t is independently an integer of 11. In some embodiments, each t is independently an integer of 12. In some embodiments, each t is independently an integer of 13. In some embodiments, each t is independently an integer of 14. In some embodiments, each t is independently an integer of 15. In some embodiments, each t is independently an integer of 16. In some embodiments, each t is independently an integer of 17. In some embodiments, each t is independently an integer of 18. In some embodiments, each t is independently an integer of 19. In some embodiments, each t is independently an integer of 20.- 102 - IPTS / 200358788.1Attorney Docket No. JUDO-005WO

[0261] In various embodiments, targeting moieties of the present disclosure comprise or have one of the following structures of Formula (Xia), (Xlb), or (XIc):wherein:G is -(CH2)t-*, -(CH2)t-(CH2OCH2)s-(CH2>-*, -(CH2)t-C(O)NH-(CH2)t-*, or -(CH2)t-NHC(O)-(CH2)t-*, whereinindicates the attachment point to the oxygen atom;GNis -(CH2)t-NHC(O)-*, -(CH2)t-C(O)-* or -(CH2)t-(CH2OCH2)s-(CH2-C(O)-*, or -(CH2)t-(CH2OCH2)s-(CH2)t-*, whereinindicates the attachment point to the nitrogen atom;RN1is hydrogen, Ci-Ce alkyl optionally substituted with one or more halogen, HO-Ci-Ce alkylene, RNA-C(O)-, RNAO-C(O)-, N(RNA)2-C(O)-, (H2N)(HN=)C- or RNA-S(O)2-;RN2is hydrogen, Ci-Ce alkyl, or -C(O)-Ci-Ce alkyl, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN1and RN2together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN3and RN4are each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-Ce alkyl, -C(=NH)NH2, wherein the Ci-Ce alkyl or-C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN3and RN4together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN5and RN6are each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-C6alkyl, Ci-C6alkyl ene-OC(O)-Ci-C6alkyl, -C(=NH)NH2, wherein the Ci-C6alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN5and RN6together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;- 103 - IPTS / 200358788.1Attorney Docket No. JUDO-005WORN7and RN8are each independently hydrogen, Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, -C(=NH)NH2, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN7and RN8together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN9is hydrogen, -CH3, or -C(O)CH3;RN1° is hydrogen, or -C(O)-RNA, -C(O)-ORNA, -C(O)-N(RNA)2, -S(O)2-RNA, optionally substituted phenyl, or combines with -R6being Rcor R7being -ORCto form a heterocycle;RNAis each independently Ci-Ce alkyl optionally substituted with one or more halogen, C2-Ce heteroalkyl, optionally substituted aryl, or optionally substituted heteroaryl;R6is hydrogen, -C(O)-Ci-Ce alkyl optionally substituted with one or more halogen, or Rc, wherein Rccombines with RN1° to form a heterocycle;R7is hydrogen, -OH, or -ORC, wherein -ORecombines with RN1° to form a heterocycle; Raand Rbare each independently hydrogen or -CH3;Rcis -C(O)-, -S(O)-, -S(O)2- or-C(=NH)-;s is an integer from 1 to 10;t is an integer from 0 to 20.

[0262] In some embodiments of Formula (Xia), (Xlb), or (XIc), when (i) each of RN1, RN2RN3, RN4, RN5, RN6, RN7, and RN8is hydrogen; (ii) RN9is -CH3; and (iii) RN1° is hydrogen and R7is -OH, or RNlt)combines with -C(O)- and R7being -ORCto make an oxazolidinone ring, G is not -(CH2)-(CH2OCH2)2-(CH2)-*.

[0263] In some embodiments, the targeting moiety B comprises or has a structure of Formula (XI), and whereinR2is RG-(CH2)t-*, RG-(CH2)t-(CH2OCH2)s-(CH2)t-*, or RG-(CH2)t-NHC(O)-(CH2)t-*, wherein indicates the attachment point to the oxygen atom;R6is hydrogen;R9is hydrogen or -CH2OH; andRN1and RN2are each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-C6alkyl, or -C(=NH)NH2; orRN1and RN2together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring.- 104 - IPTS / 200358788.1Attorney Docket No. JUDO-005WO

[0264] In some embodiments, the targeting moiety B comprises or has a structure of Formula (XI), and whereinR2is hydrogen;R6is RG-(CH2)t-*, RG-(CH2)t-(CH2OCH2)s-(CH2)t-*, or RG-(CH2)t-NHC(O)-(CH2)t-*, wherein indicates the attachment point to the oxygen atom;R9is hydrogen or -CH2OH; andRN1is hydrogen, Ci-C6alkyl, Ci-C6alkylene-OH, -C(O)-Ci-C6alkyl, or -C(=NH)NH2, and RN1is hydrogen or Ci-Ce alkyl, or RN1and RN2together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring.

[0265] In some embodiments, the targeting moiety B comprises or has a structure of Formula (XI), and whereinR2is hydrogen;R6is hydrogen;R9is -CH2S-(CH2)t-RG; andRN1is hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-Ce alkyl, or -C(=NH)NH2, and RN1is hydrogen or Ci-Ce alkyl, or RN1and RN2together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring.

[0266] In some embodiments, the targeting moiety B comprises or has a structure of Formula (XI), and whereinR2is hydrogen;R6is hydrogen;R9is hydrogen or -CH2OH;RN1is RG-(CH2)t-C(O)-* or RG-(CH2)t-(CH2OCH2)s-(CH2)t-C(O)-*, whereinindicates the attachment point to the nitrogen atom; andRN2is hydrogen or Ci-Ce alkyl.

[0267] In some embodiments, the targeting moiety B comprises or has a structure of Formula (XI), and wherein: when RN1is not RG-GN-, at least one of RN3, RN4, RN5, RN6, RN7, and RN8is not hydrogen, and / or -NRN1RN2is not -NH2or -NHCH3.

[0268] In some embodiments, the targeting moiety B comprises or has a structure of Formula (XI), and wherein when: when RN1is RG-GN-, at least one of RN3, RN4, RN5, RN6, RN7, and RN8is not hydrogen, and / or RN2is not hydrogen or -CH3.- 105 - IPTS / 200358788.1Attorney Docket No. JUDO-005WO

[0269] In some embodiments, RN1is hydrogen, -CH3, -CH2CH3, -C(O)CHs, -C(O)CF3, -CH2CH2OH, or -C(=NH)NH2, and RN2is hydrogen or -CH3; or RN1and RN2together with the atom to which they are attached form a morpholine ring.

[0270] In some embodiments, RN1is hydrogen, -CH3, -CH2CH3, -C(O)CH3, -C(O)CF3, -CH2CH2OH, or -C(=NH)NH2, and RN2is hydrogen. In some embodiments, RN1is hydrogen, and RN2is hydrogen. In some embodiments, RN1is -CH3, and RN2is hydrogen. In some embodiments, RN1is -CH2CH3, and RN2is hydrogen. In some embodiments, RN1is -C(O)CH3, and RN2is hydrogen. In some embodiments, RN1is -C(O)CFs, and RN2is hydrogen. In some embodiments, RN1is -CH2CH2OH, and RN2is hydrogen. In some embodiments, RN1is -C(=NH)NH2, and RN2is hydrogen.

[0271] In some embodiments, RN1is hydrogen, -CH3, -CH2CH3, -C(O)CH3, -C(O)CF3, -CH2CH2OH, or -C(=NH)NH2, and RN2is -CH3. In some embodiments, RN1is hydrogen, and RN2is -CH3. In some embodiments, RN1is -CH3, and RN2is -CH3. In some embodiments, RN1is -CH2CH3, and RN2is -CH3. In some embodiments, RN1is -C(O)CH3, and RN2is -CH3. In some embodiments, RN1is -C(O)CF3, and RN2is -CH3. In some embodiments, RN1is -CH2CH2OH, and RN2is -CH3. In some embodiments, RNIis -C(=NH)NH2, and RN2is -CH3.

[0272] In some embodiments, RN1and RN2together with the atom to which they are attached form a morpholine ring.

[0273] In some embodiments, RN3is hydrogen or -CH3, and RN4is hydrogen, -CH3, -CH2CH3, -C(O)CH3, -C(O)CF3, -CH2CH2OH, or -C(=NH)NH2; or RN3and RN4together with the atom to which they are attached form a morpholine ring.

[0274] In some embodiments, RN3is hydrogen, and RN4is hydrogen, -CH3, -CH2CH3, -C(O)CH3, -C(O)CF3, -CH2CH2OH, or -C(=NH)NH2. In some embodiments, RN3is hydrogen, and RN4is hydrogen. In some embodiments, RN3is hydrogen, and RN4is -CH3. In some embodiments, RN3is hydrogen, and RN4is -CH2CH3. In some embodiments, RN3is hydrogen, and RN4is -C(O)CH3. In some embodiments, RN3is hydrogen, and RN4is -C(O)CF3. In some embodiments, RN3is hydrogen, and RN4is -CH2CH2OH. In some embodiments, RN3is hydrogen, and RN4is -C(=NH)NH2.

[0275] In some embodiments, RN3is -CH3, and RN4is hydrogen, -CH3, -CH2CH3, -C(O)CH3, - C(O)CF3, -CH2CH2OH, or -C(=NH)NH2. In some embodiments, RN3is -CH3, and RN4is hydrogen. In some embodiments, RN3is -CH3, and RN4is -CH3. In some embodiments, RN3is - - 106 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOCH3, and RN4is -CH2CH3. Tn some embodiments, RN3is -CH3, and RN4is -C(O)CHs. In some embodiments, RN3is -CH3, and RN4is -C(O)CF3. In some embodiments, RN3is -CH3, and R4is -CH2CH2OH. In some embodiments, RN3is -CH3, and RN4is -C(=NH)NH2.

[0276] In some embodiments, RN3and RN4together with the atom to which they are attached form a morpholine ring.

[0277] In some embodiments, RN5is hydrogen or-CHi, and RN6is hydrogen, -CH3, -CH2CH3, -C(O)CH3, -C(O)CF3, -CH2CH2OH, or -C(=NH)NH2; or RN5and RN6together with the atom to which they are attached form a morpholine ring.

[0278] In some embodiments, RN5is hydrogen, and RN6is hydrogen, -CH3, -CH2CH3, -C(O)CH3, -C(O)CF3, -CH2CH2OH, or -C(=NH)NH2. In some embodiments, RN5is hydrogen, and RN6is hydrogen. In some embodiments, RN5is hydrogen, and RN6is -CH3. In some embodiments, Rx?is hydrogen, and RN6is -CH2CH3. In some embodiments, RN?is hydrogen, and RN6is -C(O)CHB. In some embodiments, RN5is hydrogen, and RN6is -C(O)CF3. In some embodiments, RN5is hydrogen, and RN6is -CH2CH2OH. In some embodiments, RN3is hydrogen, and RN6is -C(=NH)NH2.

[0279] In some embodiments, RN5is -CH3, and RN6is hydrogen, -CH3, -CH2CH3, -C(O)CH3, -C(O)CF3, -CH2CH2OH, or -C(=NH)NH2. In some embodiments, RN5is -CH3, and RN6is hydrogen. In some embodiments, RN5is RN5is -CFb, and RN6is -CH3. In some embodiments, RN5is RN5is -CFb, and RN6is -CH2CH3. In some embodiments, RN5is RN5is -CFb, and RN6is -C(O)CFb. In some embodiments, RN5is RN?is -CFb, and RN6is -C(O)CF3. In some embodiments, RN5 JSRN5 -S-CJk,anj RN6 -CFbC OH. In some embodiments, RN5is RN5is -CFb, and RN6is -C(=NH)NH2.

[0280] In some embodiments, Rxand RN6together with the atom to which they are attached form a morpholine ring.

[0281] In some embodiments, RN7is hydrogen or -CFb, and RN8is hydrogen, -CFb, -CH2CH3, -C(O)CFb, -C(O)CF3, -CFbCFbOH, or -C(=NH)NH2; or RN7and RN8together with the atom to which they are attached form a morpholine ring.

[0282] In some embodiments, RN7is hydrogen, and RN8is hydrogen, -CH3, -CH2CH3, -C(O)CH3, -C(O)CF3, -CH2CH2OH, or -C(=NH)NH2. In some embodiments, RN7is hydrogen, and RN8is hydrogen. In some embodiments, RN7is hydrogen, and RN8is -CFb. In some embodiments, RN7is hydrogen, and RN8is -CH2CH3. In some embodiments, RN7is hydrogen, and RN8is -C(O)CH3.- 107 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOIn some embodiments, RN7is hydrogen, and RN8is -C(O)CF3. Tn some embodiments, RN7is hydrogen, and RN8is -CH2CH2OH. In some embodiments, RN7is hydrogen, and RN8is -C(=NH)NH2.

[0283] In some embodiments, RN7is -CH3, and RN8is hydrogen, -CH3, -CH2CH3, -C(O)CH3, -C(O)CFs, -CH2CH2OH, or -C(=NH)NH2. In some embodiments, RN7is -CH3, and RN8is hydrogen. In some embodiments, RN7is -CH3, and RN8is -CH3. In some embodiments, RN7is -CH3, and RN8is -CH2CH3. In some embodiments, RN7is -CH3, and RN8is -C(O)CHs. In some embodiments, RN7is -CH3, and RN8is -C(O)CF3. In some embodiments, RN7is -CH3, and R8is -CH2CH2OH. In some embodiments, RN7is -CH3, and RN8is -C(=NH)NH2.

[0284] In some embodiments, RN7and RN8together with the atom to which they are attached form a morpholine ring.

[0285] In some embodiments, RN9is hydrogen. In some embodiments, RN9is -CH3. In some embodiments, RN9is -C(O)CH3.

[0286] In some embodiments, RN1° is hydrogen. In some embodiments, RN1° is -C(O)-RNA. In some embodiments, RN1° is -C(O)-ORNA. In some embodiments, RN1° is -C(O)-N(RNA)2. In some embodiments, RN1° is -S(O)2-RNA. In some embodiments, RN1° is optionally substituted phenyl. In some embodiments, RN1° combines with R6being Rcor R7being -ORCto form a heterocycle.

[0287] In some embodiments, RNAis each independently Ci-Ce alkyl optionally substituted with one or more halogen. In some embodiments, RNAis each independently C2-C6 heteroalkyl. In some embodiments, RNAis each independently optionally substituted aryl. In some embodiments, RNAis each independently optionally substituted heteroaryl.

[0288] In some embodiments, R6is hydrogen. In some embodiments, R6is -C(O)-Ci-Ce alkyl optionally substituted with one or more halogen. In some embodiments, R6is Rc, wherein Rccombines with RN1° to form a heterocycle.

[0289] In some embodiments, R7is hydrogen. In some embodiments, R7is -OH. In some embodiments, R7is -ORC, wherein -ORCcombines with R1° to form a heterocycle.

[0290] In some embodiments, Raand Rbare each independently hydrogen. In some embodiments, Raand Rbare each independently -CH3.

[0291] In some embodiments, Rcis -C(O)-. In some embodiments, Rcis-S(O)-. In some embodiments, Rcis -S(O)2- In some embodiments, Rcis -C(=NH)-.- 108 - IPTS / 200358788.1Attorney Docket No. JUDO-005WO

[0292] In some embodiments, G is -(CH2)t-*, wherein indicates the attachment point to the oxygen atom. In some embodiments, G is -(CH2)t-(CH2OCH2)s-(CH2)t-:,:, wherein indicates the attachment point to the oxygen atom. In some embodiments, G is -(CH2)t-C(O)NH-(CH2)t-*, wherein indicates the attachment point to the oxygen atom. In some embodiments, G is -(CH2)t-NHC(O)-(CH2)t-*, whereinindicates the attachment point to the oxygen atom.

[0293] In some embodiments, GNis -(CH2)t-NHC(O)-*, wherein indicates the attachment point to the nitrogen atom. In some embodiments, Gxis-(CH2)t-C(O)-*, whereinindicates the attachment point to the nitrogen atom. In some embodiments, GNis -(CH2)t-(CH2OCH2)s-(CH2)t-C(O)-*, whereinindicates the attachment point to the nitrogen atom. In some embodiments, GNis (CH2)t (CH2OCH2)s (CH2)t *, whereinindicates the attachment point to the nitrogen atom.

[0294] In some embodiments, each s is independently an integer of 1. In some embodiments, each s is independently an integer of 2. In some embodiments, each s is independently an integer of 3. In some embodiments, each s is independently an integer of 4. In some embodiments, each s is independently an integer of 5. In some embodiments, each s is independently an integer of 6. In some embodiments, each s is independently an integer of 7. In some embodiments, each s is independently an integer of 8. In some embodiments, each s is independently an integer of 9. In some embodiments, each s is independently an integer of 10.

[0295] In some embodiments, each t is independently an integer of 0. In some embodiments, each t is independently an integer of 1. In some embodiments, each t is independently an integer of 2. In some embodiments, each t is independently an integer of 3. In some embodiments, each t is independently an integer of 4. In some embodiments, each t is independently an integer of 5. In some embodiments, each t is independently an integer of 6. In some embodiments, each t is independently an integer of 7. In some embodiments, each t is independently an integer of 8. In some embodiments, each t is independently an integer of 9. In some embodiments, each t is independently an integer of 10. In some embodiments, each t is independently an integer of 11. In some embodiments, each t is independently an integer of 12. In some embodiments, each t is independently an integer of 13. In some embodiments, each t is independently an integer of 14. In some embodiments, each t is independently an integer of 15. In some embodiments, each t is independently an integer of 16. In some embodiments, each t is independently an integer of 17. In- 109 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOsome embodiments, each t is independently an integer of 18. In some embodiments, each t is independently an integer of 19. In some embodiments, each t is independently an integer of 20.

[0296] In some embodiments, targeting moieties of the present disclosure comprise or have one of the following structure of Formula (XI’ a):(Xl’a)wherein G is -(CH2)t-*, -(CH2)t-(CH2OCH2)s-(CH2)t-*, -(CH2 -C(O)NH-(CH2)t-*, or -(CH2)t-NHC(O)-(CH2)t-*, wherein indicates the attachment point to the oxygen atom.

[0297] In some embodiments, G is -(CH2)t-*, whereinindicates the attachment point to the oxygen atom. In some embodiments, G is -(CH2)t-*, whereinindicates the attachment point to the oxygen atom. In some embodiments, G is -(CH2)t-(CH2OCH2)s-(CH2)t-*, whereinindicates the attachment point to the oxygen atom. In some embodiments, G is -(CH2)t-C(O)NH-(CH2)t-*, whereinindicates the attachment point to the oxygen atom. In some embodiments, G is -(CH2)t-NHC(O)-(CH2)t-*, whereinindicates the attachment point to the oxygen atom.

[0298] In some embodiments, the targeting moiety is an aminoglycoside moiety or a derivative or analog thereof. In some embodiments, the targeting moiety is a neamine moiety or an derivative or analog thereof. In some embodiments, the targeting moiety is a nebramine moiety or an derivative or analog thereof. In some embodiments, the targeting moiety is a gentamine moiety or an derivative or analog thereof. In some embodiments, the targeting moiety is a gentamicin moiety or an derivative or analog thereof. In some embodiments, the targeting moiety is a kanamycin moiety or an derivative or analog thereof. In some embodiments, the targeting moiety is a neomycin moiety or an derivative or analog thereof. In some embodiments, the targeting moiety is a paromomycin moiety or an derivative or analog thereof.

[0299] In some embodiments, the targeting moiety is an aminoglycoside moiety derived from a compound in Table 2a. In some embodiments, the targeting moiety is an aminoglycoside moiety derived from compound AG2-0, AG4-0, AG4-6, AG4-7, AG5-0, or AG7-0.- 110 - IPTS / 200358788.1Attorney Docket No. JUDO-005WO

[0300] In some embodiments, the aminoglycoside moiety is attached to the rest of the molecule at position 5 (e.g., conjugated at position 5 to a payload moiety, optionally via a linker). In some embodiments, the aminoglycoside moiety is attached to the rest of the molecule at position 6’ (e.g., conjugated at position 6’ to a payload moiety, optionally via a linker). In some embodiments, the aminoglycoside moiety is attached to the rest of the molecule at position 2” (e.g., conjugated at position 2” to a payload moiety, optionally via a linker). In some embodiments, the aminoglycoside moiety is attached to the rest of the molecule at position 6” (e.g., conjugated at position 6” to a payload moiety, optionally via a linker). In some embodiments, the aminoglycoside moiety is attached to the rest of the molecule at position 5” (e.g., conjugated at position 5” to a payload moiety, optionally via a linker).

[0301] In some embodiments, the targeting moiety comprises or has a structure selected from Table 2b. In some embodiments, the targeting moiety comprises or has a structure selected from AG2-0a, AG4-0a, AG4-6a, AG4-7a, AG5-0a, AG5-0c, and AG7-0a.

[0302] In some embodiments, the targeting moiety comprises or has a structure selected from Table 2c. In some embodiments, the targeting moiety comprises or has a structure selected from AG2-0a-l, AG2-0a-2, AG4-0a-l, AG4-0a-2, AG4-6a-l, AG4-6a-2, AG4-7a-l, AG4-7a-2, AG5-0a-l, AG5-0a-2, AG5-0c-2, AG7-0a-l, and AG7-0a-2.

[0303] In some embodiments, the targeting moiety is an aminoglycoside moiety derived from a compound in Table 31.Table 2a. Structures of exemplary aminoglycosidesCpd. No. Structure Cpd. No. StructureGentamine and gentamine derived aminoglycosidesAG1-0 NH2AG1-1 NHH2N^NH NH2( HNH2N A ^O-AV^-AVNH2v^Tl HNH*HNN \\OH HN NH A-f^A ^NH,H2N OH Neamine and neamine derived aminoglycosidesAG2-0 NH2HO'-'V^xHO^-*M NH2H2N A^A -.HO-N-* ^VNH2OH- ill - IPTS / 200358788.1Attorney Docket No. JUDO-005WONebramine and nebramine derived aminoglycosidesAG7-0 NH2HO^V<OyNH,H2N°0A-*^X-NH2OHGentamicin and gentamicin derived aminoglycosidesAG3-0 NH2XH2N3N\H2HOA_^T\NH02" N / - H HO AG4-0 NH2AG4-1 NMe2vVoH2NJ NH2Me? yN? Jl. N \Me2....HOA-ZA H 0 N M e2NH02OHO~J^2X- - — N A" N / L-O i0 0rAG4-2 NH AG4-3 NHAcH2N^NH ^V-0 / HNVcS ^NH*HN HO^--V^NHACHN. NH (I ^ XNH207 HO-*-'TX"H2N 0NH— N 0— N 0 Y0 YAG4-4 \NH AG4-5 \N—5^HQA-^VNH2^^A^VNH20 0HOA!^2Z- — N J) — N 0r Y0 0- 112 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOAG4-6 HN^OHAG4-7o4^ N— 'M-OHoA-i*^NH20H0J^z 0— N A HO-~2^2Z- O Y — N oo YAG4-8 NH2AG4-9 NH2U0H=NI -N 1Z^0A^Y^NH20 0HO^2^2Z- — N A — N A0 Y 0 YAG4-10 NH2OH AG4-11 NH2> Uo VPH pt M. JEUHAAA^VNH2HAA2^MNH20 o— N A — N AO Y o YAG4-12 NH2AG4-13 NH2< o UoMAU / HO-^V^NXHO^^MNH0 0HOA^SZ- HO-^2Z- — N A — N Ao Y 0 YIPTS / 200358788.1Attorney Docket No. JUDO-005WOAG4-14 NH2AG4-15 NH2OH Jvo°V HCA'^VNH0 0HO-Z^-SX- HO^2Z- — N A — N J,o r 0 YAG4-16 NH2AG4-17 NH2v-V-o^" T2^i NHH N ^Z2Ax'nnr HN / o H2N^0A-^NH20 0HO^ZOV, HOxJJ^Z- ”\ iHAG4-18 NH2AG4-19 NH2T1 — / v'* N HNH2N H2N^OA-^VNH2HO-^-^NH20 0HO-'Z^QZ- ^ OHAG4-20 NH2AG4-21( OHA oHN^ H2N.tf0A-^^NH20 0H0HO^ZOV,'xZf-2Z- VH K AH AG4-22 NHTFA AG4-23 NHTFATFAHNI HO-X-^\^ NHTFA HOA2-AZ^NHTFA0 oAcO HO~ji^2Z- — N A ~Nor r°o 0- 114 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOAG4-24 NH2AG4-25 NHTFAX Xo...VN_HTFATFA RQAAAXNHTFA N0 9 OAc AcoX^SZ- — N 1 —Noo ir roAG4-26 NH2AG4-27A— oHQA-^A^NH20 bHO-. Z< XZ- Ac— QH6AG4-28 NH2AG4-29 NH,V^9H, NXOX^A_-NH20 b— Si Q. N J Yzs; N'o" 'b HAG4-30 NHZAG4-31 NH, / *,x.oA— ^NH29HO-J-rSZ-' HO. ZrSZ-'\T TM 1 ''■ IH „VN. OHR ° RRis alkyl, aryl, or heteroaryl R is alkyl, aryl, or heteroaryl AG4-32 NH, NHZ AG4-33 / 2,.A°OX^X~NH2“OX-X_., NH20 bHO-Z^Z- HO.4-2Z- 0 ' J„V\ OHcy-\ inR R--6Ris alkyl, aryl, or heteroaryl R is alkyl, aryl, or heteroarylIPTS / 200358788.1Attorney Docket No. JUDO-005WOAG4-34 NH2AG4-35 NHo / A, O v-VOb °bS^A-NH2b°X--N, OH HO.2; AAOH FSCs- R is alkyl, aryl, or heteroarylAG4-36 NH-, / AG4-37 HM-A O{ Rb >-VA^. NH2HO2^ o\ OH HO-J^SZ- W 6HR is alkyl, aryl, or heteroaryl AG4-38 AG4-39 pV0°O-\-^A--NH2°OX2A--NH o b2HO^Z^SZ- HO-. Z^2Z- --NH JH--NH AR is alkyl, aryl, or heteroaryl R is alkyl, aryl, or heteroaryl AG4-40 0 / NH A N zR<RO^-yA-— X0HOAZSZ-- --NH QHR is alkyl, aryl, or heteroarylKanamycin and kanamycin derived aminoglycosidesAG5-0 NH2HO HO'-'V-^-ATRH NH2S0A^VNHo2HHHOA2«7«< Z-O —H -" OHHN- 116 - IPTS / 200358788.1Attorney Docket No. JUDO-005WONeomycin and neomycin derived aminoglycosidesAG6-0 NH2HO— A—OHO-*-T'n NHH2N2HO^UOA--T\-NH2l / °sj OHHO H2N \ / H2NXod-°ohOHParomomycin and paromomycin derived aminoglycosidesAG8-0 NH2HO— A-0HO-*-^“ANH2H2NHOAj XH2N OH y—fy21o / ''o OHOH NH2Streptamine and streptamine derived aminoglycosidesAG9-0 HOH22N-yA^VOHV--YA-OHNH2Table 2b. Structures of exemplary aminoglycoside moietiesCpd. No. Structure Cpd. No. StructureGentamine and gentamine derived aminoglycosidesNH2NH AGl-Oa AGl-laH2N^NHH2N NH2( HNU0A-^VNH2''Ti N ^HN%NX OH \\HN NH AUO-vA-X >^NH y A—XV-NH22H2N X0HNeamine and neamine derived aminoglycosidesAG2-0a NH2AG2-0bH0^V<OvHO-^yS NH2HO'^^2\ H2N (UUOXAA-^VNH2Ho-'—Tn NH2X OH H2N Ao-YA - - ft A-^A^NH2OHIPTS / 200358788.1Attorney Docket No. JUDO-005WONebramine and nebramine derived aminoglycosidesAG7-0a NH2NH2H2N°0A-^\_-NH2X OHGentamicin and gentamicin derived aminoglycosidesAG3-0a NH, AG3-0b~NHAoHUX NH2AoA— -T\ HzN ^ NH2V NH,X0 HOA_. r\NH, xAy 0~Xl / H HOH0Xsz~~N / ~H HO AG3-0c NH, AG4-0bX-NHXoNH2HOA— r\2£0A2^VNH NH2o 0xxXy HOJ^S^ ^N / - — N QH HO0 rAG4-0a NH, AG4-0c NH2x£3H2N 3 NH2_ NH2HOA_ r\XxV^— NHO2, VA— NH022~'N / - " N / - A00ozAG4-la NMe2AG4-2a NHH2NXA^o NH / HNvA AQ _A— - N M ©2NH2HNNH \\X 0 HN^ NH > AH,X QA^XMH2HOJ^A H2N X0— N A HOA^SX- r0x°0IPTS / 200358788.1Attorney Docket No. JUDO-005WOAG4-3a NHAc AG4-4a \NHAcH^°^A>^XNHACX o °^^VNH20— N r o HoJ^0 — N Xr0AG4-5a \N— AG4-6a HN'^^OH4^%S^VNH2°0^VNH2X 0 X oHOX^2Z- — N A — N or r0 0AG4-7a AG4-12a NH2o N— ' XoXo XXN.„..,0A--yVNiX oX 0 HoJ^SZ- — N oHO-^SX- X— N X 0o rAG4-13a NH2AG4-14a NH2Jxo OHo X oHoJ^X— N o — N Ar0 o rIPTS / 200358788.1Attorney Docket No. JUDO-005WOAG4-15a NH2AG4-22a NHTFAAcN£| °A TFAHN IN>HTFAO-X-r<^NHTFAX 0 X oAcO— N A ~NOr r0 0AG4-23a NHTFA AG4-23b"\TFATFAHN! XTFAoA— ■ -^A^NHTFA TFAHN I J^TAX o NHTFA0HO^ / ^SZ- — N o HOJ^SZ^— N0 r 1roAG4-24b ^NH AG4-25a NHTFAJVoTFAHN! X^ATFAROX-AXNHTFA0 X o0AcACOX^2Z- HO— N — N oorr 00AG4-26a NH,Ao°QX^\^NH2X oHOAc—NxOHKanamycin and kanamycin derived aminoglycosidesAG5-0a NH2AG5-0c NH2HO^VAL°\ HO^VX°\HO-*-*Tn NH2HO-*-'Tn NH2UOA-^VNH2HO A-^AAHO-^A^NH2X00HHOO\47<4Z-OHHO^2ZotTs^ H2NH2N- 120 - IPTS / 200358788.1Attorney Docket No. JUDO-005WONeomycin and neomycin derived aminoglycosidesAG6-0c NH2AG6-0d NH2HO— A—O HO—HO-*— TA NH2HO-*—2TA NH H N2H2NHH O-*— T^-NH2 HO^ %A^VNH2 / q / ■. L°xl OHHO \ K \ H x z OH2N \ / / zO f HO H2N \ / H N^j2o£Z^O OHOH iN2od '°OHz / r\ r1H OH\ \ NJParomomycin and paromomycin o derived aminoglycosidesAG8-0c NH2I yzI HO— A-O NJHO-*— TA NH2|_0H2N A °O-AVA^-AVNH21 L, ON OHH2N OH r“fX'£tO7^O OHOH NH2Streptamine and streptamine derived amino glycosidesAG9-0a0 ^H22N-\A-^VOHV-^V-OHNH2Table 2c. Structures of exemplary aminoglycoside moietiesCpd. Structure Cpd. StructureNo. No.Gentamine and gentamine derived aminoglycosidesAG1- AG1- NHOal-1 la-1 H2NYNH / HNVV*ATSA N ^HNH2HN \\HN NH A^N A-NH, yUOA^Y-NH2H2N / — / OH^00^Neamine and neamine derived aminoglycosidesAG2- NH2AG2- NH2Oa-1 Oa-2HO^VASHO-*— TA NH2H HOO'^-V*—A TSA NH2H2N H2N i^U0-^vA-A0 O-W NH2A-^VNH2OH- 121 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOAG2- NH2AG2- NH2Oa-3 Oa-41 _tHOAALQ\ HO'^VYS1 \ „ Ho-*-T‘n NH22NHo H N2o 0A— NH2 o OA- YL-NH20^ OH \ OHNH ^NHAG2- 0Ob-2HO^-'TS NH2H2NHO-^— ^NH2OHNebramine and nebramine derived aminoglycosidesAG7- NH2AG7- NH2Oa-1 Oa-2H0AAA°X HQ-ATAR'" n NH2VT1 NH2H2N A^VA H2N A-'V-AZ-X°0A^VNH2°0A-^VNH2x- / ^O'^xZOH OHAG7- 1 _ NH2AG7- NH2Oa-3 onOa-4\ _KHQAA° H0A^A°\\VT] NH2\ *’■ ' 1 NH20A H2N H2N 0--V-AMMH0A— «^X-NH2^NH O-*-A^'-'NH2V-Z OH OHo' o'Gentamicin and gentamicin derived aminoglycosidesAG3- AG3- Ob-2 Oa-1 Xo NHH^ _ NH2oA-G, — / A— NH2AsH~2N J NH O^ / -O O2HOA__AxZ—7 HOxNH2^Z_ o~~N / ^H HOHO^97Ai rH HO NH2AG3- Oc-1 XopA HX(NVH2\ HOA—^^^NH2°A?^°^0yASI / H HO- 122 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOAG4- NH2AG4- Oa-1 Oa-2£2H2NJ NH2H2N3 NH2X / X / X, C A2 ZT\xN— NH' 02oHO'^oy "7I / )r ' 'Qo Y7'°O AG4- NH, AG4- / Oa-lb Ob-2Z R, HJ'N!JN,H2Z O 0j'<r 412bHoJ^jZ-6AG4- NH, AG4- Oc-1 x la-1 1 NMe2IZA2bZVl NMeH^ _ NH / —2Lo z \...0 1 / — Q_A — -~^i\ ^NM.e HOA—2T\NHo2O / / — N A" N / "G-O < r0O AG4- NH AG4- NHAcH2N—2a- 1 NH 3a- 1 / HNNtNH’HN °^A-^\^NHACHN. NH Z^NH,y'0A— ■ -rb^NH2H2N - / oO^° / — / HoJ^Z- O^° HoJ^ / — / —0N A. — / —NA< < r0o YAG4-4a \NH AG4- - 1 \ N—5aJVo5^%^^NH2%X^VNH2 / — / oHO^^A / —7—NO! — / — N 0 <o r < 0 YIPTS / 200358788.1Attorney Docket No. JUDO-005WOAG4- HN-^OHAG4- HNXXX-'0H6a- 1 4^ 6a-2%^VNH2°0^X^VNH< T2°j x o A —HOJ O, M CZZ^SZ- — N X \ OX— N Xo Y 0 YAG4- AG4- 7a- 1 o N— ' 7a-2 c N— 'Jvo°O5Z-XVNH2HXX2^*L / —f00^0HoJ^Z. _ / — N A — N X< o Y o YAG4- NH2AG4- NH212a-l Xo 13a-l Xo< r' / O AOT70^0^° HoJ^Z. —Z— N o / — / — N A < 0 Y < 0 YAG4- NH2AG4- 14a-l VA\ OH 15a-lOwLtgL-, r°o\—.... NH1 / — / oOoJ HOZ A^SOZ-7■T “V°0AG4- NHTFA AG4- NHTFA22a- 1 23a-lTFAHN ToI — AtHTFAFAHNJ NHTFA Y^OX^QX^OX-^VNHTFA Y^O^.O / ^;6X-^VNHTFA Acozi^sz HO^2Z—nA ~No0 Y0 Y- 124 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOAG4- yz''Xx'°'' / XNTFA AG4- 023b-l 24b-2A" OHOA-^-NHTFA0 HQA-^NH0 AHO-J^2X— N Ar — N Ao r0AG4- NHTFA AG4- NH225a- 1 26a- 1 ±oTFA°A^VNH2°?OAco— ' 0— N o HO^SX- r0 | — 'Ac NxOH Kanamycin and kanamycin derived aminoglycosidesAG5- NH2AG5- NH2wOa-1 HO^VX°\ Oa-2 HO^V^Q,HO-S-*TA NH2HO-*-*M NH2§ i HO A^CJ-^UOA^VNH2U0A-^\^NH2 / —z0 Z-V — / 0tl 1 OHHOJ^2Z3H'OHHO } — O'?" —x ° H2N H2NAG5- Oc-2S XNeomycin and neomycin derived aminoglycosidesAG6- NH2AG6- NH2Oc-2! \ HO ' Od-2 HO^VA-O\ HOA-" M NH2HO-^-nS NH2H2N H2N A-V-X-X \-s^ °OA^VNH2HO^ ^A-YV-NH,, L°J OH x V°>johHO H2N \ _ J \ > HO H2N \ ii:4 ° OH XNX ^° OHOH O7H OHParomomycin and paromomycin derived aminoglycosidesIPTS / 200358788.1Attorney Docket No. JUDO-005WO

[0304] In certain embodiments, targeting moieties of the present disclosure comprise or have the following structure of Formula (XA):whereinRi is selected from: H, Me,branched linker, or the attachment point to the rest of the molecule;R2 is H or Me;R3 is H or Me;R5 is H or optionally combines with C=O and R15 to make an oxazolidinone ring;Re is H or OH or OR15, where R15 combines with C=O and Rs to make an oxazolidinone ring;R7 is H or CH2OH;Rs is Me or OH;- 126 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOX) 2-20R9is H,, a branched linker, or the attachment point to the rest of the molecule;Rio is H or OH;Rii is H or OH;R12 is OH or NH2;XR13 is H,, a branched linker, or the attachment point to the rest of the molecule;R14 is H or Me; and- 127 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOL - MX is, whereinL is an optional linker, andOHYis; Y Z P'- O n! ' ij-13 M is °, wherein Y = O or S, and Z = nucleicprovided that the conjugate agent is not any of the structures selected from:whereinwhere each of Ra, Rb, and Rcis selected from H and CH3;the linker is a bivalent linker; andthe payload is a payload moiety.

[0305] In certain embodiments, targeting moieties of the present disclosure comprise or have the following structure of Formula (XB):- 128 - IPTS / 200358788.1Attorney Docket No. JUDO-005WO(XB) wherein:Ri is NH2 or OH;XR2 is OH, NHR3,- 129 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOand Z = nucleic acid, and L is an optional linker.

[0306] In certain embodiments, a targeting moiety of the present disclosure does not comprise or have a structure of Formula (XA). In certain embodiments, a targeting moiety of the present disclosure does not comprise or have a structure of Formula (XB). In certain embodiments, a targeting moiety of the present disclosure does not comprise or have any of the following structures:- 130 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOwherein Rx, Ry, and Rz are each independently hydrogen or -CH3.Table 2d. Exemplary azide-modifted aminoglycosides (suitable for use in forming conjugates, e.g., via click chemistry reactions)Gentamicin (original)2-((4,6-diamino-3 -((3 -amino-6- (aminomethyl)tetrahydro-2H-pyran-2- yl)oxy)-2-(2-(2-(2- azidoethoxy)ethoxy)ethoxy)cyclohexyl)oxy)-5-methyl-4- (methylamino)tetrahydro-2H-pyran- 3,5-diolGentamicin (oxazolidinone analog)6-((4,6-diamino-3 -((3 -amino-6- (aminomethyl)tetrahydro-2H-pyran-2- yl)oxy)-2-(2-(2-(2- azi doethoxy )ethoxy )ethoxy )cy cl ohexyl)oxy)-7-hydroxy-l,3a- dimethy lhexahy dro-2H-pyrano[4, 3 - d]oxazol-2-oneIPTS / 200358788.1Attorney Docket No. JUDO-005WOGentamine (fragment analog)4, 6-diamino-3 -((3 -amino-6- (aminomethyl)tetrahydro-2H-pyran-2- yl)oxy)-2-(2-(2-(2- azidoethoxy)ethoxy)ethoxy)cyclohexan-l-olGentamicin (regio-isomer)5-(2-(2-(2- azidoethoxy)ethoxy)ethoxy)-6-((4,6- diamino-3-((3-amino-6- (aminomethyl)tetrahydro-2H-pyran-2- yl)oxy)-2-hydroxycyclohexyl)oxy)-3- methyl-4-(methylamino)tetrahydro- 2H-pyran-3-olGentamicin (regio- isomer / oxazolindinone analog)7-(2-(2-(2- azidoethoxy)ethoxy)ethoxy)-6-((4,6- diamino-3-((3-amino-6- (aminomethyl)tetrahydro-2H-pyran-2- \ yl)oxy)-2-hydroxycyclohexyl)oxy)- l,3a-dimethylhexahydro-2H- pyrano[4,3-d]oxazol-2-oneNeamine 6’-azide \N-((5-amino-6-((4,6-diamino-2,3- dihydroxycyclohexyl)oxy)-3,4- dihydroxytetrahydro-2H-pyran-2- yl)methyl)-5-azidopentanamide- 132 - IPTS / 200358788.1Attorney Docket No. JUDO-005WO Gentamicin 6’-azideN-((5-amino-6-((4,6-diamino-3-((3,5- dihydroxy-5-methyl-4- (methylamino)tetrahydro-2H-pyran-2- yl)oxy)-2- hydroxycyclohexyl)oxy)tetrahydro- 2H-pyran-2-yl)methyl)-5- azidopentanamideParomomycin 6”’-azideN-((5-amino-6-((5-((3,5-diamino-2- ((3-amino-4,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran- 2-yl)oxy)-6-hydroxycyclohexyl)oxy)- 4-hydroxy-2- (hydroxymethyl)tetrahydrofuran-3- yl)oxy)-3,4-dihydroxytetrahydro-2H- pyran-2-yl)methyl)-5- azidopentanamideKanamycin 6’-azide5-azido-N-((6-((4,6-diamino-3-((4- amino-3,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran- 2-yl)oxy)-2-hydroxycyclohexyl)oxy)- 33, 5 -trihydroxy tetrahydro-2H-pyran- 2-yl)methyl)pentanamideIPTS / 200358788.1Attorney Docket No. JUDO-005WONeomycin-5"-S-azide5-amino-2-(aminomethyl)-6-((2-(((6- azidohexyl)thio)methyl)-5-((3,5- diamino-2-((3-amino-6- (aminomethyl)-4,5- dihydroxytetrahydro-2H-pyran-2- yl)oxy)-6-hydroxycyclohexyl)oxy)-4- hy droxytetrahy drofuran-3 - yl)oxy)tetrahydro-2H-pyran-3,4-diolb. Glucosamines and Glucosamines-Related Targeting Moieties

[0307] In certain aspects, a targeting moiety of the present disclosure comprises or has an glucosamines or glucosamines-related structure, or other such compound.

[0308] In some embodiments, targeting moieties of the present disclosure comprise or have the following structure of Formula (XII):R3'"(XII)wherein:R4-"I — \ / 0-G"R1'11is Gnor HO7R5'"R2 1is -OH or -NRN1-nRN2-n;R3'11is -OH or — NRN3’nRN4’n;R4 11is -OH or -NRN5 IIRN6 n;R5'11is -OH or -NRN7-nRN8’n;- 134 - IPTS / 200358788.1Attorney Docket No. JUDO-005WORN1’nand RN2-neach independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-C6alkyl, -C(=NH)NH2; orRN1'nand RN2-ntogether with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN3'nand RN4’neach independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-C6alkyl, -C(=NH)NH2; orRN3'nand RN4'ntogether with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN5'nand RN6’neach independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-C6alkyl, -C(=NH)NH2; orRN5 nand RN6 ntogether with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN7'nand RN8’neach independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-C6alkyl, -C(=NH)NH2; orRN7'nand RN8'ntogether with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring; andGnis -(CH2)t-*, -(CH2-(CH2OCH2)s-(CH2)t-*, -(CH2)t-C(O)NH-(CH2)t-*, or -(CH2)t-NHC(O)-(CH2)t-*, wherein indicates the attachment point to the oxygen atom; each s is independently an integer from 1 to 10; andeach t is independently an integer from 0 to 20, and.

[0309] In some embodiments, one of R2'11and R3 11is -NR1'nRN2'nor -NRN3’nRN4’n. In some embodiments, one of R411and R5 11is -NRN IIRN6’nor -NRN7’nRN8’n

[0310] In some embodiments, R2'11is -NRN1'URN2'U, R3-11is -NRN3’nRN4’n, R4 1is -NRN5‘nRN6‘n, and R5'11is are -NRN7’nRN8’n.

[0311] In some embodiments, RN1‘nis hydrogen or -CHs. In some embodiments, RN1'nis hydrogen. In some embodiments, RN1'nis -CHs. In some embodiments, RN2'nis hydrogen, -CHs, -CH2CHS, -C(O)CHS, -CH2CH2OH, or -C(=NH)NH2. In some embodiments, RN2'nis hydrogen. In some embodiments, RN2’nis -CHs. In some embodiments, RN2'nis -CH2CHs. In some embodiments, RN2'nis -C(O)CHs. In some embodiments, RN2'nis -CH2CH2OH. In some embodiments, RN2'nis -C(=NH)NH2.- 135 - IPTS / 200358788.1Attorney Docket No. JUDO-005WO

[0312] In some embodiments, RN1'nand RN2’ntogether with the atom to which they are attached form a morpholine ring.

[0313] In some embodiments, RN3'nis hydrogen or -CH3. In some embodiments, RN3'nis hydrogen. In some embodiments, RN3'nis -CH3. In some embodiments, RN4'nis hydrogen, -CH3, -CH2CH3, -C(O)CH3, -CH2CH2OH, or -C(=NH)NH2. In some embodiments, RN4'nis hydrogen. In some embodiments, RN4’nis -CH3. In some embodiments, RN4'nis -CH2CH3. In some embodiments, RN4'Uis -C(O)CH3. In some embodiments, RN4'nis -CH2CH2OH. In some embodiments, RN4'nis -C(=NH)NH2.

[0314] In some embodiments, RN3’nand RN4’ntogether with the atom to which they are attached form a morpholine ring.

[0315] In some embodiments, RN5 nis hydrogen or -CH3. In some embodiments, RN5 11is hydrogen. In some embodiments, RN nis -CH3. In some embodiments, RN6'nis hydrogen, -CH3, -CH2CH3, -C(O)CH3, -CH2CH2OH, or -C(=NH)NH2. In some embodiments, RN6'nis hydrogen. In some embodiments, RN6’nis -CH3. In some embodiments, RN6'nis -CH2CH3. In some embodiments, RN6'Uis -C(O)CH3. In some embodiments, RN641is -CH2CH2OH. In some embodiments, RN6'nis -C(=NH)NH2.

[0316] In some embodiments, RN5'nand RN6’ntogether with the atom to which they are attached form a morpholine ring.

[0317] In some embodiments, RN7'nis hydrogen or -CH3. In some embodiments, RN7’nis hydrogen. In some embodiments, RN7'nis -CH3. In some embodiments, RN8'nis hydrogen, -CH3, -CH2CH3, -C(O)CH?, -CH2CH2OH, or-C(=NH)NH2. In some embodiments, RN8'n 1is hydrogen. In some embodiments, RN8 11is -CH3. In some embodiments, RN8 nis -CH2CH3. In some embodiments, RN8 1is -C(O)CH3. In some embodiments, RN8 1is -CH2CH2OH. In some embodiments, RN8'nis -C(=NH)NH2.

[0318] In some embodiments, RN7'nand RN8’ntogether with the atom to which they are attached form a morpholine ring.

[0319] In some embodiments, -NRN1-nRN2’nis -NH2. In some embodiments, -NRV3-" R4'" is -NH2. In some embodiments, -NRN IIRN6‘nis -NH2. In some embodiments, -NRN7'nRN8'nis -NH2.

[0320] In some embodiments, Gnis -(CH2)t-*, whereinindicates the attachment point to the oxygen atom. In some embodiments, G11is -(CH2)t-(CH2OCH2)s-(CH2)t-*, wherein- 136 - IPTS / 200358788.1Attorney Docket No. JUDO-005WOindicates the attachment point to the oxygen atom. Tn some embodiments, Gnis -(CH2)t-C(O)NH-(CH2)t-*, whereinindicates the attachment point to the oxygen atom. In some embodiments, G11is -(CH2)t-NHC(O)-(CH2)t-*, whereinindicates the attachment point to the oxygen atom.

[0321] In some embodiments, each s is independently an integer of 1. In some embodiments, each s is independently an integer of 2. In some embodiments, each s is independently an integer of 3. In some embodiments, each s is independently an integer of 4. In some embodiments, each s is independently an integer of 5. In some embodiments, each s is independently an integer of 6. In some embodiments, each s is independently an integer of 7. In some embodiments, each s is independently an integer of 8. In some embodiments, each s is independently an integer of 9. In some embodiments, each s is independently an integer of 10.

[0322] In some embodiments, each t is independently an integer of 0. In some embodiments, each t is independently an integer of 1. In some embodiments, each t is independently an integer of 2. In some embodiments, each t is independently an integer of 3. In some embodiments, each t is independently an integer of 4. In some embodiments, each t is independently an integer of 5. In some embodiments, each t is independently an integer of 6. In some embodiments, each t is independently an integer of 7. In some embodiments, each t is independently an integer of 8. In some embodiments, each t is independently an integer of 9. In some embodiments, each t is independently an integer of 10. In some embodiments, each t is independently an integer of 11. In some embodiments, each t is independently an integer of 12. In some embodiments, each t is independently an integer of 13. In some embodiments, each t is independently an integer of 14. In some embodiments, each t is independently an integer of 15. In some embodiments, each t is independently an integer of 16. In some embodiments, each t is independently an integer of 17. In some embodiments, each t is independently an integer of 18. In some embodiments, each t is independently an integer of 19. In some embodim...

Claims

1. Goodwin Docket No.: JUDO-005WOWHAT IS CLAIMED IS:

1. A compound comprising a targeting moiety B, wherein the targeting moiety B comprises or has the following structure of Formula (XI) or (XI’):RN4N-RN3RN6£^\-N-RN5ORl 1°(XI’)wherein:R1is hydrogen or RN9;R2is hydrogen or -G-RG;R3is -OH or-NRN7RN8;R4and R5are each independently hydrogen or -OH;R6is hydrogen, -G-RG, -C(O)-Ci-Ce alkyl opticsubstituted with one or more halogen, or Rc, wherein Rccombines with RN1° to form a heterocycle;R7is hydrogen, -OH, or -ORC, wherein -ORecombines with RN1° to form a heterocycle; R8is -CH3or -OH;R9is hydrogen, -CH2OH, -CH2O-G-RG, or -CH2S-G-RG;R10is Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, or -G-RG, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen;RGis the attachment point to the rest of the molecule;RN1is hydrogen, Ci-Ce alkyl optionally substituted with one or more halogen, HO-Ci-Ce alkylene, RNA-C(O)-, RNAO-C(O)-, N(RNA)2-C(O)-, (H2N)(HN=)C-, RNA-S(O)2- or-GN-RG;RN2is hydrogen, Ci-Ce alkyl, or C(O) Ci-Ce alkyl, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; or- 924 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WORN1and RN2together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN3and RN4are each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-Ce alkyl, -C(=NH)NH2, wherein the Ci-Ce alkyl or-C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN3and RN4together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN5and RN6are each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-Ce alkyl, C1-C6 alkylene-OC(O)-Ci-C6 alkyl, or -C(=NH)NH2, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN5and RN6together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN7and RN8are each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-Ce alkyl, -C(=NH)NH2, wherein the Ci-Ce alkyl or-C(O)-Ci-C6 alkyl is optionally substituted with one or more halogen; orRN7and RN8together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN9is hydrogen, -CH3, or -C(0)CH3;RN1° is hydrogen, -C(O)-RNA, -C(O)-ORNA, -C(O)-N(RNA)2, or -S(O)2-RNA, optionally substituted phenyl, or combines with R6being Rcor R7being -ORCto form a heterocycle;RNAis each independently Ci-Ce alkyl optionally substituted with one or more halogen, C2-C6 heteroalkyl, optionally substituted aryl, or optionally substituted heteroaryl;Raand Rbare each independently hydrogen or -CH3;Rcis -C(O)-, -S(O)-, -S(O)2- or -C(=NH)-;Gis -(CH2)t-*, -(CH2-(CH2OCH2)s-(CH2)t-*, -(CH2)t-C(O)NH-(CH2)t-*, or-(CH2)t-NHC(O)-(CH2)t-*, wherein indicates the attachment point to the oxygen atom;GNis -(CH2)t-NHC(O)-*, -(CH2)t-C(O)-*, -(CH2)t-(CH2OCH2)s-(CH2)t-C(O)-*, or -(CH2)t-(CH2OCH2)s-(CH2)t-*, whereinindicates the attachment point to the nitrogen atom;each s is independently an integer from 1 to 10; andeach t is independently an integer from 0 to 20.- 925 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WO2. The compound of claim 1, wherein the targeting moiety B does not comprise or have a structure selected from:Ry, and Rz are each independently hydrogen or -CH3.

3. The compound of claim 1 or 2, wherein the targeting moiety B comprises or has one of the following structures of Formula (Xia), (Xlb), and (XIc):(Xlb) wherein:G is -(CH2)t-*, -(CH2)t-(CH2OCH2)s-(CH2)t-*, -(CH2)t-C(O)NH-(CH2)t-*, or -(CH2)t-NHC(O)-(CH2)t-*, whereinindicates the attachment point to the oxygen atom;GNis -(CH2)t-NHC(O)-*, -(CH2)t-C(O)-*, -(CH2)t-(CH2OCH2)s-(CH2)t-C(O)-*, or -(CH2)t-(CH2OCH2)s-(CH2)t-*, wherein indicates the attachment point to the nitrogen atom;- 926 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WORN1is hydrogen, Ci-Ce alkyl optionally substituted with one or more halogen, HO-Ci-Ce alkylene, RNA-C(O)-, RNAO-C(O)-, N(RNA)2-C(O)-, (H2N)(HN=)C- or RNA-S(O)2-;RN2is hydrogen, Ci-Ce alkyl, or -C(O)-Ci-Ce alkyl, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN1and RN2together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN3and RN4are each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-Ce alkyl, -C(=NH)NH2, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN3and RN4together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN5and RN6are each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-Ce alkyl, Ci-Ce alkylene-OC(O)-Ci-C6 alkyl, or -C(=NH)NH2, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN5and RN6together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN7and RN8are each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-Ce alkyl, or -C(=NH)NH2, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN7and RN8together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN9is hydrogen, -CH3, or -C(O)CH3;RN1° is hydrogen, -C(O)-RNA, -C(O)-ORNA, -C(O)-N(RNA)2, -S(O)2-RNA, optionally substituted phenyl, or combines with R6being Rcor R7being -ORCto form a heterocycle;RNAis each independently Ci-Ce alkyl optionally substituted with one or more halogen, C2-C6heteroalkyl, optionally substituted aryl, or optionally substituted heteroaryl;R6is hydrogen, -C(O)-Ci-Ce alkyl optionally substituted with one or more halogen, or Rc, wherein Rccombines with RN1° to form a heterocycle;R7is hydrogen, -OH, or -ORC, wherein -ORecombines with RN1° to form a heterocycle; Raand Rbare each independently hydrogen or -CH3;Rcis -C(O)-, -S(O)-, -S(O)2-, or -C(=NH)-;- 927 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOs is an integer from 1 to 10;t is an integer from 0 to 20, andwith a proviso that when (i) each of RN1, RN2RN3, RN4, RN\ RN6, RN7, and RN8is hydrogen; (ii) RN9is -CH3; and (iii) RN1° is hydrogen and R7is -OH, or RN1° combines with -C(O)- and R7being -ORCto make an oxazolidinone ring, G is not -(CH2)-(CH2OCH2)2-(CH2)-*.

4. The compound of claim 1, wherein the targeting moiety B comprises or has the following structure of Formula (XI’ a):I2I(Xl’a)whereinG is -(CH2)t-*, -(CH2 -(CH2OCH2)s-(CH2)t-*, -(CH2)t-C(O)NH-(CH2)t-*, or-(CH2)t- NHC(O)-(CH2)t-*, whereinindicates the attachment point to the oxygen atom;s is an integer from 1 to 10; andt is an integer from 0 to 20.

5. A compound comprising a targeting moiety B, where the targeting moiety B comprises or has the following structure of Formula (Xll):Ra'"R3-"(XII)wherein:R4-"R1’11is G11or HO R5’11- 928 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOR2 1is -OH or -NRN1-nRN2-n;R3'11is -OH or -NX3-"4-";R4'" is -OH or -NRN5-nRN6’n;R541is -OH or -NRN7-nRN8’n;RN1’nand RN2’neach independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-Ce alkyl, or -C(=NH)NH2; orRM-Hanj RN2-II together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN3-Hanj RN4-IIeacindependently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-C6alkyl, or-C(=NH)NH2; orRN3 nand RN4 ntogether with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN5'nand RN6’neach independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-C6alkyl, or -C(=NH)NH2; orRN5-Hanj RN6-II together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN7'nand RN8’neach independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-C6alkyl, or-C(=NH)NH2; orRN7'nand RN8'ntogether with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;Gnis -(CH2)t-*, -(CH2)t-(CH2OCH2)s-(CH2)t-*, -(CH2>-C(O)NH-(CH2)t-*, or -(CH2)t-NHC(O)-(CH2)t-*, wherein indicates the attachment point to the oxygen atom; each s is independently an integer from 1 to 10; andeach t is independently an integer from 0 to 20.

6. The compound of claim 5, wherein one ofR2'11and R3'11is -NRN1'IIRN2'11or -NR3‘nRN4'n; and / or one of R4'11and R5’11is -NRN5-nRN6’nor -NRN7-nRN8-n7. The compound of claim 5, wherein R2'11is -NRN1’nRN2’n, R3 11is -NRN3’nRN4’n, R441is -NRN5-IIRN6.nand R5-II is-NRN -IlRNS-II- 929 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WO8. A compound comprising a targeting moiety B, wherein the targeting moiety B comprises or has the following structure of Formula (VI):wherein:Al is absentor, whereinindicates the attachment point to A2;A2 is absentor, wherein “#” indicates the attachment point to A3;A3 is absent or, whereinindicates the attachment point to G; R1is C3-C7 alkyl, aryl, or Ci-Ce alkylene-aryl, wherein the C3-7 alkyl or aryl is optionally substituted,R2'Vis hydrogen or C1-6 alkyl,RN1’Vand RN2’Vare each independently hydrogen, Ci-Cs alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-C6 alkyl, or -C(=NH)NH2, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN1’Vand RN2’Vtogether with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;- 930 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WORN3'Vand RN4-Vare each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-Ce alkyl, or -C(=NH)NH2, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN3’Vand RN4’Vtogether with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN5'Xand RN6are each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-Ce alkyl, or -C(=NH)NH2, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN5’Vand RN6’Vtogether with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN7 Vand RN8 Vare each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-C6 alkyl, or -C(=NH)NH2, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN7’Vand RN8together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN9’Vand RN,0-Vare each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-Ce alkyl, or -C(=NH)NH2, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN9’Vand RN10'Vtogether with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RO1'Vis hydrogen or -C(O)-Ci-Ce alkyl;Gvis -(CH2)t-C(O)-* or -(CH2)t-(CH2OCH2)s-(CH2)t-C(O)-*, whereinindicates the attachment point to the nitrogen atom;each s is independently an integer from 1 to 10; andeach t is independently an integer from 0 to 20.

9. The compound of claim 8, wherein(i) when RN1’V, RN2'V, RN3’V, RN4'V, RN5'V, and RN6'Vare each hydrogen, Al is present, and A2 and A3 are absent, -NRN7'VRN8'Vis not -NH2or -NHC(=NH)NH2; or- 931 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WO(ii) when RN1’ RN2‘V, RN3'V, RN4’ RN5and RN6are each hydrogen, and Al, A2, and A3 are present, -NRN7'VRN8’Vand -NRN9'VRN10'Vare not both -NH2 or both - NHC(=NH)NH2.

10. The compound of claim 8 or 9, wherein A2 is absent or is selected from11. The compound of any one of claims 8-10, wherein the targeting moiety B comprises or has one of the following structures of Formula (Via), (VIb), and (Vic):(Via)(VIb)- 932 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WO(Vic)12. The compound of any one of claims 8-11, wherein R1is13. The compound of any one of claims 1-12, wherein the compound comprises 1, 2, 3, 4, 5, or 6 of the targeting moiety B, and wherein when more than one targeting moiety B is present, each targeting moiety B is independently the same as or different from the other targeting moi eties B.

14. The compound of any one of claims 1-13, wherein the compound further comprises a nucleic acid A and / or a linker.

15. The compound of claim 14, wherein the targeting moiety B is conjugated to the nucleic acid A via the linker.

16. The compound of claim 15, wherein the linker between the nucleic acid A and the targeting moiety B has the following structure:ZiA I |— Lo— P11— L— I I BZ2wherein- 933 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOZi is O or S;Z2 is -OH or O';Lois absent or an oligonucleotide of 2-10 nucleotides in length; andL comprises or has following structure of Formula (III):|— X— RM,- Lc— RM2— LS— RM3— Lt— Y-jn(III)wherein:RMi, RM2, and RM3 are each independently a bond or a reactive moiety;Lcis absent or a cleavable linker;Lsis absent or a stretcher;Li is absent or a linear or branched linkage moiety;X is M, M-W, W-M, or M-W-M, whereinM is -NH-, -O-, or -S-, andW is an optionally substituted alkylene or heteroalkylene;each Y is independently Q, T, Q-T, T-Q, or Q-T-Q-T, whereinQ is a bond, -C(O)-, -C(O)O- -C(O)NH- -NH-, -NHC(O)-, - o NI '-NNHC(O)NH- -O-, -OC(O)-, N=N?orN, andT is an optionally substituted alkylene or heteroalkylene; andn is 0, 1, 2, 3, 4, 5, or 6.

17. A compound comprising a nucleic acid A conjugated to one or more targeting moieties B via one or more linkers, wherein:each targeting moiety B independently comprises a glucosamine moiety, an aminoglycoside moiety, a polymyxin moiety, or an analog thereof;each linker may be attached to more than one targeting moiety B; andeach linker independently has the following structure:- 934 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOwhereinZi is O or S;Z2 is -OH or O’;Lo is absent, a nucleotide, or an oligonucleotide of 2-10 nucleotides in length; and L comprises or has following structure of Formula (III’):|— x— RM-J-Lc— RM2— LS— RM3— L{--Y— RM4-|n(IIP)wherein:RMi, RM2, RM3, and RM4 are each independently a bond or a reactive moiety; Lcis absent or a cleavable linker;Lsis absent or a stretcher;Lt is absent or a linear or branched linkage moiety;X is M, M-W, W-M, or M-W-M, whereinM is -NH-, -O-, or -S-, andW is an optionally substituted alkylene or heteroalkylene;each Y is independently Q, T, Q-T, T-Q, or Q-T-Q-T, whereinQ is a -C(O)-, -C(O)O- -C(O)NH- -NH-, -NHC(O)-, -NHC(O)NH-T is an optionally substituted alkylene or heteroalkylene; andn is 0, 1, 2, 3, 4, 5, or 6.

18. The compound of claim 17, wherein, when more than one targeting moiety B is present, each targeting moiety B is independently the same as or different from the other targeting moieties B.

19. The compound of claim 17 or 18, wherein, when the compound comprises exactly one nucleic acid A, exactly one linker, and exactly 1, 2, or 3 identical targeting moiety B,(i) the linker is not selected from moieties 3-27a, 5-la, 5- lb, 5-2a, 5-2b, 5-3a, 5-4a, 5- 5a, 5-6a, and 5-6b; or- 935 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WO (ii) the targeting moiety B does not comprise a structure selected from the following:- 936 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WO20. The compound of claim 17 or 18, wherein, when the compound comprises exactly one nucleic acid A, exactly one linker, and exactly 1, 2, or 3 identical targeting moiety B,(iii) the linker is not selected from moieties 3-27b, 3-27c, 5-la, 5-lb, 5-lc, 5-2a, 5-2b, 5-3a, 5-3b, 5-5a, 5-5b, 5-6a, or 5-6b; or(iv) the targeting moiety B does not comprise a structure selected from the following:wherein Rx, Ry, and Rz are each independently hydrogen or -CH3.

21. The compound of any one of claim 16-20, wherein Lois absent or an oligonucleotide of 2-5 nucleotides in length, optionally wherein the oligonucleotide comprises the following sequence: dTdT, wherein d = deoxyribose and T = nucleobase thymine.

22. The compound of any one of claims 16-21, wherein X is M-W, optionally wherein M is - O-, and W is Ci -20 alkylene, optionally wherein X is -O-Ce alkylene.- 937 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WO23. The compound of any one of claims 16-22, wherein RMi is a bond, -C(O)-, -C(O)NH--C(O)O-, -NH-, -NHC(O)-, -NHC(O)NH-, O, or N=N, optionally wherein RMi is -NH-, or -NHC(O)-.

24. The compound of any one of claims 16-23, wherein Lcis absent or a cleavable linker.

25. The compound of claim 24, wherein(i) Lchas the following structure:Formula (LC-1)(ii) Lccomprises a disulfide linkage, optionally wherein Lccomprises has the following structure:Formula (LC-2)(iii) Lc comprises a peptide, optionally wherein the peptide has a structure selected from the following:F ormul a (LC -3 ) F ormul a (LC -4 )optionally wherein Formula (LC-3) and (LC-4) have the following stereochemistry:Formula (LC-3’) Formula (LC-4’)- 938 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WO(iv) Lc comprises a nitrogen-containing heterocycle moiety, optionally wherein Lchas a structure of Formula (LC-5) or Formula (LC-6):N N IL, NFormula (LC-5) Formula (LC-6)26. The compound of any one of claims 16-25, wherein RM2 is a bond, -C(O)-, -C(O)NH-,-C(O)O- -NH-, -NHC(O)-, -NHC(O)NH- -O-, orN, optionally whereinRM2 is -C(O)- or27. The compound of any one of claims 16-26, wherein Lsis absent, C1-30 alkylene, C2-30 alkenylene, C2-30 alkynylene, or 3-50 membered heteroalkylene, each of which is optionally substituted (e.g., with oxo);optionally wherein Lsis -(CH2)P-, -(CFbCFhC^q-, -(OCH2CH2)q-, -(CH2)P-(CH2CH2O)q-, -(OCH2CH2)q-(CH2)P- -(CH2)P-(CH2OCH2)q-(CH2)P-, or-(CH2)P-U-(CH2)P-(CH2OCH2)q-(CH2)P-, wherein U is -C(O)NH- or -NHC(O)-, optionally one or more hydrogens in each (CH2)Pis independently substituted with C1-3 alkyl, each p is independently an integer from 0 to 30, each q is independently an integer from 0 to 30, and not all p and q are 0; optionally wherein Ls is -(CH2)2-, -(CH2)3-, -(CH2)2o-, -(CH2OCH2)-, -(CH2)- (CH2OCH2) (CH2), (CH2) (CH2OCH2)2 (CH2), (CH2) (CH2OCH2)3 (CH2), (CH2)-(CH2OCH2)5-(CH2)-, -(CMe2)-(CH2OCH2)5-(CMe2)-, -(CH2)-(CH2OCH2)i2- (CH2)-, -(CH2)-(CH2OCH2)18-(CH2)-, or -(CH2)3-NHC(O)-(CH2)-(CH2OCH2)5- (CH2)-.

28. The compound of any one of claims 16-27, wherein RM3 is a bond, -C(O)-, -C(O)NH--C(O)O-, -NH-, -NHC(O)-, -NHC(O)NH-, or -O-.

29. The compound of any one of claims 16-28, wherein Lt is absent, and n is 0 or 1.- 939 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WO30. The compound of any one of claims 16-28, wherein Lt has a structure selected from the following:RMa-La-RMb-Lb-RMcRMaLaRMbLbRMC, QJ- (i)O Ma-La-RMb-Lb-RMc5H OLaRMbLbRMC, and n is 2;O. RMa— La-RMb-Lb-RM,0 RLLRMa— La— RMb-Lb— RM,RMa— La— RMb— Lb— RM, RMa- L^- RMb— Lb- RM, 0 or RMa— La— RMb— Lb— RM,, and n is 3; RMa-La— RMb— Lb— RM, RMa— La— RMb— Lb— RM, RMa-La- RMb— Lb— RM,RMaLaRMbLbRMC,ancj n i S 4; Or RMa— La— RMb— Lb— RM, RMa— La— RMb— Lb— RM, RMa— La— RMb— Lb— RM, O— ' RMa-La— RMb— Lb— RM, O RMa-La— RMb— Lb— RM, RMa— La— RMb— Lb— RMC, and n is 6, wherein:RMa, RMb, and RMCare each independently a bond, -C(O)-, -C(O)NRRM-, -C(O)O-, - NRRM-, -NRRMC(O)-, -NHC(O)NH-, -NHC(O)O-, -O-, or -OC(O)-;Lais absent or La is C1-30 alkylene, C2-30 alkenylene, C2-30 alkynylene, or 3-50 membered heteroalkylene;- 940 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOLb is absent or Lb is C1-30 alkylene, C2-30 alkenylene, C2-30 alkynylene, 3-50 membered heteroalkylene, G1, C1-6 alkylene-G1, or 2-6 membered heteroalkylene-G1; andRLLis hydrogen or C 1-3 alkyl;RRM jshydrogenor 3alkyl;G1is C3-10 cycloalkylene, 3-10 membered heterocyclyl, Ce-io aryl, or 5-10 membered heteroaryl.

31. The compound of claim 30, wherein RMa is a bond, -C(O)-, -C(O)NH- -C(O)NCH3-, -NH-, or -NCH3-.

32. The compound of claim 30 or 31, wherein Lais absent, -(CH2)P- -(CH2CH2O)q-, -(OCH2CH2)q-, -(CH2)P-(CH2CH2O)q-, -(OCH2CH2)q-(CH2)P-, -(CH2)p-(CH2OCH2)q-(CH2)p-, or -(CH2)p-(CH2NRLACH2)q-(CH2)p-,wherein RLAis hydrogen or C1-3 alkyl; each p is independently an integer from 0 to 30; each q is independently an integer from 0 to 30; and not all p and q are 0;optionally wherein La is -(CH2)2-, -(CH2)3-, -(CH2)io-, -(CH2)-(CH2OCH2)-(CH2)-, -(CH2)-(CH2OCH2)2-(CH2)-, -(CH2)-(CH2OCH2)3-(CH2)-, or -(CH2)-(CH2N(CH3)CH2)3-(CH2)-.

33. The compound of any one of claims 30-32, wherein RMb is a bond, -NH-, -NHC(O)-, or -NHC(O)O-34. The compound of any one of claims 30-33, wherein Lb is absent, C1-30 alkylene, 3-50 membered heteroalkylene, C3-10 cycloalkylene, 3-10 membered heterocyclyl, Ce-io aryl, C1-6 alkylene-Cs-io cycloalkylene, C1-6 alkylene-3-10 membered heterocyclyl, or C1-6 alkylene-Ce-io aryl;- 941 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOoptionally wherein Lb is -(CH2)2-, -(CH2)3-, -(CH2)IO-35. The compound of any one of claims 30-34, wherein RMCis a bond, -C(O)-, -NH-, or -O-.

36. The compound of any one of claims 30-35, wherein Y is Q, and optionally RM4 is a bond.

37. The compound of any one of claims 30-35, wherein Y is Q-T, and optionally RM4 is a bond, — C(O)—, -C(O)NH-, -O-, or -S-; optionally wherein RM4 is a bond or -C(O)-.

38. The compound of any one of claims 36-37, wherein Q is a bond, -C(O)-, -C(O)NH-, -NH-, or39. The compound of any one of claims 36-38, wherein T is C1-30 alkylene or 3-50 membered heteroalkylene;optionally wherein T is -(CH2)P- -(CH2CH2O)q-, -(OCH2CH2)q-, -(CH2)p-(CH2CH2O)q-, -(OCH2CH2)q-(CH2)P-, or -(CH2)p-(CH2OCH2)q-(CH2)P-, wherein each p is independently an integer from 0 to 30, each q is independently an integer from 0 to 30, and not all p and q are 0;optionally wherein T is -(CH2)4-, -(CH2)6- -(CH2)-(CH2OCH2)2-(CH2)-, -(CH2)-(CH2OCH2)5-(CH2)-, or -(CH2)-(CH2OCH2)i2-(CH2)-.

40. The compound of any one of claims 30-35, wherein Y is Q-T-Q-T, and optionally RM4 is a bond;- 942 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOoptionally wherein Yis41. The compound of any one of claims 16-40, wherein the linker comprises or has the following structure of Formula (III- 1), (III-2), (III-3), or (III-4):OHI Jo-19 (III-l)OH0-30L J L J0-30L Jo-30 (III-2)(III-3)- 943 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WO(III-4)42. The compound of any one of claims 16-40, wherein the linker comprises or has the following structure of Formula (III’-l), (III’-2), (III’ -3), or (IIF-4):OH(iir-i)OH O L JO-19(iir-2)1H 1 • Nx Ab-RMc-Q,o o o-. o-3ol JO-3OL O JO-1 0 OHO r 1 O FH 1 N o -Nx^Lb — RMC— Q o. J0-19HO-3OL.. O-3OL Jo-30 L d Jo-1 0O O I_J U*-N.■N- J XRMC-Q.o. RM4-|0-:. o-3ol JO-3O L O JO-1 0-1 oL..0-10L Jo-10(iir-3)- 944 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WO0-30L J L J0-30l Jo-30 0-10L J L JO-IOL Jo-10(iir-4)43. The compound of any one of claims 16-42, wherein the linker comprises or has a structure selected from:(i) Table 10a, Ila, 12a, and 13a;(ii) Table 10b, lib, 12b, and 13b;(v) Table 10c, 11b, 12c, and 13c;(vi) Table 14a or 14b;(vii) Table 31;(viii) moieties 3-13, 3-15, 3-28, and 3-37;(ix) moieties 3-13a, 3-13b, 3-15a, 3-28a, and 3-37a;(x) moieties 3-13a’, 3-13b’, 3-15a’, 3-28a’, and 3-37a’.

44. The compound of any one of claims 17-43, wherein at least one targeting moiety B comprises or has a neamine, nebramine, gentamine, gentamicin (e.g., gentamicin Cl), kanamycin, neomycin, or paromomycin moiety, or an analog thereof.

45. The compound of any one of claims 17-43, wherein at least one targeting moiety B comprises or has a structure of Formula (VI):- 945 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOwherein:|_HflN— RN7’VAl is absentor RN8'V, whereinindicates the attachment point to A2;j H flA2 is absentorr2 V oh, whereinindicates the attachment point to A3;l_HLL__ IN— RN9-VA3 is absentor RN1°-V, whereinindicates the attachment point to G; R1is C3-C7 alkyl, aryl, or Ci-Ce alkylene-aryl, wherein the C3-7 alkyl or aryl is optionally substituted,R2is hydrogen or Ci-Ce alkyl,RN1'Vand RN2’Vare each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-C6 alkyl, or -C(=NH)NH2, wherein the Ci-Ce alkyl or -C(O)-Ci-C6 alkyl is optionally substituted with one or more halogen; orRN1'Vand RN2’Vtogether with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;- 946 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WORN3'Vand RN4-Vare each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-Ce alkyl, or -C(=NH)NH2, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN3’Vand RN4’Vtogether with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN5'Xand RN6are each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-Ce alkyl, or -C(=NH)NH2, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN5’Vand RN6’Vtogether with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN7 Vand RN8 Vare each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-C6 alkyl, or -C(=NH)NH2, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN7’Vand RN8together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN9’Vand RN,0-Vare each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-Ce alkyl, or -C(=NH)NH2, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN9’Vand RN10'Vtogether with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RO1'Vis hydrogen or -C(O)-Ci-Ce alkyl;Gvis -(CH2)t-C(O)-* or -(CH2)t-(CH2OCH2)s-(CH2)t-C(O)-*, whereinindicates the attachment point to the nitrogen atom;each s is independently an integer from 1 to 10; andeach t is independently an integer from 0 to 20.

46. The compound of any one of claims 17-43, wherein at least one targeting moiety B comprises or has a structure of Formula (XII):- 947 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOwherein:R241is -OH or -NRN1-nRN2-n;R3'11is -OH or -NRN3-nRN4-n;R4 1is -OH or -NRN5-nRN6’n;R541is -OH or -NRN7-nRN8-n;RN1-nand RN2’neach independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-C6alkyl, or -C(=NH)NH2; orRM-Hanj RN2-II together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN3-Hanj RN4-IIeach independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-C6alkyl, or -C(=NH)NH2; orRN3-Hanj RN4-II together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN5-nand RN6’neach independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-C6alkyl, or -C(=NH)NH2; orRN5-Hanj RN6-II together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN7'nand RN8’neach independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-C6alkyl, or -C(=NH)NH2; orRN7-nand RN8'ntogether with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;- 948 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOGnis -(CH2)t-*, -(CH2)t-(CH2OCH2)s-(CH2-*, -(CH2)t-C(O)NH-(CH2)t-*, or -(CH2)t-NHC(O)-(CH2)t-*, wherein indicates the attachment point to the oxygen atom; each s is independently an integer from 1 to 10; andeach t is independently an integer from 0 to 20.

47. The compound of any one of claims 17-44, wherein at least one targeting moiety B comprises or has a structure of Formula (XI) or (XI’):RN4N-RN3RN6HO"HO N-RN5ORI1°(xr)wherein:RN9R1is hydrogen orR2is hydrogen or -G-RG;R3is -OH or-NRN7RN8;R4and R3are each independently hydrogen or -OH;R6is hydrogen, -G-RG, -C(O)-Ci-Ce alkyl optionally substituted with one or more halogen, or Rc, wherein Rccombines with RN1CIto form a heterocycle;R7is hydrogen, -OH, or -ORC, wherein -ORCcombines with RN1° to make an oxazolidinone ring;R8is -CH3or -OH;R9is hydrogen, -CH2OH, -CH2O-G-RG, or -CH2S-G-RG;R10is Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, or -G-RG, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen;RGis the attachment point to the rest of the molecule;- 949 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WORN1is hydrogen, Ci-Ce alkyl optionally substituted with one or more halogen, HO-Ci-Ce alkylene, RNA-C(O)-, RNAO-C(O)-, N(RNA)2-C(O)-, (H2N)(HN=)C- RNA-S(O)2-, or -GN-RG;RN2is hydrogen, Ci-Ce alkyl, or -C(O)-Ci-Ce alkyl, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN1and RN2together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN3and RN4are each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-Ce alkyl, or -C(=NH)NH2, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN3and RN4together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN5and RN6are each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-Ce alkyl, Ci-Ce alkylene-OC(O)-Ci-C6 alkyl, or -C(=NH)NH2, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN5and RN6together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN7and RN8are each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-Ce alkyl, or -C(=NH)NH2, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN7and RN8together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN9is hydrogen, -CH3, or -C(O)CH3;RN1° is hydrogen, -C(O)-RNA, -C(O)-ORNA, -C(O)-N(RNA)2, -S(O)2-RNA, optionally substituted phenyl, or combines with R6being Rcor R7being -ORCto form a heterocycle;RNAis each independently Ci-Ce alkyl optionally substituted with one or more halogen, C2-C6heteroalkyl, optionally substituted aryl, or optionally substituted heteroaryl;Raand Rbare each independently hydrogen or -CH3;Rcis -C(O)-, -S(O)-, -S(O)2-, or -C(=NH)-;G is -(CH2)t-*, -(CH2-(CH2OCH2)s-(CH2)t-*, -(CH2-C(O)NH-(CH2)t-*, or-(CH2)t-NHC(O)-(CH2)t-*, whereinindicates the attachment point to the oxygen atom;- 950 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOGNis -(CH2)t-NHC(O)-*, -(CH2)t-C(O)-*, -(CH2-(CH2OCH2)s-(CH2)t-C(O)-*, or -(CH2)t-(CH2OCH2)s-(CH2)t-*, wherein indicates the attachment point to the nitrogen atom;each s is independently an integer from 1 to 10; andeach t is independently an integer from 0 to 20.

48. A compound comprising a nucleic acid A conjugated to one or more targeting moieties B via one or more linkers, wherein each linker may be attached to more than one targeting moiety B, and wherein:(i) each targeting moiety B independently comprises or has a structure of Formula (XI), (XI’), (XII), or (VI):R1is hydrogen or RN9- 951 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOR2is hydrogen or -G-RG;R3is -OH or -NRN7RN8;R4and R5are each independently hydrogen or -OH;R6is hydrogen, -G-RG, -C(O)-Ci-Ce alkyl optionally substituted with one or more halogen, or Rc, wherein Rccombines with RN1° to form a heterocycle;R7is hydrogen, -OH, or -ORC, wherein Rccombines with RN1° to form a heterocycle;R8is -CH3 or -OH;R9is hydrogen, -CH2OH, -CH2O-G-RG, or -CH2S-G-RG;R10is Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, or -G-RG, wherein the Ci-Ce alkyl or - C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen;RGis the attachment point to the rest of the molecule;R1is hydrogen, Ci-Ce alkyl optionally substituted with one or more halogen, HO- C1-C6 alkylene, RNA-C(O)-, RNAO-C(O)-, N(RNA)2-C(O)-, (H2N)(HN=)C-, RNA-S(O)2-, or-Gx-RG;R2is hydrogen, Ci-Ce alkyl, or -C(O)-Ci-Ce alkyl, wherein the Ci-Ce alkyl or - C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orR1and RN2together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;R3and RN4are each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, - C(O)-Ci-Ce alkyl, or -C(=NH)NH2, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN3and RN4together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;R5and RN6are each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, - C(O)-Ci-Ce alkyl, Ci-Ce alkylene-OC(O)-Ci-C6 alkyl, or -C(=NH)NH2, wherein the Ci- Ce alkyl or-C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; or R3and RN6together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;- 952 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOR7and RN8are each independently hydrogen, Ci-Cs alkyl, Ci-Cs alkylene-OH, - C(O)-Ci-Ce alkyl, or -C(=NH)NH2, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orR7and RN8together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;R9is hydrogen, -CH3, or -C(O)CHs;R1° is hydrogen, -C(O)-RNA, -C(O)-ORNA, -C(O)-N(RNA)2, -S(O)2-RNA, optionally substituted phenyl, or combines with R6being Rcor R7being -ORCto form a heterocycle;RAis each independently Ci-Ce alkyl optionally substituted with one or more halogen, C2-C6 heteroalkyl, optionally substituted aryl, or optionally substituted heteroaryl;Raand Rbare each independently hydrogen or -CH3;Rcis -C(O)-, -S(O)-, -S(O)2-, or -C(=NH)-;G is -(CH2)t-*, -(CH2)t-(CH2OCH2)s-(CH2 -*, -(CH2)t-C(O)NH-(CH2)t-*, or - (CH2)t-NHC(O)-(CH2)t-*, whereinindicates the attachment point to the oxygen atom;GNis -(CH2)t-NHC(O)-*, -(CH2)t-C(O)-*, -(CH2)t-(CH2OCH2)s-(CH2)t-C(O)- *, or -(CH2)t-(CH2OCH2)s-(CH2)t-*, wherein indicates the attachment point to the nitrogen atom;R1'11is GnorR2 11is -OH or -NRN1 IIRN2-n;R3'11is -OH or -NRN3 IIR4 n;R4‘" is -OH or -NRN5 IIR6 n;R5 11is -OH or -NRN7-nR8 n;R1'TIand RN2’ITeach independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, - C(O)-Ci-Ce alkyl, or -C(=NH)NH2; orRN1'nand RN2'ntogether with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;- 953 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOR3‘nand RN4’neach independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, - C(O)-Ci-C6alkyl, or -C(=NH)NH2; orR3-nand RX4‘" together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN5'nand RN6’neach independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, - C(O)-Ci-Ce alkyl, or -C(=NH)NH2; orR 5-Hanj j^N6-n tOgetherwith the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;R7‘nand RN8’neach independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, - C(O)-C1-C6alkyl, or -C(=NH)NH2; orR7 nand RN8-ntogether with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;Gnis -(CH2)t-*, -(CH2)t-(CH2OCH2)s-(CH2)t-*, -(CH2)t-C(O)NH-(CH2)t-*, or -(CH2)t-NHC(O)-(CH2)t-*, wherein indicates the attachment point to the oxygen atom;; H ° |Il^N— RN7’VAl is absent or RNS-V,wherein indicates the attachment point to A2;A2 is absentor R2"v 0H, wherein “#” indicates the attachment point to A3;i_ H j| |#rNv *L^N-RN9-VA3 is absent or RNIO-V,whereinindicates the attachment point to G;R1is C3-C7 alkyl, aryl, or C1-6 alkylene-aryl, wherein the C3-7 alkyl or aryl is optionally substituted,R2 Vis hydrogen or C1-6 alkyl,- 954 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WORN1 Vand RN2-Vare each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-Ce alkyl, or -C(=NH)NH2, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orR1‘Vand RN2together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;R3and RN4-Vare each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-Ce alkyl, or -C(=NH)NH2, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orRN3 Vand RN4together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RN5 Vand RN6 Vare each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-Ci-Ce alkyl, or -C(=NH)NH2, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orR5and RN6‘Vtogether with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;R7'Vand RN8-Vare each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene-OH, -C(O)-C1-C6 alkyl, or -C(=NH)NH2, wherein the Ci-C6alkyl or -C(O)-Ci-C6alkyl is optionally substituted with one or more halogen; orR7'Vand RN8’Vtogether with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;R9'Vand RN1°-Vare each independently hydrogen, Ci-Ce alkyl, Ci-Ce alkylene- OH, - C(O)- Ci-Ce alkyl, or -C(=NH)NH2, wherein the Ci-Ce alkyl or -C(O)-Ci-C6 alkyl is optionally substituted with one or more halogen; orR9'Vand RN1°-Vtogether with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;RO1‘Vis hydrogen or -C(O)-Ci-C6 alkyl;Gvis -(CH2)t-C(O)-* or -(CH2>-(CH2OCH2)s-(CH2)t-C(O)-*, wherein indicates the attachment point to the nitrogen atom;each s is independently an integer from 1 to 10; andeach t is independently an integer from 0 to 20, and- 955 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WO(ii) the nucleic acid A comprises an antisense strand of 12 to 60 linked nucleotides in length targeted to a solute carrier family 6 member 19 (SLC6A19) RNA, wherein(a) the antisense strand comprises a region of complementarity to the SLC6A19 RNA, and wherein the region of complementarity comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from a nucleotide sequence of 15 contiguous nucleotides comprised in any one of the antisense nucleotide sequences of SEQ IDNOs: 8-777 and 1555-2331; or(b) the antisense strand has at least about 80% complementarity to a target region of the SLC6A19 RNA and is capable of hybridizing with 12 or more nucleotides of nucleotides 3 to 25, nucleotides 8 to 30, nucleotides 13 to 35, nucleotides 38 to 60, nucleotides 43 to 65, nucleotides 48 to 70, nucleotides 93 to 115, nucleotides 98 to 120, nucleotides 103 to 125, nucleotides 108 to 130, nucleotides 111 to 133, nucleotides 113 to 135, nucleotides 118 to 140, nucleotides 214 to 236, nucleotides 219 to 241, nucleotides 244 to 266, nucleotides 249 to 271, nucleotides 252 to 274, nucleotides 253 to 275, nucleotides 254 to 276, nucleotides 255 to 277, nucleotides 256 to 278, nucleotides 257 to 286, nucleotides 259 to 281, nucleotides 264 to 286, nucleotides 289 to 311, nucleotides 294 to 316, nucleotides 339 to 361, nucleotides 397 to 419, nucleotides 460 to 480, nucleotides 461 to 481, nucleotides 481 to 503, nucleotides 486 to 508, nucleotides 491 to 513, nucleotides 557 to 579, nucleotides 561 to 583, nucleotides 562 to 584, nucleotides 564 to 586, nucleotides 566 to 586, nucleotides 567 to 589, nucleotides 616 to 638, nucleotides 617 to 639, nucleotides 618 to 640, nucleotides 621 to 643, nucleotides 626 to 648, nucleotides 670 to 692, nucleotides 671 to 691, nucleotides 672 to 694, nucleotides 674 to 694, nucleotides 675 to 697, nucleotides 680 to 702, nucleotides 685 to 707, nucleotides 690 to 712, nucleotides 695 to 717, nucleotides 700 to 722, nucleotides 705 to 727, nucleotides 710 to 732, nucleotides 715 to 737, nucleotides 720 to 742, nucleotides 725 to 747, nucleotides 730 to 752, nucleotides 735 to 757, nucleotides 738 to 760, nucleotides 739 to 761, nucleotides 740 to 762, nucleotides 741 to 763, nucleotides 742 to 764, nucleotides 745 to 767, nucleotides 750 to 772, nucleotides 751 to 773, nucleotides 752 to 774, nucleotides 753 to 775, nucleotides 754 to 776, nucleotides 755 to 777, nucleotides 756 to 778, nucleotides 757 to 779, nucleotides 760 to 782, nucleotides 765 to 787, nucleotides 770 to 792, nucleotides 775 to 797, nucleotides 798 to 823, nucleotides - 956 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WO800 to 822, nucleotides 825 to 847, nucleotides 826 to 848, nucleotides 877 to 899, nucleotides 890 to 912, nucleotides 895 to 917, nucleotides 900 to 922, nucleotides 905 to 927, nucleotides 910 to 932, nucleotides 911 to 937, nucleotides 915 to 937, nucleotides 918 to 940, nucleotides 972 to 994, nucleotides 973 to 995, nucleotides 974 to 996, nucleotides 975 to 997, nucleotides 977 to 1000, nucleotides 977 to 999, nucleotides 978 to 1000, nucleotides 981 to 1003, nucleotides 983 to 1005, nucleotides 984 to 1006, nucleotides 1033 to 1055, nucleotides 1034 to 1056, nucleotides 1035 to 1057, nucleotides 1058 to 1080, nucleotides 1059 to 1081, nucleotides 1060 to 1082, nucleotides 1063 to 1085, nucleotides 1064 to 1086, nucleotides 1065 to 1087, nucleotides 1066 to 1088, nucleotides 1067 to 1089, nucleotides 1068 to 1090, nucleotides 1070 to 1092, nucleotides 1074 to 1096, nucleotides 1075 to 1097, nucleotides 1077 to 1099, nucleotides 1078 to 1100, nucleotides 1079 to 1101, nucleotides 1080 to 1102, nucleotides 1081 to 1103, nucleotides 1082 to 1104, nucleotides 1085 to 1107, nucleotides 1086 to 1106, nucleotides 1090 to 1112, nucleotides 1095 to 1117, nucleotides 1100 to 1122, nucleotides 1105 to 1127, nucleotides 1110 to 1132, nucleotides 1115 to 1137, nucleotides 1115 to 1137, nucleotides 1117 to 1139, nucleotides 1177 to 1199, nucleotides 1178 to 1200, nucleotides 1179 to 1201, nucleotides 1182 to 1204, nucleotides 1187 to 1209, nucleotides 1191 to 1214, nucleotides 1192 to 1214, nucleotides 1195 to 1217, nucleotides 1233 to 1255, nucleotides 1234 to 1256, nucleotides 1235 to 1257, nucleotides 1236 to 1258, nucleotides 1239 to 1261, nucleotides 1242 to 1264, nucleotides 1244 to 1266, nucleotides 1247 to 1268, nucleotides 1249 to 1271, nucleotides 1251 to 1270, nucleotides 1254 to 1276, nucleotides 1259 to 1281, nucleotides 1263 to 1282, nucleotides 1264 to 1286, nucleotides 1266 to 1285, nucleotides 1269 to 1291, nucleotides 1326 to 1348, nucleotides 1331 to 1353, nucleotides 1334 to 1356, nucleotides 1342 to 1364, nucleotides 1335 to 1357, nucleotides 1336 to 1358, nucleotides 1337 to 1359, nucleotides 1337 to 1359, nucleotides 1338 to 1360, nucleotides 1340 to 1362, nucleotides 1341 to 1363, nucleotides 1342 to 1364, nucleotides 1346 to 1368, nucleotides 1351 to 1373, nucleotides 1353 to 1372, nucleotides 1377 to 1399, nucleotides 1382 to 1404, nucleotides 1383 to 1403, nucleotides 1387 to 1409, nucleotides 1392 to 1414, nucleotides 1397 to 1419, nucleotides 1402 to 1424, nucleotides 1407 to 1429, nucleotides 1412 to 1434, nucleotides 1417 to 1439, nucleotides 1456 to 1478, nucleotides 1458 to 1477, nucleotides 1481 to 1503, nucleotides - 957 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WO1486 to 1508, nucleotides 1491 to 1513, nucleotides 1496 to 1518, nucleotides 1521 to 1543, nucleotides 1568 to 1590, nucleotides 1569 to 1591, nucleotides 1574 to 1596, nucleotides 1578 to 1621, nucleotides 1579 to 1601, nucleotides 1583 to 1605, nucleotides 1583 to 1605, nucleotides 1584 to 1606, nucleotides 1584 to 1606, nucleotides 1585 to 1607, nucleotides 1585 to 1607, nucleotides 1587 to 1609, nucleotides 1588 to 1610, nucleotides 1589 to 1611, nucleotides 1594 to 1616, nucleotides 1595 to 1617, nucleotides 1599 to 1621, nucleotides 1601 to 1620, nucleotides 1602 to 1624, nucleotides 1642 to 1664, nucleotides 1749 to 1775, nucleotides 1750 to 1772, nucleotides 1755 to 1777, nucleotides 1757 to 1779, nucleotides 1758 to 1780, nucleotides 1760 to 1782, nucleotides 1761 to 1792, nucleotides 1764 to 1783, nucleotides 1765 to 1787, nucleotides 1770 to 1792, nucleotides 1809 to 1831, nucleotides 1810 to 1829, nucleotides 1812 to 1832, nucleotides 1814 to 1836, nucleotides 1852 to 1881, nucleotides 1853 to 1875, nucleotides 1854 to 1876, nucleotides 1858 to 1880, nucleotides 2168 to 2188, nucleotides 2333 to 2353, nucleotides 2454 to 2474, nucleotides 2507 to 2527, nucleotides 2593 to 2613, nucleotides 3244 to 3264, nucleotides 3288 to 3308, nucleotides 3304 to 3324, nucleotides 3332 to 3352, nucleotides 3333 to 3353, nucleotides 3501 to 3523, nucleotides 3595 to 3615, nucleotides 3595 to 3617, nucleotides 3643 to 3671, nucleotides 3646 to 3668, nucleotides 3646 to 3668, nucleotides 3647 to 3669, nucleotides 3648 to 3668, nucleotides 3648 to 3670, nucleotides 3648 to 3670, nucleotides 3649 to 3671, nucleotides 3651 to 3670, nucleotides 3651 to 3673, nucleotides 3651 to 3673, nucleotides 3652 to 3671, nucleotides 3712 to 3733, nucleotides 3713 to 3735, nucleotides 3763 to 3786, nucleotides 3763 to 3785, nucleotides 3764 to 3786, nucleotides 3791 to 3811, nucleotides 3796 to 3816, nucleotides 3801 to 3829, nucleotides 3801 to 3820, nucleotides 3802 to 3821, nucleotides 3804 to 3826, nucleotides 3809 to 3831, nucleotides 3810 to 3832, nucleotides 3812 to 3833, nucleotides 3812 to 3834, nucleotides 3813 to 3835, nucleotides 3814 to 3833, nucleotides 3814 to 3836, nucleotides 3814 to 3836, nucleotides 3839 to 3859, nucleotides 3840 to 3862, nucleotides 3902 to 3924, nucleotides 3965 to 3987, nucleotides 3995 to 4015, nucleotides 3998 to 4020, nucleotides 4100 to 4124, nucleotides 4102 to 4124, nucleotides 4141 to 4163, nucleotides 4141 to 4163, nucleotides 4142 to 4164, nucleotides 4143 to 4165, nucleotides 4144 to 4166, nucleotides 4146 to 4168, nucleotides 4150 to 4172, nucleotides 4151 to 4173, nucleotides 4192 to 4214, nucleotides 4197 to - 958 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WO4219, nucleotides 4201 to 4223, nucleotides 4265 to 4287, nucleotides 4270 to 4292, nucleotides 4318 to 4338, nucleotides 4319 to 4341, nucleotides 4329 to 4349, nucleotides 4348 to 4386, nucleotides 4349 to 4371, nucleotides 4350 to 4369, nucleotides 4350 to 4372, nucleotides 4350 to 4372, nucleotides 4351 to 4370, nucleotides 4352 to 4371, nucleotides 4352 to 4374, nucleotides 4353 to 4372, nucleotides 4353 to 4375, nucleotides 4354 to 4376, nucleotides 4359 to 4381, nucleotides 4361 to 4383, nucleotides 4362 to 4384, nucleotides 4362 to 4384, nucleotides 4364 to 4386, nucleotides 4365 to 4387, nucleotides 4395 to 4415, nucleotides 4396 to 4416, nucleotides 4409 to 4431, nucleotides 4410 to 4432, nucleotides 4412 to 4434, nucleotides 4637 to 4657, nucleotides 4638 to 4658, nucleotides 4640 to 4660, nucleotides 5103 to 5123, nucleotides 5124 to 5144, nucleotides 5126 to 5146, or nucleotides 5127 to 5147 of SEQ ID NO: 1.

49. The compound of claim 48, wherein, when more than one targeting moiety B is present, each targeting moiety B is independently the same as or different from the other targeting moi eties B.

50. The compound of any one of claims 47-49, wherein at least one targeting moiety B comprises or has a structure of Formula (XI), and wherein(i) R2is RG-(CH2>-*, RG-(CH2)t-(CH2OCH2)s-(CH2)t-*, or RG-(CH2>-NHC(0)- (CH2)t-*, whereinindicates the attachment point to the oxygen atom;R6is hydrogen;R9is hydrogen or -CH2OH; andRN1is hydrogen, Ci-Ce alkyl optionally substituted with one or more halogen, Ci- Ce alkylene-OH, -C(O)-RA, -C(O)-ORNA, -N(RNA)2-C(O), -C(=NH)NH2, or - S(O)2-RNA; and RN2is hydrogen, Ci-Ce alkyl, or -C(O)-Ci-Ce alkyl, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orR1and RN2together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;(ii) R2is hydrogen;- 959 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOR6is RG-(CH2>-*, RG-(CH2)t-(CH2OCH2)s-(CH2)t-*, or RG-(CH2>-NHC(O)- (CH2)t-*, wherein indicates the attachment point to the oxygen atom;R9is hydrogen or -CH2OH; andR1is hydrogen, Ci-Ce alkyl optionally substituted with one or more halogen, Ci- Ce alkylene-OH, -C(O)-RNA, -C(O)-ORNA, -N(RNA)2-C(O), -C(=NH)NH2, or - S(O)2-RNA; and RN2is hydrogen, Ci-Ce alkyl, or -C(O)-Ci-Ce alkyl, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orR1and RN2together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring;(iii) R2is hydrogen;R6is hydrogen;R9is -CH2S-(CH2)t-RG; andR1is hydrogen, Ci-Ce alkyl optionally substituted with one or more halogen, Ci- Ce alkylene-OH, -C(O)-RA, -C(O)-ORNA, -N(RNA)2-C(O), -C(=NH)NH2, or - S(O)2-RNA; and RN2is hydrogen, Ci-Ce alkyl, or -C(O)-Ci-Ce alkyl, wherein the Ci-Ce alkyl or -C(O)-Ci-Ce alkyl is optionally substituted with one or more halogen; orR1and RN2together with the atom to which they are attached form an optionally substituted 3-7-membered heterocyclyl ring; or(iv) R2is hydrogen;R6is hydrogen;R9is hydrogen or -CH2OH;RN1is RG-(CH2)t-NHC(O)-*, RG-(CH2)t-C(O)-*, RG-(CH2)t-(CH2OCH2)s-(CH2)t-C(O)-*, or RG-(CH2)t-(CH2OCH2)s-(CH2)t-*, wherein indicates the attachment point to the nitrogen atom; andR2is hydrogen or Ci-Ce alkyl.

51. The compound of any one of claims 47-50, wherein, when the compound comprises exactly one nucleic acid A, exactly one linker, and exactly one, two, or three identical targeting moiety B each comprising or having a structure of Formula (XI),- 960 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WO(iii) if RN1is not RG-GN- then (a) at least one of RN3, RN4, RN5, RN6, RN7, and RN8is not hydrogen, and / or (b) -NRN1RN2is not -NH2 or -NHCH3; or(iv) if RN1isG-GX, then (a) at least one of RN3, RN4, RN5, RN6, RN7, and RN8is not hydrogen, and / or (b) RN2is not hydrogen or -CH3.

52. The compound of any one of claims 1-4 and 47-51, whereinRN1is hydrogen, -CH3, -CH2CH3, -C(O)CH3, -C(O)CF3, -CH2CH2OH, or -C(=NH)NH2, andRN2is hydrogen or -CH3; orRN1and RN2together with the atom to which they are attached form a morpholine ring.

53. The compound of any one of claims 1-4 and 47-52, whereinRN3is hydrogen or -CH3, andRN4is hydrogen, -CH3, -CH2CH3, -C(O)CH3, -C(O)CF3,-CH2CH2OH, or -C(=NH)NH2; orRN3and RN4together with the atom to which they are attached form a morpholine ring.

54. The compound of any one of claims 1-4 and 47-53, whereinRN5is hydrogen or -CH3, andRN6is hydrogen, -CH3, -CH2CH3, -C(O)CH3, -C(O)CF3, -CH2CH2OH, or-C(=NH)NH2; orRN5and RN6together with the atom to which they are attached form a morpholine ring.

55. The compound of any one of claims 1-4 and 47-54, whereinRN7is hydrogen or -CH3, andRN8is hydrogen, -CH3, -CH2CH3, -C(O)CH3, -C(O)CF3, -CH2CH2OH, or-C(=NH)NH2; orRN7and RN8together with the atom to which they are attached form a morpholine ring.

56. The compound of any one of claims 1-4, 17-44, and 47-55, wherein at least one targeting moiety B is an aminoglycoside moiety derived from a compound in Table 2a;- 961 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOoptionally wherein the targeting moiety B is an aminoglycoside moiety derived from compound AG2-0, AG4-0, AG4-6, AG4-7, AG5-0, or AG7-0.

57. The compound of claim 56, whereinthe aminoglycoside moiety is attached to the rest of the molecule at position 5;the aminoglycoside moiety is attached to the rest of the molecule at position 6’;the aminoglycoside moiety is attached to the rest of the molecule at position 2”;the aminoglycoside moiety is attached to the rest of the molecule at position 6”; or the aminoglycoside moiety is attached to the rest of the molecule at position 5”.

58. The compound of any one of claims 1-4, 17-44, and 47-57, whereinat least one targeting moiety B comprises or has a structure selected from Table 2b, optionally wherein the targeting moiety B comprises or has a structure selected from AG2-0a, AG4-0a, AG4-6a, AG4-7a, AG5-0a, AG5-0c, and AG7-0a; orat least one targeting moiety B comprises or has a structure selected from Table 2c, optionally wherein the targeting moiety B comprises or has a structure selected from AG2-0a-l, AG2-0a-2, AG4-0a-l, AG4-0a-2, AG4-6a-l, AG4-6a-2, AG4-7a-l, AG4-7a-2, AG5-0a-l, AG5-Oa-2, AG5-0c-2, AG7-0a-l, and AG7-0a-2.

59. The compound of any one of claims 14-44 and 47-58, whereinthe linker comprises or has a structure of moiety 3-13, and the targeting B comprises or has a structure selected from AG2-0a-2, AG4-0a-2, AG4-6a-2, AG4-7a-2, AG5-0a-2, AG5-0c-2, and AG7-0a-2; orthe linker comprises or has a structure of moiety 3-13, 3-15, 3-27, 3-28, or 3-37, and the targeting B comprises or has a structure selected from AG2-0a-l, AG4-0a-l, AG4-6a-l, AG4-7a-1, AG5-0a-l, AG5-0c-2, and AG7-0a-l.

60. The compound of any one of claims 1-4, 17-44, and 47-58, wherein, when the compound comprises exactly one nucleic acid A, exactly one linker, and exactly one, two, or three identical - 962 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOtargeting moiety B each comprising or having a structure of Formula (XI), each targeting moiety B does not have the following structure of Formula (A):(A)whereinRi is hydrogen, -CH3, or the attachment point to the rest of the molecule;R2 is hydrogen or -CH3;R3 is hydrogen or -CH3;R9— N JR4 is hydrogen or;Rs is hydrogen or combines with -C(O)- and Ris to make an oxazolidinone ring;Re is hydrogen, -OH, or -ORis, wherein Ris combines with -C(O)- and Rs to make an oxazolidinone ring;R7 is hydrogen or -CH2OH;Rs is -CH3 or -OH;R9 is hydrogen or the attachment point to the rest of the molecule;Rio is hydrogen or -OH;R11 is hydrogen or -OH;R12 is -OH or -NH2;R13 is hydrogen or the attachment point to the rest of the molecule andR14 is hydrogen or -CH3.

61. The compound of any one of claims 5-7, 17-43, 46, and 48, wherein at least one targeting moiety B comprises or has a structure of Formula (XII), and wherein:the targeting moiety B is a moiety derived from a compound in Table 2e;- 963 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOthe targeting moiety B comprises or has a structure selected from Table 2f; orthe targeting moiety B comprises or has a structure selected from Table 31.

62. The compound of claim 45 or 48, wherein, when the compound comprises exactly one nucleic acid A, exactly one linker, and exactly one, two, or three identical targeting moieties B each comprising or having a structure of Formula (VI),(i) if RN1’V, RN2’V, RN3-\ RN4’V, RN5'V, and RN6'Vare each hydrogen, Al is present, and A2 and A3 are absent, then -NR7' RX' is not -NH2 or -NHC(=NH)NH2; or (ii) if RN1RN2’V, RN3RN4’ RV, and RN6‘Vare each hydrogen, and Al, A2, and A3 are present, then -NRN7'VRN8'Vand \|RX9'VRI0-'' are not both -NH2 and are not both -NHC(=NH)NH2.

63. The compound of any one of claims 8-12, 17-43, 45, 48, and 62 whereinRN Vis hydrogen, -CH3, or -C(O)CF3, andRN2 Vis hydrogen, -CH3, -CH2CH3, -C(O)CH3, -C(O)CF3, -CH2CH2OH, or -C(=NH)NH2; orRN1’Vand RN2 Vtogether with the atom to which they are attached form a morpholine ring.

64. The compound of any one of claims 8-12, 17-43, 45, 48, and 62-63, whereinRN3-Vis hydrogen, -CH3, or -C(O)CF3, andRN4 Vis hydrogen, -CH3, -CH2CH3, -C(O)CH3, -C(O)CF3, -CH2CH2OH, or -C(=NH)NH2; orRN3’Vand RN4-Vtogether with the atom to which they are attached form a morpholine ring.

65. The compound of any one of claims 8-12, 17-43, 45, 48, and 62-64, whereinRN5’Vis hydrogen, -CH3, or -C(O)CF3, andRN6 Vis hydrogen, -CH3, -CH2CH3, -C(O)CH3, -C(O)CF3, -CH2CH2OH, or -C(=NH)NH2; orRN5’Vand RN6’Vtogether with the atom to which they are attached form a morpholine ring.

66. The compound of any one of claims 8-12, 17-43, 45, 48, and 62-65 wherein- 964 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WORN7'Vis hydrogen or -CH3, andRN8 Vis hydrogen, -CH3, -CH2CH3, -C(O)CH3, -C(O)CF3, -CH2CH2OH, or -C(=NH)NH2; orRN7’Vand RN8’Vtogether with the atom to which they are attached form a morpholine ring.

67. The compound of any one of claims 8-12, 17-43, 45, 48, and 62-66, whereinRN9’Vis hydrogen, -CH3, or -C(O)CF3, andRN10 Vis hydrogen, -CH3, -CH2CH3, -C(O)CH3, -C(O)CF3, -CH2CH2OH, or -C(=NH)NH2; orRN9’Vand RN1O'Vtogether with the atom to which they are attached form a morpholine ring.

68. The compound of any one of claims 8-12, 17-43, 45, 48, and 62-67, at least one targeting moiety B comprises or has a structure of Formula (VI), and wherein:the targeting moiety B is derived from a compound in Table 2a-V;the targeting moiety B comprises or has a structure selected from Table 2b-V; or the targeting moiety B comprises or has a structure selected from Table 31-V.

69. The compound of any one of claims 14-68, wherein the nucleic acid A has a 3’ terminus and a 5’ terminus, and is conjugated to one or more targeting moieties B at the 3’ terminus, the 5’ terminus, or both the 3’ and 5’ termini.

70. The compound of any one of claims 14-69, wherein the nucleic acid A is single stranded or double stranded,optionally wherein the single stranded nucleic acid A is a single stranded antisense oligonucleotide (ASO) or a single- stranded RNAi (ssRNAi), andoptionally wherein the double stranded nucleic acid A is a double stranded RNA (e.g., a double stranded siRNA).

71. The compound of any one of claims 14-70, wherein the nucleic acid A is or comprises RNA, DNA, and / or peptide nucleic acid (PNA),- 965 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOoptionally wherein the RNA is an RNA inhibitory (RNAi) agent, optionally wherein the RNAi agent is or comprises a short interfering RNA (siRNA), andoptionally wherein the DNA is or comprises a DNA analog, optionally wherein the DNA analog comprises one or more morpholino subunits linked together by phosphorus-containing linkage(s), optionally wherein the DNA analog is or comprises a phosphorodiamidate morpholino nucleic acid (PMO).

72. The compound of any one of claims 14-71, wherein the nucleic acid A comprises a modification selected from: a modified backbone, a modified nucleobase, a modified ribose, a modified deoxyribose, or a combination thereof.

73. The compound of any one of claims 14-47, wherein the nucleic acid A comprises a sequence element that is at least 80% complementary to a portion of a target sequence, optionally wherein the target sequence is a solute carrier family 6 member 19 (SLC6A19) RNA, optionally wherein the SLC6A19 RNA is the human SLC6A19 RNA of SEQ ID NO: 1, optionally wherein the nucleic acid A comprises an antisense strand having 12 to 60 linked nucleotides in length.

74. The compound of claim 73, wherein the antisense strand has at least about 80% complementarity to a target region of the human SLC6A19 RNA.

75. The compound of claim 74, wherein the nucleic acid A comprises an antisense strand having 12 to 60 linked nucleotides in length targeted to a solute carrier family 6 member 19 (SLC6A19), optionally whereinthe antisense strand has at least about 80% complementarity to a target region of the human SLC6A19 RNA, and hybridizes with 12 or more nucleotides of nucleotides 3 to 25, nucleotides 8 to 30, nucleotides 13 to 35, nucleotides 38 to 60, nucleotides 43 to 65, nucleotides 48 to 70, nucleotides 93 to 115, nucleotides 98 to 120, nucleotides 103 to 125, nucleotides 108 to 130, nucleotides 111 to 133, nucleotides 113 to 135, nucleotides 118 to 140, nucleotides 214 to 236, nucleotides 219 to 241, nucleotides 244 to 266, nucleotides 249 to 271, nucleotides 252 to 274, nucleotides 253 to 275, nucleotides 254 to 276, nucleotides 255 to 277, nucleotides 256 to 278, nucleotides 257 to 286, nucleotides 259 to 281, nucleotides 264 to 286, nucleotides 289 to 311,- 966 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOnucleotides 294 to 316, nucleotides 339 to 361, nucleotides 397 to 419, nucleotides 460 to 480, nucleotides 461 to 481, nucleotides 481 to 503, nucleotides 486 to 508, nucleotides 491 to 513, nucleotides 557 to 579, nucleotides 561 to 583, nucleotides 562 to 584, nucleotides 564 to 586, nucleotides 566 to 586, nucleotides 567 to 589, nucleotides 616 to 638, nucleotides 617 to 639, nucleotides 618 to 640, nucleotides 621 to 643, nucleotides 626 to 648, nucleotides 670 to 692, nucleotides 671 to 691, nucleotides 672 to 694, nucleotides 674 to 694, nucleotides 675 to 697, nucleotides 680 to 702, nucleotides 685 to 707, nucleotides 690 to 712, nucleotides 695 to 717, nucleotides 700 to 722, nucleotides 705 to 727, nucleotides 710 to 732, nucleotides 715 to 737, nucleotides 720 to 742, nucleotides 725 to 747, nucleotides 730 to 752, nucleotides 735 to 757, nucleotides 738 to 760, nucleotides 739 to 761, nucleotides 740 to 762, nucleotides 741 to 763, nucleotides 742 to 764, nucleotides 745 to 767, nucleotides 750 to 772, nucleotides 751 to 773, nucleotides 752 to 774, nucleotides 753 to 775, nucleotides 754 to 776, nucleotides 755 to 777, nucleotides 756 to 778, nucleotides 757 to 779, nucleotides 760 to 782, nucleotides 765 to 787, nucleotides 770 to 792, nucleotides 775 to 797, nucleotides 798 to 823, nucleotides 800 to 822, nucleotides 825 to 847, nucleotides 826 to 848, nucleotides 877 to 899, nucleotides 890 to 912, nucleotides 895 to 917, nucleotides 900 to 922, nucleotides 905 to 927, nucleotides 910 to 932, nucleotides 911 to 937, nucleotides 915 to 937, nucleotides 918 to 940, nucleotides 972 to 994, nucleotides 973 to 995, nucleotides 974 to 996, nucleotides 975 to 997, nucleotides 977 to 1000, nucleotides 977 to 999, nucleotides 978 to 1000, nucleotides 981 to 1003, nucleotides 983 to 1005, nucleotides 984 to 1006, nucleotides 1033 to 1055, nucleotides 1034 to 1056, nucleotides 1035 to 1057, nucleotides 1058 to 1080, nucleotides 1059 to 1081, nucleotides 1060 to 1082, nucleotides 1063 to 1085, nucleotides 1064 to 1086, nucleotides 1065 to 1087, nucleotides 1066 to 1088, nucleotides 1067 to 1089, nucleotides 1068 to 1090, nucleotides 1070 to 1092, nucleotides 1074 to 1096, nucleotides 1075 to 1097, nucleotides 1077 to 1099, nucleotides 1078 to 1100, nucleotides 1079 to 1101, nucleotides 1080 to 1102, nucleotides 1081 to 1103, nucleotides 1082 to 1104, nucleotides 1085 to 1107, nucleotides 1086 to 1106, nucleotides 1090 to 1112, nucleotides 1095 to 1117, nucleotides 1100 to 1122, nucleotides 1105 to 1127, nucleotides 1110 to 1132, nucleotides 1115 to 1137, nucleotides 1115 to 1137, nucleotides 1117 to 1139, nucleotides 1177 to 1199, nucleotides 1178 to 1200, nucleotides 1179 to 1201, nucleotides 1182 to 1204, nucleotides 1187 to 1209, nucleotides 1191 to 1214, nucleotides 1192 to 1214, nucleotides 1195 to 1217, nucleotides 1233 to 1255, nucleotides 1234 to 1256, nucleotides 1235 to 1257, nucleotides 1236 to 1258,- 967 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOnucleotides 1239 to 1261, nucleotides 1242 to 1264, nucleotides 1244 to 1266, nucleotides 1247 to 1268, nucleotides 1249 to 1271, nucleotides 1251 to 1270, nucleotides 1254 to 1276, nucleotides 1259 to 1281, nucleotides 1263 to 1282, nucleotides 1264 to 1286, nucleotides 1266 to 1285, nucleotides 1269 to 1291, nucleotides 1326 to 1348, nucleotides 1331 to 1353, nucleotides 1334 to 1356, nucleotides 1342 to 1364, nucleotides 1335 to 1357, nucleotides 1336 to 1358, nucleotides 1337 to 1359, nucleotides 1337 to 1359, nucleotides 1338 to 1360, nucleotides 1340 to 1362, nucleotides 1341 to 1363, nucleotides 1342 to 1364, nucleotides 1346 to 1368, nucleotides 1351 to 1373, nucleotides 1353 to 1372, nucleotides 1377 to 1399, nucleotides 1382 to 1404, nucleotides 1383 to 1403, nucleotides 1387 to 1409, nucleotides 1392 to 1414, nucleotides 1397 to 1419, nucleotides 1402 to 1424, nucleotides 1407 to 1429, nucleotides 1412 to 1434, nucleotides 1417 to 1439, nucleotides 1456 to 1478, nucleotides 1458 to 1477, nucleotides 1481 to 1503, nucleotides 1486 to 1508, nucleotides 1491 to 1513, nucleotides 1496 to 1518, nucleotides 1521 to 1543, nucleotides 1568 to 1590, nucleotides 1569 to 1591, nucleotides 1574 to 1596, nucleotides 1578 to 1621, nucleotides 1579 to 1601, nucleotides 1583 to 1605, nucleotides 1583 to 1605, nucleotides 1584 to 1606, nucleotides 1584 to 1606, nucleotides 1585 to 1607, nucleotides 1585 to 1607, nucleotides 1587 to 1609, nucleotides 1588 to 1610, nucleotides 1589 to 1611, nucleotides 1594 to 1616, nucleotides 1595 to 1617, nucleotides 1599 to 1621, nucleotides 1601 to 1620, nucleotides 1602 to 1624, nucleotides 1642 to 1664, nucleotides 1749 to 1775, nucleotides 1750 to 1772, nucleotides 1755 to 1777, nucleotides 1757 to 1779, nucleotides 1758 to 1780, nucleotides 1760 to 1782, nucleotides 1761 to 1792, nucleotides 1764 to 1783, nucleotides 1765 to 1787, nucleotides 1770 to 1792, nucleotides 1809 to 1831, nucleotides 1810 to 1829, nucleotides 1812 to 1832, nucleotides 1814 to 1836, nucleotides 1852 to 1881, nucleotides 1853 to 1875, nucleotides 1854 to 1876, nucleotides 1858 to 1880, nucleotides 2168 to 2188, nucleotides 2333 to 2353, nucleotides 2454 to 2474, nucleotides 2507 to 2527, nucleotides 2593 to 2613, nucleotides 3244 to 3264, nucleotides 3288 to 3308, nucleotides 3304 to 3324, nucleotides 3332 to 3352, nucleotides 3333 to 3353, nucleotides 3501 to 3523, nucleotides 3595 to 3615, nucleotides 3595 to 3617, nucleotides 3643 to 3671, nucleotides 3646 to 3668, nucleotides 3646 to 3668, nucleotides 3647 to 3669, nucleotides 3648 to 3668, nucleotides 3648 to 3670, nucleotides 3648 to 3670, nucleotides 3649 to 3671, nucleotides 3651 to 3670, nucleotides 3651 to 3673, nucleotides 3651 to 3673, nucleotides 3652 to 3671, nucleotides 3712 to 3733, nucleotides 3713 to 3735, nucleotides 3763 to 3786, nucleotides 3763 to 3785, nucleotides 3764 to 3786, nucleotides 3791 to 3811, nucleotides 3796- 968 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOto 3816, nucleotides 3801 to 3829, nucleotides 3801 to 3820, nucleotides 3802 to 3821, nucleotides 3804 to 3826, nucleotides 3809 to 3831, nucleotides 3810 to 3832, nucleotides 3812 to 3833, nucleotides 3812 to 3834, nucleotides 3813 to 3835, nucleotides 3814 to 3833, nucleotides 3814 to 3836, nucleotides 3814 to 3836, nucleotides 3839 to 3859, nucleotides 3840 to 3862, nucleotides 3902 to 3924, nucleotides 3965 to 3987, nucleotides 3995 to 4015, nucleotides 3998 to 4020, nucleotides 4100 to 4124, nucleotides 4102 to 4124, nucleotides 4141 to 4163, nucleotides 4141 to 4163, nucleotides 4142 to 4164, nucleotides 4143 to 4165, nucleotides 4144 to 4166, nucleotides 4146 to 4168, nucleotides 4150 to 4172, nucleotides 4151 to 4173, nucleotides 4192 to 4214, nucleotides 4197 to 4219, nucleotides 4201 to 4223, nucleotides 4265 to 4287, nucleotides 4270 to 4292, nucleotides 4318 to 4338, nucleotides 4319 to 4341, nucleotides 4329 to 4349, nucleotides 4348 to 4386, nucleotides 4349 to 4371, nucleotides 4350 to 4369, nucleotides 4350 to 4372, nucleotides 4350 to 4372, nucleotides 4351 to 4370, nucleotides 4352 to 4371, nucleotides 4352 to 4374, nucleotides 4353 to 4372, nucleotides 4353 to 4375, nucleotides 4354 to 4376, nucleotides 4359 to 4381, nucleotides 4361 to 4383, nucleotides 4362 to 4384, nucleotides 4362 to 4384, nucleotides 4364 to 4386, nucleotides 4365 to 4387, nucleotides 4395 to 4415, nucleotides 4396 to 4416, nucleotides 4409 to 4431, nucleotides 4410 to 4432, nucleotides 4412 to 4434, nucleotides 4637 to 4657, nucleotides 4638 to 4658, nucleotides 4640 to 4660, nucleotides 5103 to 5123, nucleotides 5124 to 5144, nucleotides 5126 to 5146, or nucleotides 5127 to 5147 of SEQ ID NO: 1; orthe antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides, no more than 2 nucleotides, or no more than 1 nucleotide from a nucleotide sequence of 15 contiguous nucleotides and comprised in any one of the nucleotide sequences of SEQ ID NOs: 8-777 and 1555-2331.

76. The compound of any one of claims 14-75, wherein the nucleic acid A comprises a sense strand of 12 to 60 nucleobases in length,optionally wherein the nucleic acid A comprises a double stranded ribonucleic acid (dsRNA), wherein the dsRNA comprises a sense strand and an antisense strand forming a double stranded region.- 969 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WO77. The compound of claim 76, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from a nucleotide sequence of 15 contiguous nucleotides and comprised in SEQ ID NO: 1,optionally wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the nucleotide sequences of nucleotides 3 to 23, nucleotides 8 to 28, nucleotides 13 to 33, nucleotides 38 to 58, nucleotides 43 to 63, nucleotides 48 to 68, nucleotides 93 to 113, nucleotides 98 to 118, nucleotides 103 to 123, nucleotides 108 to 128, nucleotides 111 to 131, nucleotides 113 to 133, nucleotides 118 to 138, nucleotides 214 to 234, nucleotides 219 to 239, nucleotides 244 to 264, nucleotides 249 to 269, nucleotides 252 to 272, nucleotides 252 to 272, nucleotides 253 to 273, nucleotides 254 to 274, nucleotides 255 to 275, nucleotides 256 to 276, nucleotides 259 to 279, nucleotides 264 to 284, nucleotides 289 to 309, nucleotides 294 to 314, nucleotides 339 to 359, nucleotides 397 to 417, nucleotides 460 to 480, nucleotides 461 to 481, nucleotides 481 to 501, nucleotides 486 to 506, nucleotides 491 to 511, nucleotides 557 to 577, nucleotides 561 to 581, nucleotides 562 to 582, nucleotides 564 to 584, nucleotides 567 to 587, nucleotides 616 to 636, nucleotides 617 to 637, nucleotides 618 to 638, nucleotides 621 to 641, nucleotides 626 to 646, nucleotides 670 to 690, nucleotides 672 to 692, nucleotides 675 to 695, nucleotides 680 to 700, nucleotides 685 to 705, nucleotides 690 to 710, nucleotides 695 to 715, nucleotides 700 to 720, nucleotides 705 to 725, nucleotides 710 to 730, nucleotides 715 to 735, nucleotides 720 to 740, nucleotides 725 to 745, nucleotides 730 to 750, nucleotides 735 to 755, nucleotides 738 to 758, nucleotides 739 to 759, nucleotides 740 to 760, nucleotides 741 to 761, nucleotides 742 to 762, nucleotides 745 to 765, nucleotides 748 to 768, nucleotides 749 to 769, nucleotides 750 to 770, nucleotides 751 to 771, nucleotides 752 to 772, nucleotides 753 to 773, nucleotides 754 to 774, nucleotides 755 to 775, nucleotides 756 to 776, nucleotides 757 to 777, nucleotides 760 to 780, nucleotides 765 to 785, nucleotides 770 to 790, nucleotides 775 to 795, nucleotides 800 to 820, nucleotides 825 to 845, nucleotides 826 to 846, nucleotides 887 to 907, nucleotides 890 to 910, nucleotides 895 to 915, nucleotides 900 to 920, nucleotides 905 to 925, nucleotides 910 to 930, nucleotides 915 to 935, nucleotides 918 to 938, nucleotides 972 to 992, nucleotides 973 to 993, nucleotides 974 to 994, nucleotides 975 to 995, nucleotides 977 to 997, nucleotides 978 to 998, nucleotides 981 to 1001, nucleotides 982 to 1002, nucleotides 983 to 1003, nucleotides 984 to 1004, nucleotides 1033 to 1053, nucleotides 1034 to 1054, nucleotides 1035 to 1055, nucleotides 1058 to 1078, nucleotides 1059 to 1079,- 970 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOnucleotides 1060 to 1080, nucleotides 1063 to 1083, nucleotides 1064 to 1084, nucleotides 1065 to 1085, nucleotides 1066 to 1086, nucleotides 1067 to 1087, nucleotides 1070 to 1090, nucleotides 1074 to 1094, nucleotides 1075 to 1095, nucleotides 1076 to 1096, nucleotides 1077 to 1097, nucleotides 1078 to 1098, nucleotides 1079 to 1099, nucleotides 1080 to 1100, nucleotides 1081 to 1101, nucleotides 1082 to 1102, nucleotides 1085 to 1105, nucleotides 1090 to 1110, nucleotides 1095 to 1115, nucleotides 1100 to 1120, nucleotides 1105 to 1125, nucleotides 1110 to 1130, nucleotides 1115 to 1135, nucleotides 1117 to 1137, nucleotides 1177 to 1197, nucleotides 1178 to 1198, nucleotides 1179 to 1199, nucleotides 1182 to 1202, nucleotides 1187 to 1207, nucleotides 1192 to 1212, nucleotides 1195 to 1215, nucleotides 1233 to 1253, nucleotides 1234 to 1254, nucleotides 1235 to 1255, nucleotides 1236 to 1256, nucleotides 1239 to 1259, nucleotides 1242 to 1262, nucleotides 1244 to 1264, nucleotides 1249 to 1269, nucleotides 1254 to 1274, nucleotides 1259 to 1279, nucleotides 1264 to 1284, nucleotides 1269 to 1289, nucleotides 1326 to 1346, nucleotides 1331 to 1351, nucleotides 1334 to 1354, nucleotides 1334 to 1354, nucleotides 1335 to 1355, nucleotides 1336 to 1356, nucleotides 1337 to 1357, nucleotides 1337 to 1357, nucleotides 1338 to 1358, nucleotides 1340 to 1360, nucleotides 1341 to 1361, nucleotides 1342 to 1362, nucleotides 1343 to 1363, nucleotides 1346 to 1366, nucleotides 1351 to 1371, nucleotides 1377 to 1397, nucleotides 1382 to 1402, nucleotides 1385 to 1405, nucleotides 1386 to 1406, nucleotides 1387 to 1407, nucleotides 1388 to 1408, nucleotides 1389 to 1409, nucleotides 1392 to 1412, nucleotides 1397 to 1417, nucleotides 1402 to 1422, nucleotides 1407 to 1427, nucleotides 1412 to 1432, nucleotides 1417 to 1437, nucleotides 1456 to 1476, nucleotides 1481 to 1501, nucleotides 1486 to 1506, nucleotides 1491 to 1511, nucleotides 1496 to 1516, nucleotides 1521 to 1541, nucleotides 1567 to 1587, nucleotides 1568 to 1588, nucleotides 1568 to 1588, nucleotides 1569 to 1589, nucleotides 1574 to 1594, nucleotides 1575 to 1595, nucleotides 1576 to 1596, nucleotides 1577 to 1597, nucleotides 1578 to 1598, nucleotides 1579 to 1599, nucleotides 1580 to 1600, nucleotides 1581 to 1601, nucleotides 1582 to 1602, nucleotides 1583 to 1603, nucleotides 1583 to 1603, nucleotides 1584 to 1604, nucleotides 1584 to 1604, nucleotides 1585 to 1605, nucleotides 1585 to 1605, nucleotides 1586 to 1606, nucleotides 1587 to 1607, nucleotides 1587 to 1607, nucleotides 1588 to 1608, nucleotides 1589 to 1609, nucleotides 1594 to 1614, nucleotides 1595 to 1615, nucleotides 1598 to 1618, nucleotides 1599 to 1619, nucleotides 1600 to 1620, nucleotides 1601 to 1621, nucleotides 1602 to 1622, nucleotides 1641 to 1661, nucleotides 1642 to 1662, nucleotides 1643 to 1663, nucleotides 1644 to 1664, nucleotides 1750 to 1770, nucleotides 1755- 971 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOto 1775, nucleotides 1757 to 1777, nucleotides 1758 to 1778, nucleotides 1760 to 1780, nucleotides 1761 to 1781, nucleotides 1762 to 1782, nucleotides 1764 to 1784, nucleotides 1765 to 1785, nucleotides 1768 to 1788, nucleotides 1769 to 1789, nucleotides 1770 to 1790, nucleotides 1771 to 1791, nucleotides 1772 to 1792, nucleotides 1808 to 1828, nucleotides 1809 to 1829, nucleotides 1810 to 1830, nucleotides 1811 to 1831, nucleotides 1812 to 1832, nucleotides 1813 to 1833, nucleotides 1814 to 1834, nucleotides 1815 to 1835, nucleotides 1816 to 1836, nucleotides 1853 to 1873, nucleotides 1854 to 1874, nucleotides 1856 to 1876, nucleotides 1857 to 1877, nucleotides 1858 to 1878, nucleotides 1859 to 1879, nucleotides 1860 to 1880, nucleotides 2168 to 2188, nucleotides 2333 to 2353, nucleotides 2454 to 2474, nucleotides 2507 to 2527, nucleotides 2593 to 2613, nucleotides 3244 to 3264, nucleotides 3288 to 3308, nucleotides 3304 to 3324, nucleotides 3332 to 3352, nucleotides 3333 to 3353, nucleotides 3501 to 3521, nucleotides 3595 to 3615, nucleotides 3643 to 3663, nucleotides 3644 to 3664, nucleotides 3645 to 3665, nucleotides 3646 to 3666, nucleotides 3646 to 3666, nucleotides 3647 to 3667, nucleotides 3648 to 3668, nucleotides 3648 to 3668, nucleotides 3648 to 3668, nucleotides 3649 to 3669, nucleotides 3650 to 3670, nucleotides 3651 to 3671, nucleotides 3651 to 3671, nucleotides 3651 to 3671, nucleotides 3652 to 3672, nucleotides 3713 to 3733, nucleotides 3763 to 3783, nucleotides 3764 to 3784, nucleotides 3765 to 3785, nucleotides 3766 to 3786, nucleotides 3791 to 3811, nucleotides 3796 to 3816, nucleotides 3801 to 3821, nucleotides 3802 to 3822, nucleotides 3803 to 3823, nucleotides 3804 to 3824, nucleotides 3805 to 3825, nucleotides 3806 to 3826, nucleotides 3807 to 3827, nucleotides 3808 to 3828, nucleotides 3809 to 3829, nucleotides 3809 to 3829, nucleotides 3810 to 3830, nucleotides 3811 to 3831, nucleotides 3812 to 3832, nucleotides 3812 to 3832, nucleotides 3813 to 3833, nucleotides 3813 to 3833, nucleotides 3814 to 3834, nucleotides 3814 to 3834, nucleotides 3814 to 3834, nucleotides 3840 to 3860, nucleotides 3902 to 3922, nucleotides 3965 to 3985, nucleotides 3998 to 4018, nucleotides 4102 to 4122, nucleotides 4140 to 4160, nucleotides 4141 to4161, nucleotides 4141 to4161, nucleotides 4142 to 4162, nucleotides 4142 to4162, nucleotides 4143 to 4163, nucleotides 4144 to 4164, nucleotides 4146 to 4166, nucleotides 4151 to 4171, nucleotides 4192 to 4212, nucleotides 4197 to 4217, nucleotides 4198 to 4218, nucleotides 4199 to 4219, nucleotides 4200 to 4220, nucleotides 4201 to 4221, nucleotides 4265 to 4285, nucleotides 4266 to 4286, nucleotides 4267 to 4287, nucleotides 4270 to 4290, nucleotides 4318 to 4338, nucleotides 4319 to 4339, nucleotides 4319 to 4339, nucleotides 4329 to 4349, nucleotides 4349 to 4369, nucleotides 4350 to 4370, nucleotides 4350 to 4370, nucleotides 4350 to 4370, nucleotides - 972 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WO4351 to 4371, nucleotides 4352 to 4372, nucleotides 4352 to 4372, nucleotides 4353 to 4373, nucleotides 4353 to 4373, nucleotides 4354 to 4374, nucleotides 4355 to 4375, nucleotides 4356 to 4376, nucleotides 4357 to 4377, nucleotides 4358 to 4378, nucleotides 4359 to 4379, nucleotides 4360 to 4380, nucleotides 4361 to 4381, nucleotides 4362 to 4382, nucleotides 4362 to 4382, nucleotides 4363 to 4383, nucleotides 4364 to 4384, nucleotides 4364 to 4384, nucleotides 4365 to 4385, nucleotides 4395 to 4415, nucleotides 4396 to 4416, nucleotides 4410 to 4430, nucleotides 4412 to 4432, nucleotides 4637 to 4657, nucleotides 4638 to 4658, nucleotides 4640 to 4660, nucleotides 5103 to 5123, nucleotides 5124 to 5144, nucleotides 5126 to 5146, or nucleotides 5127 to 5147 of SEQ ID NO: 1.

78. The compound of claim 76 or 77, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the nucleotide sequences of nucleotides 3 to 25, nucleotides 8 to 30, nucleotides 13 to 35, nucleotides 38 to 60, nucleotides 43 to 65, nucleotides 48 to 70, nucleotides 93 to 115, nucleotides 98 to 120, nucleotides 103 to 125, nucleotides 108 to 130, nucleotides 111 to 133, nucleotides 113 to 135, nucleotides 118 to 140, nucleotides 214 to 236, nucleotides 219 to 241, nucleotides 244 to 266, nucleotides 249 to 271, nucleotides 252 to 274, nucleotides 253 to 275, nucleotides 254 to 276, nucleotides 257 to 286, nucleotides 259 to 281, nucleotides 264 to 286, nucleotides 289 to 311, nucleotides 294 to 316, nucleotides 339 to 361, nucleotides 397 to 419, nucleotides 460 to 480, nucleotides 461 to 481, nucleotides 481 to 503, nucleotides 486 to 508, nucleotides 491 to 513, nucleotides 557 to 579, nucleotides 561 to 583, nucleotides 562 to 584, nucleotides 564 to 586, nucleotides 566 to 586, nucleotides 567 to 589, nucleotides 616 to 638, nucleotides 621 to 643, nucleotides 626 to 648, nucleotides 670 to 692, nucleotides 671 to 691, nucleotides 672 to 694, nucleotides 674 to 694, nucleotides 675 to 697, nucleotides 680 to 702, nucleotides 685 to 707, nucleotides 690 to 712, nucleotides 695 to 717, nucleotides 700 to 722, nucleotides 705 to 727, nucleotides 710 to 732, nucleotides 715 to 737, nucleotides 720 to 742, nucleotides 725 to 747, nucleotides 730 to 752, nucleotides 735 to 757, nucleotides 740 to 762, nucleotides 745 to 767, nucleotides 750 to 772, nucleotides 751 to 776, nucleotides 755 to 777, nucleotides 760 to 782, nucleotides 765 to 787, nucleotides 770 to 792, nucleotides 775 to 797, nucleotides 798 to 823, nucleotides 800 to 822, nucleotides 825 to 847, nucleotides 890 to 912, nucleotides 895 to 917, nucleotides 900 to 922, nucleotides 905 to 927, nucleotides 910 to 932, nucleotides 911 to 937, nucleotides 915 to 937,- 973 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOnucleotides 972 to 994, nucleotides 973 to 995, nucleotides 977 to 1000, nucleotides 977 to 999, nucleotides 978 to 1000, nucleotides 983 to 1005, nucleotides 1035 to 1057, nucleotides 1058 to 1080, nucleotides 1059 to 1081, nucleotides 1060 to 1082, nucleotides 1063 to 1082, nucleotides 1065 to 1087, nucleotides 1068 to 1087, nucleotides 1070 to 1094, nucleotides 1070 to 1092, nucleotides 1074 to 1096, nucleotides 1075 to 1097, nucleotides 1077 to 1096, nucleotides 1080 to 1102, nucleotides 1085 to 1107, nucleotides 1086 to 1106, nucleotides 1090 to 1112, nucleotides 1095 to 1117, nucleotides 1100 to 1122, nucleotides 1105 to 1127, nucleotides 1110 to 1132, nucleotides 1115 to 1137, nucleotides 1115 to 1137, nucleotides 1117 to 1139, nucleotides 1177 to 1199, nucleotides 1182 to 1204, nucleotides 1187 to 1209, nucleotides 1191 to 1214, nucleotides 1192 to 1214, nucleotides 1195 to 1217, nucleotides 1234 to 1256, nucleotides 1239 to 1261, nucleotides 1242 to 1264, nucleotides 1244 to 1266, nucleotides 1247 to 1268, nucleotides 1249 to 1271, nucleotides 1251 to 1270, nucleotides 1254 to 1276, nucleotides 1259to 1281, nucleotides 1263 to 1282, nucleotides 1264 to 1286, nucleotides 1266 to 1285, nucleotides 1269 to 1291, nucleotides 1326 to 1348, nucleotides 1331 to 1353, nucleotides 1334 to 1361, nucleotides 1334 to 1356, nucleotides 1334 to 1356, nucleotides 1335 to 1357, nucleotides 1336 to 1358, nucleotides 1337 to 1359, nucleotides 1337 to 1359, nucleotides 1338 to 1360, nucleotides 1340 to 1362, nucleotides 1341 to 1363, nucleotides 1346 to 1368, nucleotides 1351 to 1373, nucleotides 1353 to 1372, nucleotides 1377 to 1399, nucleotides 1382 to 1404, nucleotides 1383 to 1403, nucleotides 1387 to 1409, nucleotides 1392 to 1414, nucleotides 1397 to 1419, nucleotides 1402 to 1424, nucleotides 1407 to 1429, nucleotides 1412 to 1434, nucleotides 1417 to 1439, nucleotides 1456 to 1478, nucleotides 1458 to 1477, nucleotides 1481 to 1503, nucleotides 1486 to 1508, nucleotides 1491 to 1513, nucleotides 1496 to 1518, nucleotides 1521 to 1543, nucleotides 1568 to 1590, nucleotides 1569 to 1591, nucleotides 1574 to 1596, nucleotides 1578 to 1621, nucleotides 1579 to 1601, nucleotides 1583 to 1605, nucleotides 1583 to 1605, nucleotides 1584 to 1606, nucleotides 1584 to 1606, nucleotides 1585 to 1607, nucleotides 1585 to 1607, nucleotides 1587 to 1609, nucleotides 1588 to 1610, nucleotides 1589 to 1611, nucleotides 1594 to 1616, nucleotides 1595 to 1617, nucleotides 1599 to 1621, nucleotides 1601 to 1620, nucleotides 1602 to 1624, nucleotides 1642 to 1664, nucleotides 1749 to 1775, nucleotides 1750 to 1772, nucleotides 1755 to 1777, nucleotides 1757 to 1779, nucleotides 1758 to 1780, nucleotides 1760 to 1782, nucleotides 1761 to 1792, nucleotides 1764 to 1783, nucleotides 1765 to 1787, nucleotides 1770 to 1792, nucleotides 1809 to 1831, nucleotides 1810 to 1829, nucleotides 1812 to 1832, nucleotides 1814 to 1836,- 974 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOnucleotides 1852 to 1881, nucleotides 1853 to 1875, nucleotides 1854 to 1876, nucleotides 1858 to 1880, nucleotides 2168 to 2188, nucleotides 2333 to 2353, nucleotides 2454 to 2474, nucleotides 2507 to 2527, nucleotides 2593 to 2613, nucleotides 3244 to 3264, nucleotides 3288 to 3308, nucleotides 3304 to 3324, nucleotides 3332 to 3352, nucleotides 3333 to 3353, nucleotides 3501 to 3523, nucleotides 3595 to 3615, nucleotides 3595 to 3617, nucleotides 3643 to 3671, nucleotides 3646 to 3668, nucleotides 3646 to 3668, nucleotides 3647 to 3669, nucleotides 3648 to 3668, nucleotides 3648 to 3670, nucleotides 3648 to 3670, nucleotides 3649 to 3671, nucleotides 3651 to 3670, nucleotides 3651 to 3673, nucleotides 3651 to 3673, nucleotides 3652 to 3671, nucleotides 3712 to 3733, nucleotides 3713 to 3735, nucleotides 3763 to 3786, nucleotides 3763 to 3785, nucleotides 3764 to 3786, nucleotides 3791 to 3811, nucleotides 3796 to 3816, nucleotides 3801 to 3829, nucleotides 3801 to 3820, nucleotides 3802 to 3821, nucleotides 3804 to 3826, nucleotides 3809 to 3831, nucleotides 3810 to 3832, nucleotides 3812 to 3833, nucleotides 3812 to 3834, nucleotides 3813 to 3835, nucleotides 3814 to 3833, nucleotides 3814 to 3836, nucleotides 3814 to 3836, nucleotides 3839 to 3859, nucleotides 3840 to 3862, nucleotides 3902 to 3924, nucleotides 3965 to 3987, nucleotides 3995 to 4015, nucleotides 3998 to 4020, nucleotides 4100 to 4124, nucleotides 4102 to 4124, nucleotides 4141 to 4163, nucleotides 4141 to 4163, nucleotides 4142 to4164, nucleotides 4143 to4165, nucleotides 4144 to 4166, nucleotides 4146 to 4168, nucleotides 4150 to 4172, nucleotides 4151 to 4173, nucleotides 4192 to 4214, nucleotides 4197 to 4219, nucleotides 4201 to 4223, nucleotides 4265 to 4287, nucleotides 4270 to 4292, nucleotides 4318 to 4338, nucleotides 4319 to 4341, nucleotides 4329 to 4349, nucleotides 4348 to 4386, nucleotides 4349 to 4371, nucleotides 4350 to 4369, nucleotides 4350 to 4372, nucleotides 4350 to 4372, nucleotides 4351 to 4370, nucleotides 4352 to 4371, nucleotides 4352 to 4374, nucleotides 4353 to4372, nucleotides 4353 to 4375, nucleotides 4354 to 4376, nucleotides 4359 to 4381, nucleotides 4361 to 4383, nucleotides 4362 to 4384, nucleotides 4362 to 4384, nucleotides 4364 to 4386, nucleotides 4365 to 4387, nucleotides 4395 to 4415, nucleotides 4396 to 4416, nucleotides 4409 to 4431, nucleotides 4410 to 4432, nucleotides 4412 to 4434, nucleotides 4637 to 4657, nucleotides 4638 to 4658, nucleotides 4640 to 4660, nucleotides 5103 to 5123, nucleotides 5124 to 5144, nucleotides 5126 to 5146, or nucleotides 5127 to 5147 of SEQ ID NO: 1, and the antisense strand comprises at least 15 contiguous nucleotides from the corresponding nucleotide sequence of SEQ ID NO: 2.- 975 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WO79. The compound of any one of claims 76-78, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from a nucleotide sequence of 15 contiguous nucleotides and comprised in any one of the nucleotide sequences of SEQ ID NOs: 778-1554;optionally wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 2 nucleotides from a nucleotide sequence of 15 contiguous nucleotides and comprised in any one of the nucleotide sequences of SEQ ID NOs: 778-1554;optionally wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 1 nucleotide from a nucleotide sequence of 15 contiguous nucleotides and comprised in any one of the nucleotide sequences of SEQ ID NOs: 778-1554; oroptionally wherein the sense strand comprises at least 15 contiguous nucleotides of a nucleotide sequence selected from any one of the nucleotide sequences SEQ ID NOs: 778-1554.

80. The compound of any one of claims 14-79, wherein the nucleic acid A comprises an antisense strand of 12 to 60 linked nucleotides in length, and a sense strand of 12 to 60 linked nucleotides in length;optionally wherein the antisense strand comprises a nucleotide sequence at least 75%, 80%, 85%, 90%, or 95% identical to any one of the nucleotide sequences of SEQ ID NOs: 1555-2331; andthe sense strand comprises a nucleotide sequence at least 75%, 80%, 85%, 90%, or 95% identical to any one of the nucleotide sequences of SEQ ID NOs: 778-1554;optionally wherein the antisense strand comprises a nucleotide sequence selected from any one of SEQ ID NOs: 1555-2331 or a nucleotide sequence differing in 1, 2, or 3 nucleotides therefrom;the sense strand comprises a nucleotide sequence selected from any one of SEQ ID NOs: 778-1554 or a nucleotide sequence differing in 1, 2, or 3 nucleotides therefrom;optionally wherein the antisense strand comprises or is a nucleotide sequence selected from any one of SEQ ID NOs: 1555-2331; andthe sense strand comprises or is a nucleotide sequence selected from any one of SEQ ID NOs: 778-1554.- 976 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WO81. The compound of any one of claims 14-80, wherein the nucleic acid A comprises an antisense strand and a sense strand, wherein the sense strand and the antisense strand comprise nucleotide sequences of SEQ ID NOs: 780 and 1557, respectively; SEQ ID NOs: 781 and 1558, respectively; SEQ ID NOs: 782 and 1559, respectively; SEQ ID NOs: 783 and 1560, respectively;SEQ ID NOs: 784 and 1561, respectively; SEQ ID NOs: 785 and 1562, respectively; SEQ ID NOs: 786 and 1563, respectively; SEQ ID NOs: 787 and 1564, respectively; SEQ ID NOs: 788 and 1565, respectively; SEQ ID NOs: 789 and 1566, respectively; SEQ ID NOs: 790 and 1567, respectively; SEQ ID NOs: 791 and 1568, respectively; SEQ ID NOs: 792 and 1569, respectively;SEQ ID NOs: 793 and 1570, respectively; SEQ ID NOs: 794 and 1571, respectively; SEQ ID NOs: 795 and 1572, respectively; SEQ ID NOs: 796 and 1573, respectively; SEQ ID NOs: 797 and 1574, respectively; SEQ ID NOs: 798 and 1575, respectively; SEQ ID NOs: 799 and 1576, respectively; SEQ ID NOs: 800 and 1577, respectively; SEQ ID NOs: 801 and 1578, respectively;SEQ ID NOs: 802 and 1579, respectively; SEQ ID NOs: 803 and 1580, respectively; SEQ ID NOs: 804 and 1581, respectively; SEQ ID NOs: 805 and 1582, respectively; SEQ ID NOs: 806 and 1583, respectively; SEQ ID NOs: 807 and 1584, respectively; SEQ ID NOs: 808 and 1585, respectively; SEQ ID NOs: 809 and 1586, respectively; SEQ ID NOs: 810 and 1587, respectively;SEQ ID NOs: 811 and 1588, respectively; SEQ ID NOs: 812 and 1589, respectively; SEQ ID NOs: 813 and 1590, respectively; SEQ ID NOs: 814 and 1591, respectively; SEQ ID NOs: 815 and 1592, respectively; SEQ ID NOs: 816 and 1593, respectively; SEQ ID NOs: 817 and 1594, respectively; SEQ ID NOs: 818 and 1595, respectively; SEQ ID NOs: 819 and 1596, respectively;SEQ ID NOs: 820 and 1597, respectively; SEQ ID NOs: 821 and 1598, respectively; SEQ ID NOs: 822 and 1599, respectively; SEQ ID NOs: 823 and 1600, respectively; SEQ ID NOs: 824 and 1601, respectively; SEQ ID NOs: 825 and 1602, respectively; SEQ ID NOs: 826 and 1603, respectively; SEQ ID NOs: 827 and 1604, respectively; SEQ ID NOs: 828 and 1605, respectively;SEQ ID NOs: 829 and 1606, respectively; SEQ ID NOs: 830 and 1607, respectively; SEQ ID NOs: 831 and 1608, respectively; SEQ ID NOs: 832 and 1609, respectively; SEQ ID NOs: 833 and 1610, respectively; SEQ ID NOs: 834 and 1611, respectively; SEQ ID NOs: 835 and 1612, respectively; SEQ ID NOs: 836 and 1613, respectively; SEQ ID NOs: 837 and 1614, respectively;SEQ ID NOs: 838 and 1615, respectively; SEQ ID NOs: 839 and 1616, respectively; SEQ ID NOs: 840 and 1617, respectively; SEQ ID NOs: 841 and 1618, respectively; SEQ ID NOs: 842 and 1619, respectively; SEQ ID NOs: 843 and 1620, respectively; SEQ ID NOs: 844 and 1621,- 977 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOrespectively; SEQ ID NOs: 845 and 1622, respectively; SEQ ID NOs: 846 and 1623, respectively; SEQ ID NOs: 847 and 1624, respectively; SEQ ID NOs: 848 and 1625, respectively; SEQ ID NOs: 849 and 1626, respectively; SEQ ID NOs: 850 and 1627, respectively; SEQ ID NOs: 851 and 1628, respectively; SEQ ID NOs: 852 and 1629, respectively; SEQ ID NOs: 853 and 1630, respectively; SEQ ID NOs: 854 and 1631, respectively; SEQ ID NOs: 855 and 1632, respectively; SEQ ID NOs: 856 and 1633, respectively; SEQ ID NOs: 857 and 1634, respectively; SEQ ID NOs: 858 and 1635, respectively; SEQ ID NOs: 859 and 1636, respectively; SEQ ID NOs: 860 and 1637, respectively; SEQ ID NOs: 861 and 1638, respectively; SEQ ID NOs: 862 and 1639, respectively; SEQ ID NOs: 863 and 1640, respectively; SEQ ID NOs: 864 and 1641, respectively; SEQ ID NOs: 865 and 1642, respectively; SEQ ID NOs: 866 and 1643, respectively; SEQ ID NOs: 867 and 1644, respectively; SEQ ID NOs: 868 and 1645, respectively; SEQ ID NOs: 869 and 1646, respectively; SEQ ID NOs: 870 and 1647, respectively; SEQ ID NOs: 871 and 1648, respectively; SEQ ID NOs: 872 and 1649, respectively; SEQ ID NOs: 873 and 1650, respectively; SEQ ID NOs: 874 and 1651, respectively; SEQ ID NOs: 875 and 1652, respectively; SEQ ID NOs: 876 and 1653, respectively; SEQ ID NOs: 877 and 1654, respectively; SEQ ID NOs: 878 and 1655, respectively; SEQ ID NOs: 879 and 1656, respectively; SEQ ID NOs: 880 and 1657, respectively; SEQ ID NOs: 881 and 1658, respectively; SEQ ID NOs: 882 and 1659, respectively; SEQ ID NOs: 883 and 1660, respectively; SEQ ID NOs: 884 and 1661, respectively; SEQ ID NOs: 885 and 1662, respectively; SEQ ID NOs: 886 and 1663, respectively; SEQ ID NOs: 887 and 1664, respectively; SEQ ID NOs: 888 and 1665, respectively; SEQ ID NOs: 889 and 1666, respectively; SEQ ID NOs: 890 and 1667, respectively; SEQ ID NOs: 891 and 1668, respectively; SEQ ID NOs: 892 and 1669, respectively; SEQ ID NOs: 893 and 1670, respectively; SEQ ID NOs: 894 and 1671, respectively; SEQ ID NOs: 895 and 1672, respectively; SEQ ID NOs: 896 and 1673, respectively; SEQ ID NOs: 897 and 1674, respectively; SEQ ID NOs: 898 and 1675, respectively; SEQ ID NOs: 899 and 1676, respectively; SEQ ID NOs: 900 and 1677, respectively; SEQ ID NOs: 901 and 1678, respectively; SEQ ID NOs: 902 and 1679, respectively; SEQ ID NOs: 903 and 1680, respectively; SEQ ID NOs: 904 and 1681, respectively; SEQ ID NOs: 905 and 1682, respectively; SEQ ID NOs: 906 and 1683, respectively; SEQ ID NOs: 907 and 1684, respectively; SEQ ID NOs: 908 and 1685, respectively; SEQ ID NOs: 909 and 1686, respectively; SEQ ID NOs: 910 and 1687, respectively; SEQ ID NOs: 911 and 1688, respectively; SEQ ID NOs: 912 and 1689, respectively; SEQ ID NOs: 913 and 1690, respectively; SEQ ID NOs: 914 and - 978 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WO1691, respectively; SEQ ID NOs: 915 and 1692, respectively; SEQ ID NOs: 916 and 1693, respectively; SEQ ID NOs: 917 and 1694, respectively; SEQ ID NOs: 918 and 1695, respectively; SEQ ID NOs: 919 and 1696, respectively; SEQ ID NOs: 920 and 1697, respectively; SEQ ID NOs: 921 and 1698, respectively; SEQ ID NOs: 922 and 1699, respectively; SEQ ID NOs: 923 and 1700, respectively; SEQ ID NOs: 924 and 1701, respectively; SEQ ID NOs: 925 and 1702, respectively; SEQ ID NOs: 926 and 1703, respectively; SEQ ID NOs: 927 and 1704, respectively; SEQ ID NOs: 928 and 1705, respectively; SEQ ID NOs: 929 and 1706, respectively; SEQ ID NOs: 930 and 1707, respectively; SEQ ID NOs: 931 and 1708, respectively; SEQ ID NOs: 932 and 1709, respectively; SEQ ID NOs: 933 and 1710, respectively; SEQ ID NOs: 934 and 1711, respectively; SEQ ID NOs: 935 and 1712, respectively; SEQ ID NOs: 936 and 1713, respectively; SEQ ID NOs: 937 and 1714, respectively; SEQ ID NOs: 938 and 1715, respectively; SEQ ID NOs: 939 and 1716, respectively; SEQ ID NOs: 940 and 1717, respectively; SEQ ID NOs: 941 and 1718, respectively; SEQ ID NOs: 942 and 1719, respectively; SEQ ID NOs: 943 and 1720, respectively; SEQ ID NOs: 944 and 1721, respectively; SEQ ID NOs: 945 and 1722, respectively; SEQ ID NOs: 946 and 1723, respectively; SEQ ID NOs: 947 and 1724, respectively; SEQ ID NOs: 948 and 1725, respectively; SEQ ID NOs: 949 and 1726, respectively; SEQ ID NOs: 950 and 1727, respectively; SEQ ID NOs: 951 and 1728, respectively; SEQ ID NOs: 952 and 1729, respectively; SEQ ID NOs: 953 and 1730, respectively; SEQ ID NOs: 954 and 1731, respectively; SEQ ID NOs: 955 and 1732, respectively; SEQ ID NOs: 956 and 1733, respectively; SEQ ID NOs: 957 and 1734, respectively; SEQ ID NOs: 958 and 1735, respectively; SEQ ID NOs: 959 and 1736, respectively; SEQ ID NOs: 960 and 1737, respectively; SEQ ID NOs: 961 and 1738, respectively; SEQ ID NOs: 962 and 1739, respectively; SEQ ID NOs: 963 and 1740, respectively; SEQ ID NOs: 964 and 1741, respectively; SEQ ID NOs: 965 and 1742, respectively; SEQ ID NOs: 966 and 1743, respectively; SEQ ID NOs: 967 and 1744, respectively; SEQ ID NOs: 968 and 1745, respectively; SEQ ID NOs: 969 and 1746, respectively; SEQ ID NOs: 970 and 1747, respectively; SEQ ID NOs: 971 and 1748, respectively; SEQ ID NOs: 972 and 1749, respectively; SEQ ID NOs: 973 and 1750, respectively; SEQ ID NOs: 974 and 1751, respectively; SEQ ID NOs: 975 and 1752, respectively; SEQ ID NOs: 976 and 1753, respectively; SEQ ID NOs: 977 and 1754, respectively; SEQ ID NOs: 978 and 1755, respectively; SEQ ID NOs: 979 and 1756, respectively; SEQ ID NOs: 980 and 1757, respectively; SEQ ID NOs: 981 and 1758, respectively; SEQ ID NOs: 982 and 1759, respectively; SEQ ID NOs: 983 and 1760, respectively; SEQ ID NOs:- 979 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WO984 and 1761, respectively; SEQ ID NOs: 985 and 1762, respectively; SEQ ID NOs: 986 and 1763, respectively; SEQ ID NOs: 987 and 1764, respectively; SEQ ID NOs: 988 and 1765, respectively; SEQ ID NOs: 989 and 1766, respectively; SEQ ID NOs: 990 and 1767, respectively; SEQ ID NOs: 991 and 1768, respectively; SEQ ID NOs: 992 and 1769, respectively; SEQ ID NOs: 993 and 1770, respectively; SEQ ID NOs: 994 and 1771, respectively; SEQ ID NOs: 995 and 1772, respectively; SEQ ID NOs: 996 and 1773, respectively; SEQ ID NOs: 997 and 1774, respectively; SEQ ID NOs: 998 and 1775, respectively; SEQ ID NOs: 999 and 1776, respectively; SEQ ID NOs: 1000 and 1777, respectively; SEQ ID NOs: 1001 and 1778, respectively; SEQ ID NOs: 1002 and 1779, respectively; SEQ ID NOs: 1003 and 1780, respectively; SEQ ID NOs: 1004 and 1781, respectively; SEQ ID NOs: 1005 and 1782, respectively; SEQ ID NOs: 1006 and 1783, respectively; SEQ ID NOs: 1007 and 1784, respectively; SEQ ID NOs: 1008 and 1785, respectively; SEQ ID NOs: 1009 and 1786, respectively; SEQ ID NOs: 1010 and 1787, respectively; SEQ ID NOs: 1011 and 1788, respectively; SEQ ID NOs: 1012 and 1789, respectively; SEQ ID NOs: 1013 and 1790, respectively; SEQ ID NOs: 1014 and 1791, respectively; SEQ ID NOs: 1015 and 1792, respectively; SEQ ID NOs: 1016 and 1793, respectively; SEQ ID NOs: 1017 and 1794, respectively; SEQ ID NOs: 1018 and 1795, respectively; SEQ ID NOs: 1019 and 1796, respectively; SEQ ID NOs: 1020 and 1797, respectively; SEQ ID NOs: 1021 and 1798, respectively; SEQ ID NOs: 1022 and 1799, respectively; SEQ ID NOs: 1023 and 1800, respectively; SEQ ID NOs: 1024 and 1801, respectively; SEQ ID NOs: 1025 and 1802, respectively; SEQ ID NOs: 1026 and 1803, respectively; SEQ ID NOs: 1027 and 1804, respectively; SEQ ID NOs: 1028 and 1805, respectively; SEQ ID NOs: 1029 and 1806, respectively; SEQ ID NOs: 1030 and 1807, respectively; SEQ ID NOs: 1031 and 1808, respectively; SEQ ID NOs: 1032 and 1809, respectively; SEQ ID NOs: 1033 and 1810, respectively; SEQ ID NOs: 1034 and 1811, respectively; SEQ ID NOs: 1035 and 1812, respectively; SEQ ID NOs: 1036 and 1813, respectively; SEQ ID NOs: 1037 and 1814, respectively; SEQ ID NOs: 1038 and 1815, respectively; SEQ ID NOs: 1039 and 1816, respectively; SEQ ID NOs: 1040 and 1817, respectively; SEQ ID NOs: 1041 and 1818, respectively; SEQ ID NOs: 1042 and 1819, respectively; SEQ ID NOs: 1043 and 1820, respectively; SEQ ID NOs: 1044 and 1821, respectively; SEQ ID NOs: 1045 and 1822, respectively; SEQ ID NOs: 1046 and 1823, respectively; SEQ ID NOs: 1047 and 1824, respectively; SEQ ID NOs: 1048 and 1825,- 980 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOrespectively; SEQ ID NOs: 1049 and 1826, respectively; SEQ ID NOs: 1050 and 1827, respectively; SEQ ID NOs: 1051 and 1828, respectively; SEQ ID NOs: 1052 and 1829 respectively; SEQ ID NOs: 1053 and 1830, respectively; SEQ ID NOs: 1054 and 1831 respectively; SEQ ID NOs: 1055 and 1832, respectively; SEQ ID NOs: 1056 and 1833, respectively; SEQ ID NOs: 1057 and 1834, respectively; SEQ ID NOs: 1058 and 1835 respectively; SEQ ID NOs: 1059 and 1836, respectively; SEQ ID NOs: 1060 and 1837, respectively; SEQ ID NOs: 1061 and 1838, respectively; SEQ ID NOs: 1062 and 1839, respectively; SEQ ID NOs: 1063 and 1840, respectively; SEQ ID NOs: 1064 and 1841 respectively; SEQ ID NOs: 1065 and 1842, respectively; SEQ ID NOs: 1066 and 1843, respectively; SEQ ID NOs: 1067 and 1844, respectively; SEQ ID NOs: 1068 and 1845 respectively; SEQ ID NOs: 1069 and 1846, respectively; SEQ ID NOs: 1070 and 1847 respectively; SEQ ID NOs: 1071 and 1848, respectively; SEQ ID NOs: 1072 and 1849, respectively; SEQ ID NOs: 1073 and 1850, respectively; SEQ ID NOs: 1074 and 1851 respectively; SEQ ID NOs: 1075 and 1852, respectively; SEQ ID NOs: 1076 and 1853 respectively; SEQ ID NOs: 1077 and 1854, respectively; SEQ ID NOs: 1078 and 1855, respectively; SEQ ID NOs: 1079 and 1856, respectively; SEQ ID NOs: 1080 and 1857 respectively; SEQ ID NOs: 1081 and 1858, respectively; SEQ ID NOs: 1082 and 1859, respectively; SEQ ID NOs: 1083 and 1860, respectively; SEQ ID NOs: 1084 and 1861, respectively; SEQ ID NOs: 1085 and 1862, respectively; SEQ ID NOs: 1086 and 1863 respectively; SEQ ID NOs: 1087 and 1864, respectively; SEQ ID NOs: 1088 and 1865, respectively; SEQ ID NOs: 1089 and 1866, respectively; SEQ ID NOs: 1090 and 1867 respectively; SEQ ID NOs: 1091 and 1868, respectively; SEQ ID NOs: 1092 and 1869 respectively; SEQ ID NOs: 1093 and 1870, respectively; SEQ ID NOs: 1094 and 1871, respectively; SEQ ID NOs: 1095 and 1872, respectively; SEQ ID NOs: 1096 and 1873 respectively; SEQ ID NOs: 1097 and 1874, respectively; SEQ ID NOs: 1098 and 1875, respectively; SEQ ID NOs: 1099 and 1876, respectively; SEQ ID NOs: 1100 and 1877, respectively; SEQ ID NOs: 1101 and 1878, respectively; SEQ ID NOs: 1102 and 1879 respectively; SEQ ID NOs: 1103 and 1880, respectively; SEQ ID NOs: 1104 and 1881, respectively; SEQ ID NOs: 1105 and 1882, respectively; SEQ ID NOs: 1106 and 1883 respectively; SEQ ID NOs: 1107 and 1884, respectively; SEQ ID NOs: 1108 and 1885 respectively; SEQ ID NOs: 1109 and 1886, respectively; SEQ ID NOs: 1110 and 1887,- 981 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOrespectively; SEQ ID NOs: 1111 and 1888, respectively; SEQ ID NOs: 1112 and 1889 respectively; SEQ ID NOs: 1113 and 1890, respectively; SEQ ID NOs: 1114 and 1891 respectively; SEQ ID NOs: 1115 and 1892, respectively; SEQ ID NOs: 1116 and 1893 respectively; SEQ ID NOs: 1117 and 1894, respectively; SEQ ID NOs: 1118 and 1895, respectively; SEQ ID NOs: 1119 and 1896, respectively; SEQ ID NOs: 1120 and 1897 respectively; SEQ ID NOs: 1121 and 1898, respectively; SEQ ID NOs: 1122 and 1899, respectively; SEQ ID NOs: 1123 and 1900, respectively; SEQ ID NOs: 1124 and 1901, respectively; SEQ ID NOs: 1125 and 1902, respectively; SEQ ID NOs: 1126 and 1903 respectively; SEQ ID NOs: 1127 and 1904, respectively; SEQ ID NOs: 1128 and 1905, respectively; SEQ ID NOs: 1129 and 1906, respectively; SEQ ID NOs: 1130 and 1907 respectively; SEQ ID NOs: 1131 and 1908, respectively; SEQ ID NOs: 1132 and 1909 respectively; SEQ ID NOs: 1133 and 1910, respectively; SEQ ID NOs: 1134 and 1911, respectively; SEQ ID NOs: 1135 and 1912, respectively; SEQ ID NOs: 1136 and 1913 respectively; SEQ ID NOs: 1137 and 1914, respectively; SEQ ID NOs: 1138 and 1915 respectively; SEQ ID NOs: 1139 and 1916, respectively; SEQ ID NOs: 1140 and 1917, respectively; SEQ ID NOs: 1141 and 1918, respectively; SEQ ID NOs: 1142 and 1919 respectively; SEQ ID NOs: 1143 and 1920, respectively; SEQ ID NOs: 1144 and 1921, respectively; SEQ ID NOs: 1145 and 1922, respectively; SEQ ID NOs: 1146 and 1923, respectively; SEQ ID NOs: 1147 and 1924, respectively; SEQ ID NOs: 1148 and 1925 respectively; SEQ ID NOs: 1149 and 1926, respectively; SEQ ID NOs: 1150 and 1927, respectively; SEQ ID NOs: 1151 and 1928, respectively; SEQ ID NOs: 1152 and 1929 respectively; SEQ ID NOs: 1153 and 1930, respectively; SEQ ID NOs: 1154 and 1931 respectively; SEQ ID NOs: 1155 and 1932, respectively; SEQ ID NOs: 1156 and 1933, respectively; SEQ ID NOs: 1157 and 1934, respectively; SEQ ID NOs: 1158 and 1935 respectively; SEQ ID NOs: 1159 and 1936, respectively; SEQ ID NOs: 1160 and 1937, respectively; SEQ ID NOs: 1161 and 1938, respectively; SEQ ID NOs: 1162 and 1939, respectively; SEQ ID NOs: 1163 and 1940, respectively; SEQ ID NOs: 1164 and 1941 respectively; SEQ ID NOs: 1165 and 1942, respectively; SEQ ID NOs: 1166 and 1943, respectively; SEQ ID NOs: 1167 and 1944, respectively; SEQ ID NOs: 1168 and 1945 respectively; SEQ ID NOs: 1169 and 1946, respectively; SEQ ID NOs: 1170 and 1947 respectively; SEQ ID NOs: 1171 and 1948, respectively; SEQ ID NOs: 1172 and 1949,- 982 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOrespectively; SEQ ID NOs: 1173 and 1950, respectively; SEQ ID NOs: 1174 and 1951, respectively; SEQ ID NOs: 1175 and 1952, respectively; SEQ ID NOs: 1176 and 1953, respectively; SEQ ID NOs: 1177 and 1954, respectively; SEQ ID NOs: 1178 and 1955, respectively; SEQ ID NOs: 1179 and 1956, respectively; SEQ ID NOs: 1180 and 1957, respectively; SEQ ID NOs: 1181 and 1958, respectively; SEQ ID NOs: 1182 and 1959, respectively; SEQ ID NOs: 1183 and 1960, respectively; SEQ ID NOs: 1184 and 1961, respectively; SEQ ID NOs: 1185 and 1962, respectively; SEQ ID NOs: 1186 and 1963, respectively; SEQ ID NOs: 1187 and 1964, respectively; SEQ ID NOs: 1188 and 1965, respectively; SEQ ID NOs: 1189 and 1966, respectively; SEQ ID NOs: 1190 and 1967, respectively; SEQ ID NOs: 1191 and 1968, respectively; SEQ ID NOs: 1192 and 1969, respectively; SEQ ID NOs: 1193 and 1970, respectively; SEQ ID NOs: 1194 and 1971, respectively; SEQ ID NOs: 1195 and 1972, respectively; SEQ ID NOs: 1196 and 1973, respectively; SEQ ID NOs: 1197 and 1974, respectively; SEQ ID NOs: 1198 and 1975, respectively; SEQ ID NOs: 1199 and 1976, respectively; SEQ ID NOs: 1200 and 1977, respectively; SEQ ID NOs: 1201 and 1978, respectively; SEQ ID NOs: 1202 and 1979, respectively; SEQ ID NOs: 1203 and 1980, respectively; SEQ ID NOs: 1204 and 1981, respectively; SEQ ID NOs: 1205 and 1982, respectively; SEQ ID NOs: 1206 and 1983, respectively; SEQ ID NOs: 1207 and 1984, respectively; SEQ ID NOs: 1208 and 1985, respectively; SEQ ID NOs: 1209 and 1986, respectively; SEQ ID NOs: 1210 and 1987, respectively; SEQ ID NOs: 1211 and 1988, respectively; SEQ ID NOs: 1212 and 1989, respectively; SEQ ID NOs: 1213 and 1990, respectively; SEQ ID NOs: 1214 and 1991, respectively; SEQ ID NOs: 1215 and 1992, respectively; SEQ ID NOs: 1216 and 1993, respectively; SEQ ID NOs: 1217 and 1994, respectively; SEQ ID NOs: 1218 and 1995, respectively; SEQ ID NOs: 1219 and 1996, respectively; SEQ ID NOs: 1220 and 1997, respectively; SEQ ID NOs: 1221 and 1998, respectively; SEQ ID NOs: 1222 and 1999, respectively; SEQ ID NOs: 1223 and 2000, respectively; SEQ ID NOs: 1224 and 2001, respectively; SEQ ID NOs: 1225 and 2002, respectively; SEQ ID NOs: 1226 and 2003, respectively; SEQ ID NOs: 1227 and 2004, respectively; SEQ ID NOs: 1228 and 2005, respectively; SEQ ID NOs: 1229 and 2006, respectively; SEQ ID NOs: 1230 and 2007, respectively; SEQ ID NOs: 1231 and 2008, respectively; SEQ ID NOs: 1232 and 2009, respectively; SEQ ID NOs: 1233 and 2010, respectively; SEQ ID NOs: 1234 and 2011,- 983 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOrespectively; SEQ ID NOs: 1235 and 2012, respectively; SEQ ID NOs: 1236 and 2013, respectively; SEQ ID NOs: 1237 and 2014, respectively; SEQ ID NOs: 1238 and 2015, respectively; SEQ ID NOs: 1239 and 2016, respectively; SEQ ID NOs: 1240 and 2017, respectively; SEQ ID NOs: 1241 and 2018, respectively; SEQ ID NOs: 1242 and 2019, respectively; SEQ ID NOs: 1243 and 2020, respectively; SEQ ID NOs: 1244 and 2021, respectively; SEQ ID NOs: 1245 and 2022, respectively; SEQ ID NOs: 1246 and 2023, respectively; SEQ ID NOs: 1247 and 2024, respectively; SEQ ID NOs: 1248 and 2025, respectively; SEQ ID NOs: 1249 and 2026, respectively; SEQ ID NOs: 1250 and 2027, respectively; SEQ ID NOs: 1251 and 2028, respectively; SEQ ID NOs: 1252 and 2029, respectively; SEQ ID NOs: 1253 and 2030, respectively; SEQ ID NOs: 1254 and 2031, respectively; SEQ ID NOs: 1255 and 2032, respectively; SEQ ID NOs: 1256 and 2033, respectively; SEQ ID NOs: 1257 and 2034, respectively; SEQ ID NOs: 1258 and 2035, respectively; SEQ ID NOs: 1259 and 2036, respectively; SEQ ID NOs: 1260 and 2037, respectively; SEQ ID NOs: 1261 and 2038, respectively; SEQ ID NOs: 1262 and 2039, respectively; SEQ ID NOs: 1263 and 2040, respectively; SEQ ID NOs: 1264 and 2041, respectively; SEQ ID NOs: 1265 and 2042, respectively; SEQ ID NOs: 1266 and 2043, respectively; SEQ ID NOs: 1267 and 2044, respectively; SEQ ID NOs: 1268 and 2045, respectively; SEQ ID NOs: 1269 and 2046, respectively; SEQ ID NOs: 1270 and 2047, respectively; SEQ ID NOs: 1271 and 2048, respectively; SEQ ID NOs: 1272 and 2049, respectively; SEQ ID NOs: 1273 and 2050, respectively; SEQ ID NOs: 1274 and 2051, respectively; SEQ ID NOs: 1275 and 2052, respectively; SEQ ID NOs: 1276 and 2053, respectively; SEQ ID NOs: 1277 and 2054, respectively; SEQ ID NOs: 1278 and 2055, respectively; SEQ ID NOs: 1279 and 2056, respectively; SEQ ID NOs: 1280 and 2057, respectively; SEQ ID NOs: 1281 and 2058, respectively; SEQ ID NOs: 1282 and 2059, respectively; SEQ ID NOs: 1283 and 2060, respectively; SEQ ID NOs: 1284 and 2061, respectively; SEQ ID NOs: 1285 and 2062, respectively; SEQ ID NOs: 1286 and 2063, respectively; SEQ ID NOs: 1287 and 2064, respectively; SEQ ID NOs: 1288 and 2065, respectively; SEQ ID NOs: 1289 and 2066, respectively; SEQ ID NOs: 1290 and 2067, respectively; SEQ ID NOs: 1291 and 2068, respectively; SEQ ID NOs: 1292 and 2069, respectively; SEQ ID NOs: 1293 and 2070, respectively; SEQ ID NOs: 1294 and 2071, respectively; SEQ ID NOs: 1295 and 2072, respectively; SEQ ID NOs: 1296 and 2073,- 984 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOrespectively; SEQ ID NOs: 1297 and 2074, respectively; SEQ ID NOs: 1298 and 2075, respectively; SEQ ID NOs: 1299 and 2076, respectively; SEQ ID NOs: 1300 and 2077, respectively; SEQ ID NOs: 1301 and 2078, respectively; SEQ ID NOs: 1302 and 2079, respectively; SEQ ID NOs: 1303 and 2080, respectively; SEQ ID NOs: 1304 and 2081, respectively; SEQ ID NOs: 1305 and 2082, respectively; SEQ ID NOs: 1306 and 2083, respectively; SEQ ID NOs: 1307 and 2084, respectively; SEQ ID NOs: 1308 and 2085, respectively; SEQ ID NOs: 1309 and 2086, respectively; SEQ ID NOs: 1310 and 2087, respectively; SEQ ID NOs: 1311 and 2088, respectively; SEQ ID NOs: 1312 and 2089, respectively; SEQ ID NOs: 1313 and 2090, respectively; SEQ ID NOs: 1314 and 2091, respectively; SEQ ID NOs: 1315 and 2092, respectively; SEQ ID NOs: 1316 and 2093, respectively; SEQ ID NOs: 1317 and 2094, respectively; SEQ ID NOs: 1318 and 2095, respectively; SEQ ID NOs: 1319 and 2096, respectively; SEQ ID NOs: 1320 and 2097, respectively; SEQ ID NOs: 1321 and 2098, respectively; SEQ ID NOs: 1322 and 2099, respectively; SEQ ID NOs: 1323 and 2100, respectively; SEQ ID NOs: 1324 and 2101, respectively; SEQ ID NOs: 1325 and 2102, respectively; SEQ ID NOs: 1326 and 2103, respectively; SEQ ID NOs: 1327 and 2104, respectively; SEQ ID NOs: 1328 and 2105, respectively; SEQ ID NOs: 1329 and 2106, respectively; SEQ ID NOs: 1330 and 2107, respectively; SEQ ID NOs: 1331 and 2108, respectively; SEQ ID NOs: 1332 and 2109, respectively; SEQ ID NOs: 1333 and 2110, respectively; SEQ ID NOs: 1334 and 2111, respectively; SEQ ID NOs: 1335 and 2112, respectively; SEQ ID NOs: 1336 and 2113, respectively; SEQ ID NOs: 1337 and 2114, respectively; SEQ ID NOs: 1338 and 2115, respectively; SEQ ID NOs: 1339 and 2116, respectively; SEQ ID NOs: 1340 and 2117, respectively; SEQ ID NOs: 1341 and 2118, respectively; SEQ ID NOs: 1342 and 2119, respectively; SEQ ID NOs: 1343 and 2120, respectively; SEQ ID NOs: 1344 and 2121, respectively; SEQ ID NOs: 1345 and 2122, respectively; SEQ ID NOs: 1346 and 2123, respectively; SEQ ID NOs: 1347 and 2124, respectively; SEQ ID NOs: 1348 and 2125, respectively; SEQ ID NOs: 1349 and 2126, respectively; SEQ ID NOs: 1350 and 2127, respectively; SEQ ID NOs: 1351 and 2128, respectively; SEQ ID NOs: 1352 and 2129, respectively; SEQ ID NOs: 1353 and 2130, respectively; SEQ ID NOs: 1354 and 2131, respectively; SEQ ID NOs: 1355 and 2132, respectively; SEQ ID NOs: 1356 and 2133, respectively; SEQ ID NOs: 1357 and 2134, respectively; SEQ ID NOs: 1358 and 2135,- 985 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOrespectively; SEQ ID NOs: 1359 and 2136, respectively; SEQ ID NOs: 1360 and 2137, respectively; SEQ ID NOs: 1361 and 2138, respectively; SEQ ID NOs: 1362 and 2139, respectively; SEQ ID NOs: 1363 and 2140, respectively; SEQ ID NOs: 1364 and 2141, respectively; SEQ ID NOs: 1365 and 2142, respectively; SEQ ID NOs: 1366 and 2143, respectively; SEQ ID NOs: 1367 and 2144, respectively; SEQ ID NOs: 1368 and 2145, respectively; SEQ ID NOs: 1369 and 2146, respectively; SEQ ID NOs: 1370 and 2147, respectively; SEQ ID NOs: 1371 and 2148, respectively; SEQ ID NOs: 1372 and 2149, respectively; SEQ ID NOs: 1373 and 2150, respectively; SEQ ID NOs: 1374 and 2151, respectively; SEQ ID NOs: 1375 and 2152, respectively; SEQ ID NOs: 1376 and 2153, respectively; SEQ ID NOs: 1377 and 2154, respectively; SEQ ID NOs: 1378 and 2155, respectively; SEQ ID NOs: 1379 and 2156, respectively; SEQ ID NOs: 1380 and 2157, respectively; SEQ ID NOs: 1381 and 2158, respectively; SEQ ID NOs: 1382 and 2159, respectively; SEQ ID NOs: 1383 and 2160, respectively; SEQ ID NOs: 1384 and 2161, respectively; SEQ ID NOs: 1385 and 2162, respectively; SEQ ID NOs: 1386 and 2163, respectively; SEQ ID NOs: 1387 and 2164, respectively; SEQ ID NOs: 1388 and 2165, respectively; SEQ ID NOs: 1389 and 2166, respectively; SEQ ID NOs: 1390 and 2167, respectively; SEQ ID NOs: 1391 and 2168, respectively; SEQ ID NOs: 1392 and 2169, respectively; SEQ ID NOs: 1393 and 2170, respectively; SEQ ID NOs: 1394 and 2171, respectively; SEQ ID NOs: 1395 and 2172, respectively; SEQ ID NOs: 1396 and 2173, respectively; SEQ ID NOs: 1397 and 2174, respectively; SEQ ID NOs: 1398 and 2175, respectively; SEQ ID NOs: 1399 and 2176, respectively; SEQ ID NOs: 1400 and 2177, respectively; SEQ ID NOs: 1401 and 2178, respectively; SEQ ID NOs: 1402 and 2179, respectively; SEQ ID NOs: 1403 and 2180, respectively; SEQ ID NOs: 1404 and 2181, respectively; SEQ ID NOs: 1405 and 2182, respectively; SEQ ID NOs: 1406 and 2183, respectively; SEQ ID NOs: 1407 and 2184, respectively; SEQ ID NOs: 1408 and 2185, respectively; SEQ ID NOs: 1409 and 2186, respectively; SEQ ID NOs: 1410 and 2187, respectively; SEQ ID NOs: 1411 and 2188, respectively; SEQ ID NOs: 1412 and 2189, respectively; SEQ ID NOs: 1413 and 2190, respectively; SEQ ID NOs: 1414 and 2191, respectively; SEQ ID NOs: 1415 and 2192, respectively; SEQ ID NOs: 1416 and 2193, respectively; SEQ ID NOs: 1417 and 2194, respectively; SEQ ID NOs: 1418 and 2195, respectively; SEQ ID NOs: 1419 and 2196, respectively; SEQ ID NOs: 1420 and 2197,- 986 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOrespectively; SEQ ID NOs: 1421 and 2198, respectively; SEQ ID NOs: 1422 and 2199, respectively; SEQ ID NOs: 1423 and 2200, respectively; SEQ ID NOs: 1424 and 2201, respectively; SEQ ID NOs: 1425 and 2202, respectively; SEQ ID NOs: 1426 and 2203, respectively; SEQ ID NOs: 1427 and 2204, respectively; SEQ ID NOs: 1428 and 2205, respectively; SEQ ID NOs: 1429 and 2206, respectively; SEQ ID NOs: 1430 and 2207, respectively; SEQ ID NOs: 1431 and 2208, respectively; SEQ ID NOs: 1432 and 2209, respectively; SEQ ID NOs: 1433 and 2210, respectively; SEQ ID NOs: 1434 and 2211, respectively; SEQ ID NOs: 1435 and 2212, respectively; SEQ ID NOs: 1436 and 2213, respectively; SEQ ID NOs: 1437 and 2214, respectively; SEQ ID NOs: 1438 and 2215, respectively; SEQ ID NOs: 1439 and 2216, respectively; SEQ ID NOs: 1440 and 2217, respectively; SEQ ID NOs: 1441 and 2218, respectively; SEQ ID NOs: 1442 and 2219, respectively; SEQ ID NOs: 1443 and 2220, respectively; SEQ ID NOs: 1444 and 2221, respectively; SEQ ID NOs: 1445 and 2222, respectively; SEQ ID NOs: 1446 and 2223, respectively; SEQ ID NOs: 1447 and 2224, respectively; SEQ ID NOs: 1448 and 2225, respectively; SEQ ID NOs: 1449 and 2226, respectively; SEQ ID NOs: 1450 and 2227, respectively; SEQ ID NOs: 1451 and 2228, respectively; SEQ ID NOs: 1452 and 2229, respectively; SEQ ID NOs: 1453 and 2230, respectively; SEQ ID NOs: 1454 and 2231, respectively; SEQ ID NOs: 1455 and 2232, respectively; SEQ ID NOs: 1456 and 2233, respectively; SEQ ID NOs: 1457 and 2234, respectively; SEQ ID NOs: 1458 and 2235, respectively; SEQ ID NOs: 1459 and 2236, respectively; SEQ ID NOs: 1460 and 2237, respectively; SEQ ID NOs: 1461 and 2238, respectively; SEQ ID NOs: 1462 and 2239, respectively; SEQ ID NOs: 1463 and 2240, respectively; SEQ ID NOs: 1464 and 2241, respectively; SEQ ID NOs: 1465 and 2242, respectively; SEQ ID NOs: 1466 and 2243, respectively; SEQ ID NOs: 1467 and 2244, respectively; SEQ ID NOs: 1468 and 2245, respectively; SEQ ID NOs: 1469 and 2246, respectively; SEQ ID NOs: 1470 and 2247, respectively; SEQ ID NOs: 1471 and 2248, respectively; SEQ ID NOs: 1472 and 2249, respectively; SEQ ID NOs: 1473 and 2250, respectively; SEQ ID NOs: 1474 and 2251, respectively; SEQ ID NOs: 1475 and 2252, respectively; SEQ ID NOs: 1476 and 2253, respectively; SEQ ID NOs: 1477 and 2254, respectively; SEQ ID NOs: 1478 and 2255, respectively; SEQ ID NOs: 1479 and 2256, respectively; SEQ ID NOs: 1480 and 2257, respectively; SEQ ID NOs: 1481 and 2258, respectively; SEQ ID NOs: 1482 and 2259,- 987 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOrespectively; SEQ ID NOs: 1483 and 2260, respectively; SEQ ID NOs: 1484 and 2261, respectively; SEQ ID NOs: 1485 and 2262, respectively; SEQ ID NOs: 1486 and 2263, respectively; SEQ ID NOs: 1487 and 2264, respectively; SEQ ID NOs: 1488 and 2265, respectively; SEQ ID NOs: 1489 and 2266, respectively; SEQ ID NOs: 1490 and 2267, respectively; SEQ ID NOs: 1491 and 2268, respectively; SEQ ID NOs: 1492 and 2269, respectively; SEQ ID NOs: 1493 and 2270, respectively; SEQ ID NOs: 1494 and 2271, respectively; SEQ ID NOs: 1495 and 2272, respectively; SEQ ID NOs: 1496 and 2273, respectively; SEQ ID NOs: 1497 and 2274, respectively; SEQ ID NOs: 1498 and 2275, respectively; SEQ ID NOs: 1499 and 2276, respectively; SEQ ID NOs: 1500 and 2277, respectively; SEQ ID NOs: 1501 and 2278, respectively; SEQ ID NOs: 1502 and 2279, respectively; SEQ ID NOs: 1503 and 2280, respectively; SEQ ID NOs: 1504 and 2281, respectively; SEQ ID NOs: 1505 and 2282, respectively; SEQ ID NOs: 1506 and 2283, respectively; SEQ ID NOs: 1507 and 2284, respectively; SEQ ID NOs: 1508 and 2285, respectively; SEQ ID NOs: 1509 and 2286, respectively; SEQ ID NOs: 1510 and 2287, respectively; SEQ ID NOs: 1511 and 2288, respectively; SEQ ID NOs: 1512 and 2289, respectively; SEQ ID NOs: 1513 and 2290, respectively; SEQ ID NOs: 1514 and 2291, respectively; SEQ ID NOs: 1515 and 2292, respectively; SEQ ID NOs: 1516 and 2293, respectively; SEQ ID NOs: 1517 and 2294, respectively; SEQ ID NOs: 1518 and 2295, respectively; SEQ ID NOs: 1519 and 2296, respectively; SEQ ID NOs: 1520 and 2297, respectively; SEQ ID NOs: 1521 and 2298, respectively; SEQ ID NOs: 1522 and 2299, respectively; SEQ ID NOs: 1523 and 2300, respectively; SEQ ID NOs: 1524 and 2301, respectively; SEQ ID NOs: 1525 and 2302, respectively; SEQ ID NOs: 1526 and 2303, respectively; SEQ ID NOs: 1527 and 2304, respectively; SEQ ID NOs: 1528 and 2305, respectively; SEQ ID NOs: 1529 and 2306, respectively; SEQ ID NOs: 1530 and 2307, respectively; SEQ ID NOs: 1531 and 2308, respectively; SEQ ID NOs: 1532 and 2309, respectively; SEQ ID NOs: 1533 and 2310, respectively; SEQ ID NOs: 1534 and 2311, respectively; SEQ ID NOs: 1535 and 2312, respectively; SEQ ID NOs: 1536 and 2313, respectively; SEQ ID NOs: 1537 and 2314, respectively; SEQ ID NOs: 1538 and 2315, respectively; SEQ ID NOs: 1539 and 2316, respectively; SEQ ID NOs: 1540 and 2317, respectively; SEQ ID NOs: 1541 and 2318, respectively; SEQ ID NOs: 1542 and 2319, respectively; SEQ ID NOs: 1543 and 2320, respectively; SEQ ID NOs: 1544 and 2321,- 988 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOrespectively; SEQ ID NOs: 1545 and 2322, respectively; SEQ ID NOs: 1546 and 2323 respectively; SEQ ID NOs: 1547 and 2324, respectively; SEQ ID NOs: 1548 and 2325 respectively; SEQ ID NOs: 1549 and 2326, respectively; SEQ ID NOs: 1550 and 2327 respectively; SEQ ID NOs: 1551 and 2328, respectively; SEQ ID NOs: 1552 and 2329 respectively; SEQ ID NOs: 1553 and 2330, respectively; or SEQ ID NOs: 1554 and 2331, respectively.

82. The compound of claim 81, wherein the sense strand and the antisense strand comprise nucleotide sequences ofSEQ ID NOs: 1367 and 2144, respectively;SEQ ID NOs: 1448 and 2225, respectively;SEQ ID NOs: 1527 and 2304, respectively;SEQ ID NOs: 1442 and 2219, respectively;SEQ ID NOs: 1365 and 2142, respectively;SEQ ID NOs: 1390 and 2167, respectively;SEQ ID NOs: 1526 and 2303, respectively;SEQ ID NOs: 1346 and 2123, respectively;SEQ ID NOs: 1348 and 2125, respectively;SEQ ID NOs: 1364 and 2141, respectively;SEQ ID NOs: 1394 and 2171, respectively;SEQ ID NOs: 1449 and 2226, respectively;SEQ ID NOs: 1451 and 2228, respectively;SEQ ID NOs: 1457 and 2234, respectively;SEQ ID NOs: 1459 and 2236, respectively; orSEQ ID NOs: 1531 and 2308, respectively.

83. The compound of any one of claims 14-80, wherein the nucleic acid A comprises an antisense strand and a sense strand, wherein the sense strand and the antisense strand comprise nucleotide sequences of SEQ ID NOs: 2332 and 3100, respectively; SEQ ID NOs: 2333 and 3101, respectively; SEQ ID NOs: 2334 and 3102, respectively; SEQ ID NOs: 2335 and 3103, respectively; SEQ ID NOs: 2336 and 3104, respectively; SEQ ID NOs: 2337 and 3105,- 989 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOrespectively; SEQ ID NOs: 2338 and 3106, respectively; SEQ ID NOs: 2339 and 3107, respectively; SEQ ID NOs: 2340 and 3108, respectively; SEQ ID NOs: 2341 and 3109, respectively; SEQ ID NOs: 2342 and 3110, respectively; SEQ ID NOs: 2343 and 3111, respectively; SEQ ID NOs: 2344 and 3112, respectively; SEQ ID NOs: 2345 and 3113, respectively; SEQ ID NOs: 2346 and 3114, respectively; SEQ ID NOs: 2347 and 3115, respectively; SEQ ID NOs: 2348 and 3116, respectively; SEQ ID NOs: 2349 and 3117, respectively; SEQ ID NOs: 2350 and 3118, respectively; SEQ ID NOs: 2351 and 3119, respectively; SEQ ID NOs: 2352 and 3120, respectively; SEQ ID NOs: 2353 and 3121, respectively; SEQ ID NOs: 2354 and 3122, respectively; SEQ ID NOs: 2355 and 3123, respectively; SEQ ID NOs: 2356 and 3124, respectively; SEQ ID NOs: 2357 and 3125, respectively; SEQ ID NOs: 2358 and 3126, respectively; SEQ ID NOs: 2359 and 3127, respectively; SEQ ID NOs: 2360 and 3128, respectively; SEQ ID NOs: 2361 and 3129, respectively; SEQ ID NOs: 2362 and 3130, respectively; SEQ ID NOs: 2363 and 3131, respectively; SEQ ID NOs: 2364 and 3132, respectively; SEQ ID NOs: 2365 and 3133, respectively; SEQ ID NOs: 2366 and 3134, respectively; SEQ ID NOs: 2367 and 3135, respectively; SEQ ID NOs: 2368 and 3136, respectively; SEQ ID NOs: 2369 and 3137, respectively; SEQ ID NOs: 2370 and 3138, respectively; SEQ ID NOs: 2371 and 3139, respectively; SEQ ID NOs: 2372 and 3140, respectively; SEQ ID NOs: 2373 and 3141, respectively; SEQ ID NOs: 2374 and 3142, respectively; SEQ ID NOs: 2375 and 3143, respectively; SEQ ID NOs: 2376 and 3144, respectively; SEQ ID NOs: 2377 and 3145, respectively; SEQ ID NOs: 2378 and 3146, respectively; SEQ ID NOs: 2379 and 3147, respectively; SEQ ID NOs: 2380 and 3148, respectively; SEQ ID NOs: 2381 and 3149, respectively; SEQ ID NOs: 2382 and 3150, respectively; SEQ ID NOs: 2383 and 3151, respectively; SEQ ID NOs: 2384 and 3152, respectively; SEQ ID NOs: 2385 and 3153, respectively; SEQ ID NOs: 2386 and 3154, respectively; SEQ ID NOs: 2387 and 3155, respectively; SEQ ID NOs: 2388 and 3156, respectively; SEQ ID NOs: 2389 and 3157, respectively; SEQ ID NOs: 2390 and 3158, respectively; SEQ ID NOs: 2391 and 3159, respectively; SEQ ID NOs: 2392 and 3160, respectively; SEQ ID NOs: 2393 and 3161, respectively; SEQ ID NOs: 2394 and 3162, respectively; SEQ ID NOs: 2395 and 3163, respectively; SEQ ID NOs: 2396 and 3164, respectively; SEQ ID NOs: 2397 and 3165, respectively; SEQ ID NOs: 2398 and 3166, respectively; SEQ ID NOs: 2399 and 3167,- 990 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOrespectively; SEQ ID NOs: 2400 and 3168, respectively; SEQ ID NOs: 2401 and 3169, respectively; SEQ ID NOs: 2402 and 3170, respectively; SEQ ID NOs: 2403 and 3171, respectively; SEQ ID NOs: 2404 and 3172, respectively; SEQ ID NOs: 2405 and 3173, respectively; SEQ ID NOs: 2406 and 3174, respectively; SEQ ID NOs: 2407 and 3175, respectively; SEQ ID NOs: 2408 and 3176, respectively; SEQ ID NOs: 2409 and 3177, respectively; SEQ ID NOs: 2410 and 3178, respectively; SEQ ID NOs: 2411 and 3179, respectively; SEQ ID NOs: 2412 and 3180, respectively; SEQ ID NOs: 2413 and 3181, respectively; SEQ ID NOs: 2414 and 3182, respectively; SEQ ID NOs: 2415 and 3183, respectively; SEQ ID NOs: 2416 and 3184, respectively; SEQ ID NOs: 2417 and 3185, respectively; SEQ ID NOs: 2418 and 3186, respectively; SEQ ID NOs: 2419 and 3187, respectively; SEQ ID NOs: 2420 and 3188, respectively; SEQ ID NOs: 2421 and 3189, respectively; SEQ ID NOs: 2422 and 3190, respectively; SEQ ID NOs: 2423 and 3191, respectively; SEQ ID NOs: 2424 and 3192, respectively; SEQ ID NOs: 2425 and 3193, respectively; SEQ ID NOs: 2426 and 3194, respectively; SEQ ID NOs: 2427 and 3195, respectively; SEQ ID NOs: 2428 and 3196, respectively; SEQ ID NOs: 2429 and 3197, respectively; SEQ ID NOs: 2430 and 3198, respectively; SEQ ID NOs: 2431 and 3199, respectively; SEQ ID NOs: 2432 and 3200, respectively; SEQ ID NOs: 2433 and 3201, respectively; SEQ ID NOs: 2434 and 3202, respectively; SEQ ID NOs: 2435 and 3203, respectively; SEQ ID NOs: 2436 and 3204, respectively; SEQ ID NOs: 2437 and 3205, respectively; SEQ ID NOs: 2438 and 3206, respectively; SEQ ID NOs: 2439 and 3207, respectively; SEQ ID NOs: 2440 and 3208, respectively; SEQ ID NOs: 2441 and 3209, respectively; SEQ ID NOs: 2442 and 3210, respectively; SEQ ID NOs: 2443 and 3211, respectively; SEQ ID NOs: 2444 and 3212, respectively; SEQ ID NOs: 2445 and 3213, respectively; SEQ ID NOs: 2446 and 3214, respectively; SEQ ID NOs: 2447 and 3215, respectively; SEQ ID NOs: 2448 and 3216, respectively; SEQ ID NOs: 2449 and 3217, respectively; SEQ ID NOs: 2450 and 3218, respectively; SEQ ID NOs: 2451 and 3219, respectively; SEQ ID NOs: 2452 and 3220, respectively; SEQ ID NOs: 2453 and 3221, respectively; SEQ ID NOs: 2454 and 3222, respectively; SEQ ID NOs: 2455 and 3223, respectively; SEQ ID NOs: 2456 and 3224, respectively; SEQ ID NOs: 2457 and 3225, respectively; SEQ ID NOs: 2458 and 3226, respectively; SEQ ID NOs: 2459 and 3227, respectively; SEQ ID NOs: 2460 and 3228, respectively; SEQ ID NOs: 2461 and 3229,- 991 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOrespectively; SEQ ID NOs: 2462 and 3230, respectively; SEQ ID NOs: 2463 and 3231, respectively; SEQ ID NOs: 2464 and 3232, respectively; SEQ ID NOs: 2465 and 3233, respectively; SEQ ID NOs: 2466 and 3234, respectively; SEQ ID NOs: 2467 and 3235, respectively; SEQ ID NOs: 2468 and 3236, respectively; SEQ ID NOs: 2469 and 3237, respectively; SEQ ID NOs: 2470 and 3238, respectively; SEQ ID NOs: 2471 and 3239, respectively; SEQ ID NOs: 2472 and 3240, respectively; SEQ ID NOs: 2473 and 3241, respectively; SEQ ID NOs: 2474 and 3242, respectively; SEQ ID NOs: 2475 and 3243, respectively; SEQ ID NOs: 2476 and 3244, respectively; SEQ ID NOs: 2477 and 3245, respectively; SEQ ID NOs: 2478 and 3246, respectively; SEQ ID NOs: 2479 and 3247, respectively; SEQ ID NOs: 2480 and 3248, respectively; SEQ ID NOs: 2481 and 3249, respectively; SEQ ID NOs: 2482 and 3250, respectively; SEQ ID NOs: 2483 and 3251, respectively; SEQ ID NOs: 2484 and 3252, respectively; SEQ ID NOs: 2485 and 3253, respectively; SEQ ID NOs: 2486 and 3254, respectively; SEQ ID NOs: 2487 and 3255, respectively; SEQ ID NOs: 2488 and 3256, respectively; SEQ ID NOs: 2489 and 3257, respectively; SEQ ID NOs: 2490 and 3258, respectively; SEQ ID NOs: 2491 and 3259, respectively; SEQ ID NOs: 2492 and 3260, respectively; SEQ ID NOs: 2493 and 3261, respectively; SEQ ID NOs: 2494 and 3262, respectively; SEQ ID NOs: 2495 and 3263, respectively; SEQ ID NOs: 2496 and 3264, respectively; SEQ ID NOs: 2497 and 3265, respectively; SEQ ID NOs: 2498 and 3266, respectively; SEQ ID NOs: 2499 and 3267, respectively; SEQ ID NOs: 2500 and 3268, respectively; SEQ ID NOs: 2501 and 3269, respectively; SEQ ID NOs: 2502 and 3270, respectively; SEQ ID NOs: 2503 and 3271, respectively; SEQ ID NOs: 2504 and 3272, respectively; SEQ ID NOs: 2505 and 3273, respectively; SEQ ID NOs: 2506 and 3274, respectively; SEQ ID NOs: 2507 and 3275, respectively; SEQ ID NOs: 2508 and 3276, respectively; SEQ ID NOs: 2509 and 3277, respectively; SEQ ID NOs: 2510 and 3278, respectively; SEQ ID NOs: 2511 and 3279, respectively; SEQ ID NOs: 2512 and 3280, respectively; SEQ ID NOs: 2513 and 3281, respectively; SEQ ID NOs: 2514 and 3282, respectively; SEQ ID NOs: 2515 and 3283, respectively; SEQ ID NOs: 2516 and 3284, respectively; SEQ ID NOs: 2517 and 3285, respectively; SEQ ID NOs: 2518 and 3286, respectively; SEQ ID NOs: 2519 and 3287, respectively; SEQ ID NOs: 2520 and 3288, respectively; SEQ ID NOs: 2521 and 3289, respectively; SEQ ID NOs: 2522 and 3290, respectively; SEQ ID NOs: 2523 and 3291,- 992 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOrespectively; SEQ ID NOs: 2524 and 3292, respectively; SEQ ID NOs: 2525 and 3293, respectively; SEQ ID NOs: 2526 and 3294, respectively; SEQ ID NOs: 2527 and 3295, respectively; SEQ ID NOs: 2528 and 3296, respectively; SEQ ID NOs: 2529 and 3297, respectively; SEQ ID NOs: 2530 and 3298, respectively; SEQ ID NOs: 2531 and 3299, respectively; SEQ ID NOs: 2532 and 3300, respectively; SEQ ID NOs: 2533 and 3301, respectively; SEQ ID NOs: 2534 and 3302, respectively; SEQ ID NOs: 2535 and 3303, respectively; SEQ ID NOs: 2536 and 3304, respectively; SEQ ID NOs: 2537 and 3305, respectively; SEQ ID NOs: 2538 and 3306, respectively; SEQ ID NOs: 2539 and 3307, respectively; SEQ ID NOs: 2540 and 3308, respectively; SEQ ID NOs: 2541 and 3309, respectively; SEQ ID NOs: 2542 and 3310, respectively; SEQ ID NOs: 2543 and 3311, respectively; SEQ ID NOs: 2544 and 3312, respectively; SEQ ID NOs: 2545 and 3313, respectively; SEQ ID NOs: 2546 and 3314, respectively; SEQ ID NOs: 2547 and 3315, respectively; SEQ ID NOs: 2548 and 3316, respectively; SEQ ID NOs: 2549 and 3317, respectively; SEQ ID NOs: 2550 and 3318, respectively; SEQ ID NOs: 2551 and 3319, respectively; SEQ ID NOs: 2552 and 3320, respectively; SEQ ID NOs: 2553 and 3321, respectively; SEQ ID NOs: 2554 and 3322, respectively; SEQ ID NOs: 2555 and 3323, respectively; SEQ ID NOs: 2556 and 3324, respectively; SEQ ID NOs: 2557 and 3325, respectively; SEQ ID NOs: 2558 and 3326, respectively; SEQ ID NOs: 2559 and 3327, respectively; SEQ ID NOs: 2560 and 3328, respectively; SEQ ID NOs: 2561 and 3329, respectively; SEQ ID NOs: 2562 and 3330, respectively; SEQ ID NOs: 2563 and 3331, respectively; SEQ ID NOs: 2564 and 3332, respectively; SEQ ID NOs: 2565 and 3333, respectively; SEQ ID NOs: 2566 and 3334, respectively; SEQ ID NOs: 2567 and 3335, respectively; SEQ ID NOs: 2568 and 3336, respectively; SEQ ID NOs: 2569 and 3337, respectively; SEQ ID NOs: 2570 and 3338, respectively; SEQ ID NOs: 2571 and 3339, respectively; SEQ ID NOs: 2572 and 3340, respectively; SEQ ID NOs: 2573 and 3341, respectively; SEQ ID NOs: 2574 and 3342, respectively; SEQ ID NOs: 2575 and 3343, respectively; SEQ ID NOs: 2576 and 3344, respectively; SEQ ID NOs: 2577 and 3345, respectively; SEQ ID NOs: 2578 and 3346, respectively; SEQ ID NOs: 2579 and 3347, respectively; SEQ ID NOs: 2580 and 3348, respectively; SEQ ID NOs: 2581 and 3349, respectively; SEQ ID NOs: 2582 and 3350, respectively; SEQ ID NOs: 2583 and 3351, respectively; SEQ ID NOs: 2584 and 3352, respectively; SEQ ID NOs: 2585 and 3353,- 993 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOrespectively; SEQ ID NOs: 2586 and 3354, respectively; SEQ ID NOs: 2587 and 3355, respectively; SEQ ID NOs: 2588 and 3356, respectively; SEQ ID NOs: 2589 and 3357, respectively; SEQ ID NOs: 2590 and 3358, respectively; SEQ ID NOs: 2591 and 3359, respectively; SEQ ID NOs: 2592 and 3360, respectively; SEQ ID NOs: 2593 and 3361, respectively; SEQ ID NOs: 2594 and 3362, respectively; SEQ ID NOs: 2595 and 3363, respectively; SEQ ID NOs: 2596 and 3364, respectively; SEQ ID NOs: 2597 and 3365, respectively; SEQ ID NOs: 2598 and 3366, respectively; SEQ ID NOs: 2599 and 3367, respectively; SEQ ID NOs: 2600 and 3368, respectively; SEQ ID NOs: 2601 and 3369, respectively; SEQ ID NOs: 2602 and 3370, respectively; SEQ ID NOs: 2603 and 3371, respectively; SEQ ID NOs: 2604 and 3372, respectively; SEQ ID NOs: 2605 and 3373, respectively; SEQ ID NOs: 2606 and 3374, respectively; SEQ ID NOs: 2607 and 3375, respectively; SEQ ID NOs: 2608 and 3376, respectively; SEQ ID NOs: 2609 and 3377, respectively; SEQ ID NOs: 2610 and 3378, respectively; SEQ ID NOs: 2611 and 3379, respectively; SEQ ID NOs: 2612 and 3380, respectively; SEQ ID NOs: 2613 and 3381, respectively; SEQ ID NOs: 2614 and 3382, respectively; SEQ ID NOs: 2615 and 3383, respectively; SEQ ID NOs: 2616 and 3384, respectively; SEQ ID NOs: 2617 and 3385, respectively; SEQ ID NOs: 2618 and 3386, respectively; SEQ ID NOs: 2619 and 3387, respectively; SEQ ID NOs: 2620 and 3388, respectively; SEQ ID NOs: 2621 and 3389, respectively; SEQ ID NOs: 2622 and 3390, respectively; SEQ ID NOs: 2623 and 3391, respectively; SEQ ID NOs: 2624 and 3392, respectively; SEQ ID NOs: 2625 and 3393, respectively; SEQ ID NOs: 2626 and 3394, respectively; SEQ ID NOs: 2627 and 3395, respectively; SEQ ID NOs: 2628 and 3396, respectively; SEQ ID NOs: 2629 and 3397, respectively; SEQ ID NOs: 2630 and 3398, respectively; SEQ ID NOs: 2631 and 3399, respectively; SEQ ID NOs: 2632 and 3400, respectively; SEQ ID NOs: 2633 and 3401, respectively; SEQ ID NOs: 2634 and 3402, respectively; SEQ ID NOs: 2635 and 3403, respectively; SEQ ID NOs: 2636 and 3404, respectively; SEQ ID NOs: 2637 and 3405, respectively; SEQ ID NOs: 2638 and 3406, respectively; SEQ ID NOs: 2639 and 3407, respectively; SEQ ID NOs: 2640 and 3408, respectively; SEQ ID NOs: 2641 and 3409, respectively; SEQ ID NOs: 2642 and 3410, respectively; SEQ ID NOs: 2643 and 3411, respectively; SEQ ID NOs: 2644 and 3412, respectively; SEQ ID NOs: 2645 and 3413, respectively; SEQ ID NOs: 2646 and 3414, respectively; SEQ ID NOs: 2647 and 3415,- 994 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOrespectively; SEQ ID NOs: 2648 and 3416, respectively; SEQ ID NOs: 2649 and 3417, respectively; SEQ ID NOs: 2650 and 3418, respectively; SEQ ID NOs: 2651 and 3419, respectively; SEQ ID NOs: 2652 and 3420, respectively; SEQ ID NOs: 2653 and 3421, respectively; SEQ ID NOs: 2654 and 3422, respectively; SEQ ID NOs: 2655 and 3423, respectively; SEQ ID NOs: 2656 and 3424, respectively; SEQ ID NOs: 2657 and 3425, respectively; SEQ ID NOs: 2658 and 3426, respectively; SEQ ID NOs: 2659 and 3427, respectively; SEQ ID NOs: 2660 and 3428, respectively; SEQ ID NOs: 2661 and 3429, respectively; SEQ ID NOs: 2662 and 3430, respectively; SEQ ID NOs: 2663 and 3431, respectively; SEQ ID NOs: 2664 and 3432, respectively; SEQ ID NOs: 2665 and 3433, respectively; SEQ ID NOs: 2666 and 3434, respectively; SEQ ID NOs: 2667 and 3435, respectively; SEQ ID NOs: 2668 and 3436, respectively; SEQ ID NOs: 2669 and 3437, respectively; SEQ ID NOs: 2670 and 3438, respectively; SEQ ID NOs: 2671 and 3439, respectively; SEQ ID NOs: 2672 and 3440, respectively; SEQ ID NOs: 2673 and 3441, respectively; SEQ ID NOs: 2674 and 3442, respectively; SEQ ID NOs: 2675 and 3443, respectively; SEQ ID NOs: 2676 and 3444, respectively; SEQ ID NOs: 2677 and 3445, respectively; SEQ ID NOs: 2678 and 3446, respectively; SEQ ID NOs: 2679 and 3447, respectively; SEQ ID NOs: 2680 and 3448, respectively; SEQ ID NOs: 2681 and 3449, respectively; SEQ ID NOs: 2682 and 3450, respectively; SEQ ID NOs: 2683 and 3451, respectively; SEQ ID NOs: 2684 and 3452, respectively; SEQ ID NOs: 2685 and 3453, respectively; SEQ ID NOs: 2686 and 3454, respectively; SEQ ID NOs: 2687 and 3455, respectively; SEQ ID NOs: 2688 and 3456, respectively; SEQ ID NOs: 2689 and 3457, respectively; SEQ ID NOs: 2690 and 3458, respectively; SEQ ID NOs: 2691 and 3459, respectively; SEQ ID NOs: 2692 and 3460, respectively; SEQ ID NOs: 2693 and 3461, respectively; SEQ ID NOs: 2694 and 3462, respectively; SEQ ID NOs: 2695 and 3463, respectively; SEQ ID NOs: 2696 and 3464, respectively; SEQ ID NOs: 2697 and 3465, respectively; SEQ ID NOs: 2698 and 3466, respectively; SEQ ID NOs: 2699 and 3467, respectively; SEQ ID NOs: 2700 and 3468, respectively; SEQ ID NOs: 2701 and 3469, respectively; SEQ ID NOs: 2702 and 3470, respectively; SEQ ID NOs: 2703 and 3471, respectively; SEQ ID NOs: 2704 and 3472, respectively; SEQ ID NOs: 2705 and 3473, respectively; SEQ ID NOs: 2706 and 3474, respectively; SEQ ID NOs: 2707 and 3475, respectively; SEQ ID NOs: 2708 and 3476, respectively; SEQ ID NOs: 2709 and 3477,- 995 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOrespectively; SEQ ID NOs: 2710 and 3478, respectively; SEQ ID NOs: 2711 and 3479, respectively; SEQ ID NOs: 2712 and 3480, respectively; SEQ ID NOs: 2713 and 3481, respectively; SEQ ID NOs: 2714 and 3482, respectively; SEQ ID NOs: 2715 and 3483, respectively; SEQ ID NOs: 2716 and 3484, respectively; SEQ ID NOs: 2717 and 3485, respectively; SEQ ID NOs: 2718 and 3486, respectively; SEQ ID NOs: 2719 and 3487, respectively; SEQ ID NOs: 2720 and 3488, respectively; SEQ ID NOs: 2721 and 3489, respectively; SEQ ID NOs: 2722 and 3490, respectively; SEQ ID NOs: 2723 and 3491, respectively; SEQ ID NOs: 2724 and 3492, respectively; SEQ ID NOs: 2725 and 3493, respectively; SEQ ID NOs: 2726 and 3494, respectively; SEQ ID NOs: 2727 and 3495, respectively; SEQ ID NOs: 2728 and 3496, respectively; SEQ ID NOs: 2729 and 3497, respectively; SEQ ID NOs: 2730 and 3498, respectively; SEQ ID NOs: 2731 and 3499, respectively; SEQ ID NOs: 2732 and 3500, respectively; SEQ ID NOs: 2733 and 3501, respectively; SEQ ID NOs: 2734 and 3502, respectively; SEQ ID NOs: 2735 and 3503, respectively; SEQ ID NOs: 2736 and 3504, respectively; SEQ ID NOs: 2737 and 3505, respectively; SEQ ID NOs: 2738 and 3506, respectively; SEQ ID NOs: 2739 and 3507, respectively; SEQ ID NOs: 2740 and 3508, respectively; SEQ ID NOs: 2741 and 3509, respectively; SEQ ID NOs: 2742 and 3510, respectively; SEQ ID NOs: 2743 and 3511, respectively; SEQ ID NOs: 2744 and 3512, respectively; SEQ ID NOs: 2745 and 3513, respectively; SEQ ID NOs: 2746 and 3514, respectively; SEQ ID NOs: 2747 and 3515, respectively; SEQ ID NOs: 2748 and 3516, respectively; SEQ ID NOs: 2749 and 3517, respectively; SEQ ID NOs: 2750 and 3518, respectively; SEQ ID NOs: 2751 and 3519, respectively; SEQ ID NOs: 2752 and 3520, respectively; SEQ ID NOs: 2753 and 3521, respectively; SEQ ID NOs: 2754 and 3522, respectively; SEQ ID NOs: 2755 and 3523, respectively; SEQ ID NOs: 2756 and 3524, respectively; SEQ ID NOs: 2757 and 3525, respectively; SEQ ID NOs: 2758 and 3526, respectively; SEQ ID NOs: 2759 and 3527, respectively; SEQ ID NOs: 2760 and 3528, respectively; SEQ ID NOs: 2761 and 3529, respectively; SEQ ID NOs: 2762 and 3530, respectively; SEQ ID NOs: 2763 and 3531, respectively; SEQ ID NOs: 2764 and 3532, respectively; SEQ ID NOs: 2765 and 3533, respectively; SEQ ID NOs: 2766 and 3534, respectively; SEQ ID NOs: 2767 and 3535, respectively; SEQ ID NOs: 2768 and 3536, respectively; SEQ ID NOs: 2769 and 3537, respectively; SEQ ID NOs: 2770 and 3538, respectively; SEQ ID NOs: 2771 and 3539,- 996 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOrespectively; SEQ ID NOs: 2772 and 3540, respectively; SEQ ID NOs: 2773 and 3541, respectively; SEQ ID NOs: 2774 and 3542, respectively; SEQ ID NOs: 2775 and 3543, respectively; SEQ ID NOs: 2776 and 3544, respectively; SEQ ID NOs: 2777 and 3545, respectively; SEQ ID NOs: 2778 and 3546, respectively; SEQ ID NOs: 2779 and 3547, respectively; SEQ ID NOs: 2780 and 3548, respectively; SEQ ID NOs: 2781 and 3549, respectively; SEQ ID NOs: 2782 and 3550, respectively; SEQ ID NOs: 2783 and 3551, respectively; SEQ ID NOs: 2784 and 3552, respectively; SEQ ID NOs: 2785 and 3553, respectively; SEQ ID NOs: 2786 and 3554, respectively; SEQ ID NOs: 2787 and 3555, respectively; SEQ ID NOs: 2788 and 3556, respectively; SEQ ID NOs: 2789 and 3557, respectively; SEQ ID NOs: 2790 and 3558, respectively; SEQ ID NOs: 2791 and 3559, respectively; SEQ ID NOs: 2792 and 3560, respectively; SEQ ID NOs: 2793 and 3561, respectively; SEQ ID NOs: 2794 and 3562, respectively; SEQ ID NOs: 2795 and 3563, respectively; SEQ ID NOs: 2796 and 3564, respectively; SEQ ID NOs: 2797 and 3565, respectively; SEQ ID NOs: 2798 and 3566, respectively; SEQ ID NOs: 2799 and 3567, respectively; SEQ ID NOs: 2800 and 3568, respectively; SEQ ID NOs: 2801 and 3569, respectively; SEQ ID NOs: 2802 and 3570, respectively; SEQ ID NOs: 2803 and 3571, respectively; SEQ ID NOs: 2804 and 3572, respectively; SEQ ID NOs: 2805 and 3573, respectively; SEQ ID NOs: 2806 and 3574, respectively; SEQ ID NOs: 2807 and 3575, respectively; SEQ ID NOs: 2808 and 3576, respectively; SEQ ID NOs: 2809 and 3577, respectively; SEQ ID NOs: 2810 and 3578, respectively; SEQ ID NOs: 2811 and 3579, respectively; SEQ ID NOs: 2812 and 3580, respectively; SEQ ID NOs: 2813 and 3581, respectively; SEQ ID NOs: 2814 and 3582, respectively; SEQ ID NOs: 2815 and 3583, respectively; SEQ ID NOs: 2816 and 3584, respectively; SEQ ID NOs: 2817 and 3585, respectively; SEQ ID NOs: 2818 and 3586, respectively; SEQ ID NOs: 2819 and 3587, respectively; SEQ ID NOs: 2820 and 3588, respectively; SEQ ID NOs: 2821 and 3589, respectively; SEQ ID NOs: 2822 and 3590, respectively; SEQ ID NOs: 2823 and 3591, respectively; SEQ ID NOs: 2824 and 3592, respectively; SEQ ID NOs: 2825 and 3593, respectively; SEQ ID NOs: 2826 and 3594, respectively; SEQ ID NOs: 2827 and 3595, respectively; SEQ ID NOs: 2828 and 3596, respectively; SEQ ID NOs: 2829 and 3597, respectively; SEQ ID NOs: 2830 and 3598, respectively; SEQ ID NOs: 2831 and 3599, respectively; SEQ ID NOs: 2832 and 3600, respectively; SEQ ID NOs: 2833 and 3601,- 997 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOrespectively; SEQ ID NOs: 2834 and 3602, respectively; SEQ ID NOs: 2835 and 3603, respectively; SEQ ID NOs: 2836 and 3604, respectively; SEQ ID NOs: 2837 and 3605, respectively; SEQ ID NOs: 2838 and 3606, respectively; SEQ ID NOs: 2839 and 3607, respectively; SEQ ID NOs: 2840 and 3608, respectively; SEQ ID NOs: 2841 and 3609, respectively; SEQ ID NOs: 2842 and 3610, respectively; SEQ ID NOs: 2843 and 3611, respectively; SEQ ID NOs: 2844 and 3612, respectively; SEQ ID NOs: 2845 and 3613, respectively; SEQ ID NOs: 2846 and 3614, respectively; SEQ ID NOs: 2847 and 3615, respectively; SEQ ID NOs: 2848 and 3616, respectively; SEQ ID NOs: 2849 and 3617, respectively; SEQ ID NOs: 2850 and 3618, respectively; SEQ ID NOs: 2851 and 3619, respectively; SEQ ID NOs: 2852 and 3620, respectively; SEQ ID NOs: 2853 and 3621, respectively; SEQ ID NOs: 2854 and 3622, respectively; SEQ ID NOs: 2855 and 3623, respectively; SEQ ID NOs: 2856 and 3624, respectively; SEQ ID NOs: 2857 and 3625, respectively; SEQ ID NOs: 2858 and 3626, respectively; SEQ ID NOs: 2859 and 3627, respectively; SEQ ID NOs: 2860 and 3628, respectively; SEQ ID NOs: 2861 and 3629, respectively; SEQ ID NOs: 2862 and 3630, respectively; SEQ ID NOs: 2863 and 3631, respectively; SEQ ID NOs: 2864 and 3632, respectively; SEQ ID NOs: 2865 and 3633, respectively; SEQ ID NOs: 2866 and 3634, respectively; SEQ ID NOs: 2867 and 3635, respectively; SEQ ID NOs: 2868 and 3636, respectively; SEQ ID NOs: 2869 and 3637, respectively; SEQ ID NOs: 2870 and 3638, respectively; SEQ ID NOs: 2871 and 3639, respectively; SEQ ID NOs: 2872 and 3640, respectively; SEQ ID NOs: 2873 and 3641, respectively; SEQ ID NOs: 2874 and 3642, respectively; SEQ ID NOs: 2875 and 3643, respectively; SEQ ID NOs: 2876 and 3644, respectively; SEQ ID NOs: 2877 and 3645, respectively; SEQ ID NOs: 2878 and 3646, respectively; SEQ ID NOs: 2879 and 3647, respectively; SEQ ID NOs: 2880 and 3648, respectively; SEQ ID NOs: 2881 and 3649, respectively; SEQ ID NOs: 2882 and 3650, respectively; SEQ ID NOs: 2883 and 3651, respectively; SEQ ID NOs: 2884 and 3652, respectively; SEQ ID NOs: 2885 and 3653, respectively; SEQ ID NOs: 2886 and 3654, respectively; SEQ ID NOs: 2887 and 3655, respectively; SEQ ID NOs: 2888 and 3656, respectively; SEQ ID NOs: 2889 and 3657, respectively; SEQ ID NOs: 2890 and 3658, respectively; SEQ ID NOs: 2891 and 3659, respectively; SEQ ID NOs: 2892 and 3660, respectively; SEQ ID NOs: 2893 and 3661, respectively; SEQ ID NOs: 2894 and 3662, respectively; SEQ ID NOs: 2895 and 3663,- 998 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOrespectively; SEQ ID NOs: 2896 and 3664, respectively; SEQ ID NOs: 2897 and 3665, respectively; SEQ ID NOs: 2898 and 3666, respectively; SEQ ID NOs: 2899 and 3667, respectively; SEQ ID NOs: 2900 and 3668, respectively; SEQ ID NOs: 2901 and 3669, respectively; SEQ ID NOs: 2902 and 3670, respectively; SEQ ID NOs: 2903 and 3671, respectively; SEQ ID NOs: 2904 and 3672, respectively; SEQ ID NOs: 2905 and 3673, respectively; SEQ ID NOs: 2906 and 3674, respectively; SEQ ID NOs: 2907 and 3675, respectively; SEQ ID NOs: 2908 and 3676, respectively; SEQ ID NOs: 2909 and 3677, respectively; SEQ ID NOs: 2910 and 3678, respectively; SEQ ID NOs: 2911 and 3679, respectively; SEQ ID NOs: 2912 and 3680, respectively; SEQ ID NOs: 2913 and 3681, respectively; SEQ ID NOs: 2914 and 3682, respectively; SEQ ID NOs: 2915 and 3683, respectively; SEQ ID NOs: 2916 and 3684, respectively; SEQ ID NOs: 2917 and 3685, respectively; SEQ ID NOs: 2918 and 3686, respectively; SEQ ID NOs: 2919 and 3687, respectively; SEQ ID NOs: 2920 and 3688, respectively; SEQ ID NOs: 2921 and 3689, respectively; SEQ ID NOs: 2922 and 3690, respectively; SEQ ID NOs: 2923 and 3691, respectively; SEQ ID NOs: 2924 and 3692, respectively; SEQ ID NOs: 2925 and 3693, respectively; SEQ ID NOs: 2926 and 3694, respectively; SEQ ID NOs: 2927 and 3695, respectively; SEQ ID NOs: 2928 and 3696, respectively; SEQ ID NOs: 2929 and 3697, respectively; SEQ ID NOs: 2930 and 3698, respectively; SEQ ID NOs: 2931 and 3699, respectively; SEQ ID NOs: 2932 and 3700, respectively; SEQ ID NOs: 2933 and 3701, respectively; SEQ ID NOs: 2934 and 3702, respectively; SEQ ID NOs: 2935 and 3703, respectively; SEQ ID NOs: 2936 and 3704, respectively; SEQ ID NOs: 2937 and 3705, respectively; SEQ ID NOs: 2938 and 3706, respectively; SEQ ID NOs: 2939 and 3707, respectively; SEQ ID NOs: 2940 and 3708, respectively; SEQ ID NOs: 2941 and 3709, respectively; SEQ ID NOs: 2942 and 3710, respectively; SEQ ID NOs: 2943 and 3711, respectively; SEQ ID NOs: 2944 and 3712, respectively; SEQ ID NOs: 2945 and 3713, respectively; SEQ ID NOs: 2946 and 3714, respectively; SEQ ID NOs: 2947 and 3715, respectively; SEQ ID NOs: 2948 and 3716, respectively; SEQ ID NOs: 2949 and 3717, respectively; SEQ ID NOs: 2950 and 3718, respectively; SEQ ID NOs: 2951 and 3719, respectively; SEQ ID NOs: 2952 and 3720, respectively; SEQ ID NOs: 2953 and 3721, respectively; SEQ ID NOs: 2954 and 3722, respectively; SEQ ID NOs: 2955 and 3723, respectively; SEQ ID NOs: 2956 and 3724, respectively; SEQ ID NOs: 2957 and 3725,- 999 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOrespectively; SEQ ID NOs: 2958 and 3726, respectively; SEQ ID NOs: 2959 and 3727, respectively; SEQ ID NOs: 2960 and 3728, respectively; SEQ ID NOs: 2961 and 3729, respectively; SEQ ID NOs: 2962 and 3730, respectively; SEQ ID NOs: 2963 and 3731, respectively; SEQ ID NOs: 2964 and 3732, respectively; SEQ ID NOs: 2965 and 3733, respectively; SEQ ID NOs: 2966 and 3734, respectively; SEQ ID NOs: 2967 and 3735, respectively; SEQ ID NOs: 2968 and 3736, respectively; SEQ ID NOs: 2969 and 3737, respectively; SEQ ID NOs: 2970 and 3738, respectively; SEQ ID NOs: 2971 and 3739, respectively; SEQ ID NOs: 2972 and 3740, respectively; SEQ ID NOs: 2973 and 3741, respectively; SEQ ID NOs: 2974 and 3742, respectively; SEQ ID NOs: 2975 and 3743, respectively; SEQ ID NOs: 2976 and 3744, respectively; SEQ ID NOs: 2977 and 3745, respectively; SEQ ID NOs: 2978 and 3746, respectively; SEQ ID NOs: 2979 and 3747, respectively; SEQ ID NOs: 2980 and 3748, respectively; SEQ ID NOs: 2981 and 3749, respectively; SEQ ID NOs: 2982 and 3750, respectively; SEQ ID NOs: 2983 and 3751, respectively; SEQ ID NOs: 2984 and 3752, respectively; SEQ ID NOs: 2985 and 3753, respectively; SEQ ID NOs: 2986 and 3754, respectively; SEQ ID NOs: 2987 and 3755, respectively; SEQ ID NOs: 2988 and 3756, respectively; SEQ ID NOs: 2989 and 3757, respectively; SEQ ID NOs: 2990 and 3758, respectively; SEQ ID NOs: 2991 and 3759, respectively; SEQ ID NOs: 2992 and 3760, respectively; SEQ ID NOs: 2993 and 3761, respectively; SEQ ID NOs: 2994 and 3762, respectively; SEQ ID NOs: 2995 and 3763, respectively; SEQ ID NOs: 2996 and 3764, respectively; SEQ ID NOs: 2997 and 3765, respectively; SEQ ID NOs: 2998 and 3766, respectively; SEQ ID NOs: 2999 and 3767, respectively; SEQ ID NOs: 3000 and 3768, respectively; SEQ ID NOs: 3001 and 3769, respectively; SEQ ID NOs: 3002 and 3770, respectively; SEQ ID NOs: 3003 and 3771, respectively; SEQ ID NOs: 3004 and 3772, respectively; SEQ ID NOs: 3005 and 3773, respectively; SEQ ID NOs: 3006 and 3774, respectively; SEQ ID NOs: 3007 and 3775, respectively; SEQ ID NOs: 3008 and 3776, respectively; SEQ ID NOs: 3009 and 3777, respectively; SEQ ID NOs: 3010 and 3778, respectively; SEQ ID NOs: 3011 and 3779, respectively; SEQ ID NOs: 3012 and 3780, respectively; SEQ ID NOs: 3013 and 3781, respectively; SEQ ID NOs: 3014 and 3782, respectively; SEQ ID NOs: 3015 and 3783, respectively; SEQ ID NOs: 3016 and 3784, respectively; SEQ ID NOs: 3017 and 3785, respectively; SEQ ID NOs: 3018 and 3786, respectively; SEQ ID NOs: 3019 and 3787,- 1000 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOrespectively; SEQ ID NOs: 3020 and 3788, respectively; SEQ ID NOs: 3021 and 3789, respectively; SEQ ID NOs: 3022 and 3790, respectively; SEQ ID NOs: 3023 and 3791, respectively; SEQ ID NOs: 3024 and 3792, respectively; SEQ ID NOs: 3025 and 3793, respectively; SEQ ID NOs: 3026 and 3794, respectively; SEQ ID NOs: 3027 and 3795, respectively; SEQ ID NOs: 3028 and 3796, respectively; SEQ ID NOs: 3029 and 3797, respectively; SEQ ID NOs: 3030 and 3798, respectively; SEQ ID NOs: 3031 and 3799, respectively; SEQ ID NOs: 3032 and 3800, respectively; SEQ ID NOs: 3033 and 3801, respectively; SEQ ID NOs: 3034 and 3802, respectively; SEQ ID NOs: 3035 and 3803, respectively; SEQ ID NOs: 3036 and 3804, respectively; SEQ ID NOs: 3037 and 3805, respectively; SEQ ID NOs: 3038 and 3806, respectively; SEQ ID NOs: 3039 and 3807, respectively; SEQ ID NOs: 3040 and 3808, respectively; SEQ ID NOs: 3041 and 3809, respectively; SEQ ID NOs: 3042 and 3810, respectively; SEQ ID NOs: 3043 and 3811, respectively; SEQ ID NOs: 3044 and 3812, respectively; SEQ ID NOs: 3045 and 3813, respectively; SEQ ID NOs: 3046 and 3814, respectively; SEQ ID NOs: 3047 and 3815, respectively; SEQ ID NOs: 3048 and 3816, respectively; SEQ ID NOs: 3049 and 3817, respectively; SEQ ID NOs: 3050 and 3818, respectively; SEQ ID NOs: 3051 and 3819, respectively; SEQ ID NOs: 3052 and 3820, respectively; SEQ ID NOs: 3053 and 3821, respectively; SEQ ID NOs: 3054 and 3822, respectively; SEQ ID NOs: 3055 and 3823, respectively; SEQ ID NOs: 3056 and 3824, respectively; SEQ ID NOs: 3057 and 3825, respectively; SEQ ID NOs: 3058 and 3826, respectively; SEQ ID NOs: 3059 and 3827, respectively; SEQ ID NOs: 3060 and 3828, respectively; SEQ ID NOs: 3061 and 3829, respectively; SEQ ID NOs: 3062 and 3830, respectively; SEQ ID NOs: 3063 and 3831, respectively; SEQ ID NOs: 3064 and 3832, respectively; SEQ ID NOs: 3065 and 3833, respectively; SEQ ID NOs: 3066 and 3834, respectively; SEQ ID NOs: 3067 and 3835, respectively; SEQ ID NOs: 3068 and 3836, respectively; SEQ ID NOs: 3069 and 3837, respectively; SEQ ID NOs: 3070 and 3838, respectively; SEQ ID NOs: 3071 and 3839, respectively; SEQ ID NOs: 3072 and 3840, respectively; SEQ ID NOs: 3073 and 3841, respectively; SEQ ID NOs: 3074 and 3842, respectively; SEQ ID NOs: 3075 and 3843, respectively; SEQ ID NOs: 3076 and 3844, respectively; SEQ ID NOs: 3077 and 3845, respectively; SEQ ID NOs: 3078 and 3846, respectively; SEQ ID NOs: 3079 and 3847, respectively; SEQ ID NOs: 3080 and 3848, respectively; SEQ ID NOs: 3081 and 3849,- 1001 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOrespectively; SEQ ID NOs: 3082 and 3850, respectively; SEQ ID NOs: 3083 and 3851, respectively; SEQ ID NOs: 3084 and 3852, respectively; SEQ ID NOs: 3085 and 3853, respectively; SEQ ID NOs: 3086 and 3854, respectively; SEQ ID NOs: 3087 and 3855, respectively; SEQ ID NOs: 3088 and 3856, respectively; SEQ ID NOs: 3089 and 3857, respectively; SEQ ID NOs: 3090 and 3858, respectively; SEQ ID NOs: 3091 and 3859, respectively; SEQ ID NOs: 3092 and 3860, respectively; SEQ ID NOs: 3093 and 3861, respectively; SEQ ID NOs: 3094 and 3862, respectively; SEQ ID NOs: 3095 and 3863, respectively; SEQ ID NOs: 3096 and 3864, respectively; SEQ ID NOs: 3097 and 3865, respectively; SEQ ID NOs: 3098 and 3866, respectively; or SEQ ID NOs: 3099 and 3867, respectively.

84. The compound of any one of claims 76-83, wherein:(i) the nucleic acid A comprises a double stranded region that is 17-30 (e.g., 17-25 or 17-23) nucleotide pairs in length;(ii) each of the antisense strand and the sense strand is independently no more than 30 nucleotides in length (e.g., the sense strand is 21 nucleotides in length and the antisense strand is 23 nucleotides in length);(iii) the nucleic acid A comprises a region of complementarity to the SLC6A19 RNA that is at least 17 (e.g., 19, 20, 21, 22, or 23) nucleotides in length; and / or (iv) at least one of the antisense strand and the sense strand comprises a 3’ overhang of at least 2 nucleotides.

85. The compound of any one of claims 14-84, wherein the nucleic acid A comprises at least one modified internucleoside linkage, sugar moiety, or nucleobase.

86. The compound of claim 85, wherein the modified internucleoside linkage, sugar moiety, or nucleobase comprises a modification selected from the group consisting of a deoxy -nucleoside, a 3’-terminal deoxy-thymine (dT) nucleoside, a 2’-O-methyl (2’-OMe) modified nucleoside, a 2’-fluoro (2’-F) modified nucleoside, a 2’ -deoxy -modified nucleoside, a locked nucleotide (LNA), an unlocked nucleoside, a conformationally restricted nucleoside, a constrained ethyl nucleoside, an abasic nucleoside, a 2’-O,4’-C-ethylene-bridged nucleic acid (ENA), a 2’-amino-modified - 1002 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOnucleoside, a 2’-O-allyl-modified nucleoside, 2’-C-alkyl-modified nucleoside, 2’-hydroxyl-modified nucleoside, a 2 ’-methoxy ethyl (2’-M0E) modified nucleoside, a 2’-O-alkylmodified nucleoside, a 5-methylcytosine, a morpholino nucleoside, a phosphoramidate, a non-natural base comprising nucleoside, a tetrahydropyran modified nucleoside, a 1,5-anhydrohexitol modified nucleoside, a cyclohexenyl modified nucleoside, a nucleotide comprising a 5’-phosphorothioate group, a nucleotide comprising a 5’-methylphosphonate group, a nucleotide comprising a 5’ phosphate or 5’ phosphate mimic, a nucleotide comprising vinyl phosphonate, a nucleoside comprising adenosine-glycol nucleic acid (GNA), a nucleoside comprising thymidine-glycol nucleic acid (GNA) S-Isomer, a nucleotide comprising 2-hydroxymethyl-tetrahydrofurane-5-phosphate, a nucleotide comprising 2’deoxythymidine-3’phosphate, a nucleotide comprising 2’-deoxy guanosine-3 ’ -phosphate, and a terminal nucleoside linked to a cholesteryl derivative and a dodecanoic acid bisdecylamide group; and combinations thereof;optionally wherein the modified internucleoside linkage comprises a phosphorothioate linkage, and / or the modified nucleobase comprises 5-methylcytosine.

87. The compound of any one of claims 48-86, wherein the antisense strand comprises one or more 2’-M0E modified nucleotides, optionally wherein all nucleotides of the antisense strand are 2’ -MOE modified nucleotides88. The compound of any one of claims 76-87, wherein the antisense strand and / or the sense strand comprise one or more modified nucleotides;optionally wherein substantially all nucleotides of the antisense strand, sense strand, or dsRNA comprise a modification;optionally wherein all nucleotides of the antisense strand, sense strand, or dsRNA comprise a modification.

89. The compound of claim 88, wherein the one or more modified nucleotides is selected from the group consisting ofa deoxy-nucleotide, a 3 ’-terminal deoxy -thymine (dT) nucleotide, a 2'-O-methyl modified nucleotide, a 2'-fluoro modified nucleotide, a 2'-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide,- 1003 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOan abasic nucleotide, a 2’ -ami no-modified nucleotide, a 2’-O-allyl-modified nucleotide, 2’-C-alkyl-modified nucleotide, 2’-hydroxly-modified nucleotide, a 2’ -methoxy ethyl modified nucleotide, a 2’-O-alkyl-modified nucleotide, a morpholino nucleotide (e.g., a phosphorodiamidate morpholino nucleic acid (PMO)), a phosphoramidate, a non-natural base comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a phosphoryl guanidine-based backbone, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5’-phosphate, a nucleotide comprising a 5 ’-phosphate mimic, a thermally destabilizing nucleotide, a glycol modified nucleotide (GNA), and a 2-O-(N-methylacetamide) modified nucleotide; and combinations thereof;a deoxy-nucleotide, a 2'-O-methyl modified nucleotide, a 2'-fluoro modified nucleotide, a 2'-deoxy-modified nucleotide, a glycol modified nucleotide (GNA), and a vinyl -phosphonate nucleotide; and combinations thereof;a deoxy-nucleotide, a 2'-O-methyl modified nucleotide, and a 2'-fluoro modified nucleotide; and combinations thereof;LNA, HNA, CeNA, 2'-methoxyethyl, 2'-O-alkyl, 2'-O-allyl, 2'-C- allyl, 2'-fluoro, 2'-deoxy, 2’-hydroxyl, and glycol; and combinations thereof;a C7-modified deaza-adenine, a C7-modified deaza-guanosine, a C5-modified cytosine, a C5-modified uridine, Nl-methyl-pseudouridine (mil) / ), 1-ethyl-pseudouridine (elxp), 5-methoxy-uridine (mo5U), 5-methyl-cytidine (m5C), pseudouridine (\| / ), 5-methoxymethyl uridine, 5-methylthio uridine, 1 -methoxymethyl pseudouridine, 5-methyl cytidine, 5-methoxy cytidine, or any combination thereof;a phosphorothioate (PS) modification, a phosphoryl guanidine (PN) modification, a mesyl phosphoramidate modification, a borano-phosphate modification, an alkyl phosphonate nucleic acid (phNA), a peptide nucleic acid (PNA), or any combination thereof;a deoxyribonucleic acid (DNA), optionally wherein the DNA is or comprises a DNA analog, optionally wherein the DNA analog comprises one or more morpholino subunits linked together by phosphorus-containing linkage(s), optionally wherein the DNA analog is or comprises a phosphorodiamidate morpholino nucleic acid (PMO), optionally wherein the PMO comprises about 12-40 nucleotides;a peptide nucleic acid (PNA) modification; and / or- 1004 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOone or more modification to a 5’ end of the antisense compound or dsRNA agent, optionally wherein the modification to the 5' end is a 5’ amino modification.

90. The compound of any one of claims 1-89, wherein the compound further comprises a lipid or lipid-based moiety.

91. The compound of any one of claims 1-90, wherein the compound is capable of inhibiting expression of SLC6A19;delivering the nucleic acid A to a cell, tissue, or subject, optionally wherein the delivery is enhanced compared to a reference, optionally wherein the reference is an unconjugated nucleic acid A.decreasing the level of a target gene in a cell, tissue, or subject, optionally wherein the decrease is enhanced compared to a reference, optionally wherein the reference is an unconjugated nucleic acid A; and / orreducing the expression and / or activity of the target in a cell, tissue, or subject.

92. A pharmaceutical composition comprising a compound of any one of claims 1-91, and a pharmaceutically acceptable carrier.

93. A method of treating a disease or condition in a subject suffering from or susceptible to the disease or condition, comprising administering to the subject a compound of any one of claims 1-91 or a pharmaceutical composition of claim 92.

94. The method of claim 93, whereinthe disease or condition is associated with expression of a cell surface receptor;the disease or condition comprises a cell in which both a cell surface receptor and a target recognized by the payload moiety are present;the disease or condition is a kidney disease or condition, optionally wherein the kidney disease or condition is a glomerular disorder, a renal tubular disorder, chronic kidney disease, other renal disorders, an inborn error of metabolism, a systemic metabolic disorder, a disorder of the thyroid, a disorder of the parathyroid, a disorder of the inner ear, a neurological disorder, or a viral - 1005 - IPTS / 200358790.1Goodwin Docket No.: JUDO-005WOinfection, or any combination thereof; or optionally wherein the kidney disease or condition is urea cycle disorder or autosomal dominant polycystic kidney disease (ADPKD); and / orthe disease or condition is a systemic disease or condition, optionally wherein the systemic disease or condition is phenylketonuria (PKU).

95. A method of treating a systemic disease in a subject suffering from or susceptible to a systemic disease, comprising contacting a compound of any one of claims 1-91 or a pharmaceutical composition of claim 92 with a target protein present on the surface of a kidney cell.

96. A method of delivering to a cell, tissue, or organism, comprising administering to the cell, tissue, or organism a compound of any one of claims 1-91 or a pharmaceutical composition of claim 92,optionally wherein the cell is chosen from: kidney cells, thyroid cells, parathyroid cells, cells of the inner ear or nervous system cells, or a combination thereof;optionally wherein the kidney cell is chosen from a proximal tubular epithelial cell and / or a podocyte.

97. The method of any one of claims 93-96, wherein administering the compound to the subject, cell, tissue, or organism delivers the nucleic acid A to at least 5% more target cells compared to:(i) an otherwise similar cell, tissue or organism delivered an unconjugated nucleic acid A;(ii) a non-target cell; or(iii) both (i) and (ii),optionally wherein the target cell is or comprises a kidney cell, and optionally wherein the target cell is or comprises a cell that has expression of a kidney cell surface factor chosen from Megalin or Cubilin.- 1006 - IPTS / 200358790.1

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