Compositions and methods for modulating PNPLA3 expression

Abstract

Disclosed are oligonucleotides and compositions comprising the same for inhibiting or reducing patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene expression. Methods for making and using the oligonucleotides are also disclosed, particularly for use in treating diseases, disorders, and / or conditions associated with PNPLA3 expression.

Description

[Technical Field]

[0001] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The above ASCII copy, created on April 11, 2022, is named 400930-028WO_190156_SL.txt and is 374,357 bytes in size.

[0002] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 174,932, filed April 14, 2021, which is incorporated herein by reference in its entirety.

[0003] The present disclosure relates generally to biology and medicine, and more particularly to the use of oligonucleotide compositions for inhibiting or reducing patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene expression, and their uses, particularly for the treatment of diseases, disorders and / or conditions associated with PNPLA3. [Background technology]

[0004] PNPLA3 is a protein encoded by PNPLA3 and has triacylglycerol lipase activity and acylglycerol transacylase activity. Human PNPLA3 is highly expressed in the liver and moderately expressed in adipose tissue, brain, kidney, and skin.

[0005] Of particular interest herein is the isoleucine (Ile / I) to methionine (Met / M) mutation at position 148 of human PNPLA3 (I148M or PNPLA3 148M; i.e., PNPLA3 rs738409). See Pingitore & Romeo (2019) Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1864:900-906. Compared to wild-type PNPLA3, PNPLA3 148M lacks lipase activity but appears to have increased transacylase activity. See Kumari et al. (2012) Cell Metab. 15:691-702.

[0006] PNPLA3 148M is strongly associated with a wide range of liver diseases resulting from triglyceride (TG) accumulation, liver injury, and fibrosis, including alcoholic hepatitis (AH), alcoholic liver disease (ALD), cirrhosis, hepatocellular carcinoma (HCC), nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). Delayed proteasomal degradation of PNPLA3 148M results in the accumulation of the protein on the surface of lipid droplets, preventing other proteins from metabolizing TG within hepatocytes. Therefore, reducing PNPLA3 148M expression may allow other lipases to function normally, potentially reversing the adverse effects of PNPLA3 148M across a variety of pathologies.

[0007] Some RNA-based therapeutic agents are known for inhibiting or reducing PNPLA3 expression.For example, International Patent Application Publication No. WO2016 / 130806 and International Patent Application Publication No. WO2019 / 118638 describe double-stranded (ds) RNAi constructs for inhibiting or reducing PNPLA3 expression, and the methods of using them for treating or preventing liver diseases such as NAFLD.In addition, International Patent Application Publication No. WO2020 / 061200 describes antisense oligonucleotides for inhibiting or reducing PNPLA3 expression.

[0008] Although several therapeutic agents directed against PNPLA3 exist, there is a need for additional therapeutic agents to inhibit or reduce PNPLA3 expression to treat liver disease. Summary of the Invention

[0009] To address this need, the present disclosure describes compositions and methods for treating diseases, disorders, and / or conditions associated with PNPLA3 expression. This disclosure is based, in part, on the discovery and development of ds oligonucleotides (e.g., RNAi oligonucleotides) for selectively inhibiting and / or reducing PNPLA3 expression, for example, in the liver. Accordingly, target sequences within PNPLA3 have been identified, and RNAi oligonucleotides that bind to these target sequences and inhibit PNPLA3 mRNA expression have been generated. As shown herein, the RNAi oligonucleotides inhibit PNPLA3 expression in the liver of humans and cynomolgus monkeys. Without being bound by theory, the RNAi oligonucleotides herein are useful for treating diseases, disorders, or conditions associated with PNPLA3 expression (e.g., liver diseases, such as AH, ALD, cirrhosis, HCC, cholangiocarcinoma (CCA), primary sclerosing cholangitis (PSC), NAFLD, and NASH). Generally, the RNAi oligonucleotide of this specification is useful for treating the disease, disorder or condition associated with abnormal PNPLA3 expression (for example, mutant PNPLA3 allele expression).In particular, the RNAi oligonucleotide of this specification is useful for treating the disease, disorder or condition associated with mutant PNPLA3 expression.

[0010] Thus, the present disclosure provides the nucleic acids of Table 1 (e.g., SEQ ID NOs: 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 18 5, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207 , 209, 211, 213, 215, 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 295, 297, 299, 301, 303, 305, 307, 309, 311, 313, 315, 317, 319, 321, 323, 325, 327, 329, 331, 332 33, 335, 337, 339, 341, 343, 345, 347, 349, 351, 353, 355, 357, 359, 361, 363, 365, 367, 369, 371, 373, 375, 377, 379, 381, 383, 385, 387, 389, 391, 393, 39 5, 397, 399, 401, 403, 405, 407, 409, 411, 413, 415, 417, 419, 421, 423, 425, 427, 429, 431, 433, 435, 437, 439, 441, 443, 445, 447, 449, 451, 453, 455, 457 , 459, 461, 463, 465, 467, 469, 471, 473, 475, 477, 479, 481, 483, 485, 487, 489, 491, 493, 495, 497, 499, 501, 503, 505, 507, 509, 511, 513, 515, 517, 519,521, 523, 525, 527, 529, 531, 533, 535, 537, 539, 541, 543, 545, 547, 549, 551, 553, 555, 557, 559, 561, 563, 565, 567, 569, 571, 573, 575, 577, 579, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 599, 591, 83, 585, 587, 589, 591, 593, 595, 597, 599, 601, 603, 605, 607, 609, 611, 613, 615, 617, 619, 621, 623, 625, 627, 629, 631, 633, 635, 637, 639, 641, 643, 64 5, 647, 649, 651, 653, 655, 657, 659, 661, 663, 665, 667, 669, 671, 673, 675, 677, 679, 681, 683, 685, 687, 689, 691, 693, 695, 697, 699, 701, 703, 705, 707 , 709, 711, 713, 715, 717, 719, 721, 723, 725, 727, 729, 731, 733, 735, 737, 739, 741, 743, 745, 747, 749, 751, 753, 755, 757, 759, 761, 763, 765, 767, 769, 771, 773, and 775) or Table 3 (e.g., SEQ ID NOs: 777, 779, 781, 783, 785, 787, 789, 791, 793, 795, 797, 799, 801, 803, 805, 807, 809, 811, 813, 815, 817, 819, 821, 823, 825, 827, 829, 831, 833, 835, 837, 839, 841, 843, 845, 847, 849, 851, 853, 855, 857, 859, 861, 863, 865, 867, 869, 871, 873, 875, 877, 879, 881, 883, 885, 886, 887, 888, 889, 890, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935 7, 889, 891, 893, 895, 897, 899, 901, 903, 905, 907, 909, 911, 913, 915, 917, 919, 921, 923, 925, 927, 929, 931, 933, 935, 937, 939, 941, 943, 945, 947, 949 , 951, 953, 955, 957, 959, 961, 963, 965, 967, 969, 971, 973, 975, 977, 979, 981, 983, 985, 987, 989, 991, 993, 995, 997, 999, 1001, 1003, 1005, 1007, 1009,1011, 1013, 1015, 1017, 1019, 1021, 1023, 1025, 1027, 1029, 1031, 1033, 1035, 1037, 1039, 1041, 1043, 1045, 1047, 1049, 1051, 1053, 1055, 1057, 1059, 10 61, 1063, 1065, 1067, 1069, 1071, 1073, 1075, 1077, 1079, 1081, 1083, 1085, 1087, 1089, 1091, 1093, 1095, 1097, 1099, 1101, 1103, 1105, 1107, 1109, 1111, 1113, 1115, 1117, 1119, 1121, 1123, 1125, 1127, 1129, 1131, 1133, 1135, 1137, 1139, 1141, 1143, 1145, 1147, 1149, 1151, 1153, 1155, 1157, 1159, 1161, and 1163), particularly SEQ ID NOs: 787, 843, 867, 871, 937, 1003, 1007, 1017, 1161, or 1163.

[0011] Alternatively, the present disclosure may provide a method for the preparation of a nucleic acid sequence as set forth in Table 1 (e.g., SEQ ID NOs: 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 6, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208 ,210,212,214,216,218,220,222,224,226,228,230,232,234,236,238,240,242,244,246,248,250,252,254,256,258,260,262,264,266,268,270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 333 34, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, ​​384, 386, 388, 390, 392, 394, 39 6, 398, 400, 402, 404, 406, 408, 410, 412, 414, 416, 418, 420, 422, 424, 426, 428, 430, 432, 434, 436, 438, 440, 442, 444, 446, 448, 450, 452, 454, 456, 458 , 460, 462, 464, 466, 468, 470, 472, 474, 476, 478, 480, 482, 484, 486, 488, 490, 492, 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520,522, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564, 566, 568, 570, 572, 574, 576, 578, 580, 582, 584, 586, 588, 590, 592, 594, 596, 598, 600, 602, 604, 606, 608, 610, 612, 614, 616, 618, 620, 622, 624, 626, 628, 630, 632, 634, 636, 638, 640, 642, 644, 6 46, 648, 650, 652, 654, 656, 658, 660, 662, 664, 666, 668, 670, 672, 674, 676, 678, 680, 682, 684, 686, 688, 690, 692, 694, 696, 698, 700, 702, 704, 706, 7 08, 710, 712, 714, 716, 718, 720, 722, 724, 726, 728, 730, 732, 734, 736, 738, 740, 742, 744, 746, 748, 750, 752, 754, 756, 758, 760, 762, 764, 766, 768, 77 770, 772, 774, and 776) or Table 3 (e.g., SEQ ID NOs: 778, 780, 782, 784, 786, 788, 790, 792, 794, 796, 798, 800, 802, 804, 806, 808, 810, 812, 814, 816, 818, 820, 822, 824, 826, 828, 830, 832, 834, 836, 838, 840, 842, 844, 846, 848, 850, 852, 854, 856, 858, 860, 862, 864, 866, 868, 870, 872, 874, 876, 878, 880, 882, 884, 886, , 888, 890, 892, 894, 896, 898, 900, 902, 904, 906, 908, 910, 912, 914, 916, 918, 920, 922, 924, 926, 928, 930, 932, 934, 936, 938, 940, 942, 944, 946, 948, 950, 952, 954, 956, 958, 960, 962, 964, 966, 968, 970, 972, 974, 976, 978, 980, 982, 984, 986, 988, 990, 992, 994, 996, 998, 1000, 1002, 1004, 1006, 1008,1010, 1012, 1014, 1016, 1018, 1020, 1022, 1024, 1026, 1028, 1030, 1032, 1034, 1036, 1038, 1040, 1042, 1044, 1046, 1048, 1050, 1052, 1054, 1056, 1058, 1060 , 1062, 1064, 1066, 1068, 1070, 1072, 1074, 1076, 1078, 1080, 1082, 1084, 1086, 1088, 1090, 1092, 1094, 1096, 1098, 1100, 1102, 1104, 1106, 1108, 1110, 1112 1150, 1152, 1154, 1156, 1158, 1160, 1162, and 1164), particularly SEQ ID NOs: 788, 844, 868, 872, 938, 1004, 1008, 1018, 1162, or 1164.

[0012] In certain embodiments, the present disclosure provides a method for the production of a nucleotide sequence comprising a sequence set forth in Table A, B, C, or D (e.g., SEQ ID NOs: 1178, 1180, 1182, 1184, 1186, 1188, 1190, 1192, 1194, 1196, 1198, 1200, 1202, 1204, 1206, 1208, 1210, 1212, 1214, 1216, 1218, 1220, 1222, 1224, 1226, 1228, 1230, 1232, 1234, 1236, 1238, 1240, 1241, 1242, 1243, 1244, 1245, 1246, 1247, 1248, 1249, 1250, 1251, 1252, 1253, 1254, 1255, 1256, 1257, 1258, 1259, 1260, 1261, 1262, 1263, 1264, 1265, 1266, 1267, 1268, 1269, 1270, 1271, 1272, 1273, 1274, 1275, 1276, 1277, 1278, 1279, 1280, 1281, 1282, 1283, 1284, 1285, 128 1244, 1246, 1248, 1250, 1252, 1254, 1256, 1258, 1260, 1262, 1264, 1266, 1268, 1270, 1272, 1274, 1276, 1278, 1280, 1282, 1284, 1286, 1288, 1290, 1292, 1294, 1296, 1298, or 1300).

[0013] In certain embodiments, the disclosure provides a method for the production of a nucleotide sequence comprising a sequence set forth in Table A, B, C, or D (e.g., SEQ ID NOs: 1179, 1181, 1183, 1185, 1187, 1189, 1191, 1193, 1195, 1197, 1199, 1201, 1203, 1205, 1207, 1209, 1211, 1213, 1215, 1217, 1219, 1221, 1223, 1225, 1227, 1229, 1231, 1233, 1235, 1237, 1239, 1241, 1243, 1244, 1245, 1246, 1247, 1248, 1249, 1250, 1251, 1252, 1253, 1254, 1255, 1256, 1257, 1258, 1259, 1260, 1261, 1262, 1263, 1264, 1265, 1266, 1267, 1268, 1269, 1270, 1271, 1272, 1273, 1274, 1275, 1276, 1277, 1278, 1279, 1280, 1281, 1282, 1283, 1284, 1285, 1286, 1287, 1288 , 1245, 1247, 1249, 1251, 1253, 1255, 1257, 1259, 1261, 1263, 1265, 1267, 1269, 1271, 1273, 1275, 1277, 1279, 1281, 1283, 1285, 1287, 1289, 1291, 1293, 1295, 1297, 1299, or 1301).

[0014] In some embodiments, RNAi oligonucleotides for reducing or inhibiting PNPLA3 expression are described, comprising an antisense strand and a sense strand, wherein the antisense strand has a sequence set forth in Table 1 or Table 3, and the sense strand has a sequence set forth in Table 1 or Table 3.

[0015] In some embodiments, RNAi oligonucleotides for reducing or inhibiting PNPLA3 expression are described, comprising an antisense strand and a sense strand, wherein the antisense strand has a sequence set forth in Table A, Table B, Table C, or Table D, and the sense strand has a sequence set forth in Table A, Table B, Table C, or Table D.

[0016] In some embodiments, an RNAi oligonucleotide for reducing or inhibiting PNPLA3 expression is described, comprising an antisense strand and a sense strand, wherein the antisense strand and the sense strand form a double-stranded region, and the antisense strand has a region of complementarity to any one of the PNPLA3 mRNA target sequences set forth in SEQ ID NOs: 1167-1176.

[0017] In any of the above embodiments, the antisense strand is about 15 to about 30 nucleotides in length. In some embodiments, the antisense strand is about 20 to about 25 nucleotides in length. In some embodiments, the antisense strand is 22 nucleotides in length.

[0018] In any of the above embodiments, the sense strand is about 15 to about 50 nucleotides in length. In some examples, the sense strand is about 20 to about 40 nucleotides in length. In some embodiments, the sense strand is 36 nucleotides in length.

[0019] In any of the above embodiments, the double-stranded region is about 19 to about 21 nucleotides in length. In certain embodiments, the double-stranded region is 20 nucleotides in length.

[0020] In any of the above embodiments, the region of complementarity is at least 15 contiguous nucleotides in length. In some embodiments, the region of complementarity is about 19 to about 21 contiguous nucleotides in length. In other embodiments, the region of complementarity is 19 or 21 contiguous nucleotides in length.

[0021] In any of the above embodiments, the RNAi oligonucleotide comprises a stem-loop at the 3' end on the sense strand, designated as S1-L-S2, where S1 is complementary to S2, and L forms a loop between S1 and S2 that is about 3 to about 5 nucleotides long.

[0022] In any of the above embodiments, the antisense strand, the sense strand, or both have an overhang sequence.In some embodiments, the antisense strand comprises a 3' overhang that is 1 nucleotide or more in length.In other embodiments, the 3' overhang sequence is 2 nucleotides in length, for example, GG.

[0023] Also described is an oligonucleotide comprising an antisense strand and a sense strand, wherein the antisense strand can be about 21 to about 27 nucleotides in length and has a region of complementarity to PNPLA3, and the sense strand comprises a stem-loop at its 3' end shown as S1-L-S2, where S1 is complementary to S2 and L forms a loop between S1 and S2 that is about 3 to about 5 nucleotides in length, and wherein the antisense strand and the sense strand form a duplex structure at least about 19 nucleotides in length but are not covalently linked.

[0024] In some embodiments, loop L is a triloop or tetraloop. In some instances, L is a tetraloop that is 4 nucleotides in length. In other embodiments, L comprises the sequence 5'-GAAA-3'.

[0025] In some embodiments, S1 and S2 are 1-10 nucleotides in length and have the same length. In other embodiments, S1 and S2 are 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides in length. In other embodiments, S1 and S2 are 6 nucleotides in length. In certain embodiments, the stem-loop comprises the sequence 5'-GCAGCCGAAAGGCUGC-3' (SEQ ID NO: 1177).

[0026] In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is 25 nucleotides in length, hi other embodiments, the antisense strand is 22 nucleotides in length and the sense strand is 36 nucleotides in length.

[0027] In the above embodiments, the double-stranded region comprises a 3' overhang sequence on the antisense strand. In some embodiments, the 3' overhang sequence on the antisense strand is 2 nucleotides in length.

[0028] In any of the above embodiments, at least one nucleotide in the oligonucleotide is a modified nucleotide. In some examples, the modified nucleotide includes a 2'-modification, such as 2'-aminoethyl, 2'-fluoro, 2'-O-methyl, 2'-O-methoxyethyl, and 2'-deoxy-2'-fluoro-β-arabinonucleic acid. In certain examples, all nucleotides in the oligonucleotide include a 2'-modification, such as 2'-fluoro or 2'-O-methyl.

[0029] In any of the above embodiments, at least one nucleotide in the oligonucleotide comprises a modified internucleotide linkage. In some embodiments, the modified internucleotide linkage is a phosphorothioate linkage.

[0030] In any of the above embodiments, the 4'-carbon of the sugar of the 5' nucleotide of the antisense strand comprises a phosphate analog, such as oxymethylphosphonate, vinylphosphonate, or malonylphosphonate. Alternatively, or optionally, the phosphate analog is a 4'-phosphate analog, such as 5'-methoxyphosphonate-4'-oxy.

[0031] In any of the above embodiments, at least one nucleotide of the oligonucleotide can be conjugated to one or more targeting ligands, such as amino sugars, carbohydrates, cholesterol, lipids, or polypeptides. In some embodiments, the targeting ligand is an N-acetylgalactosamine (GalNAc) moiety. In other embodiments, the GalNAc moiety is a monovalent GalNAc moiety, a divalent GalNAc moiety, a trivalent GalNAc moiety, or a tetravalent GalNAc moiety.

[0032] In some embodiments, the targeting ligand is conjugated to one or more nucleotides of L of the stem loop. In particular examples, up to four nucleotides of L of the stem loop are each conjugated to a monovalent GalNAc moiety.

[0033] In any of the above embodiments, the oligonucleotide is an RNAi oligonucleotide.In some examples, the RNAi oligonucleotide comprises a sense strand having any one of the nucleotide sequences listed in Table 1 or Table 3, particularly SEQ ID NO: 787, 843, 867, 871, 937, 1003, 1007, 1017, 1161 or 1163.In certain embodiments, the RNAi oligonucleotide comprises a sense strand having any one of the nucleotide sequences listed in Table A, B, C or D, particularly SEQ ID NO: 1188, 1190, 1220, 1224, 1230, 1232, 1244, 1246, 1250 or 1254.In some examples, the RNAi oligonucleotide comprises an antisense strand having any one of the nucleotide sequences listed in Table 1 or Table 3, particularly SEQ ID NO: 788, 844, 868, 872, 938, 1004, 1008, 1018, 1162 or 1164. In some embodiments, the RNAi oligonucleotide comprises an antisense strand having a nucleotide sequence set forth in Table A, B, C, or D, particularly any one of SEQ ID NOs: 1189, 1191, 1221, 1225, 1231, 1233, 1245, 1247, 1251, or 1255. In particular examples, the RNAi oligonucleotide comprises a sense strand having the nucleotide sequence of any one of SEQ ID NOs: 787, 843, 867, 871, 937, 1003, 1007, 1017, 1161, or 1163, or any one of SEQ ID NOs: 1188, 1190, 1220, 1224, 1230, 1232, 1244, 1246, 1250, or 1254, and an antisense strand having the nucleotide sequence of any one of SEQ ID NOs: 788, 844, 868, 872, 938, 1004, 1008, 1018, 1162, or 1164, SEQ ID NOs: 1189, 1191, 1221, 1225, 1231, 1233, 1245, 1247, 1251, or 1255. In certain embodiments, the sense and antisense strands of the RNAi oligonucleotide are each selected from the following: (a) SEQ ID NOs: 787 and 788; (b) SEQ ID NOs: 843 and 844; (c) SEQ ID NOs: 867 and 868; (d) SEQ ID NOs: 871 and 872; (e) SEQ ID NOs: 937 and 938; (f) SEQ ID NOs: 1003 and 1004; (g) SEQ ID NOs: 1007 and 1008; (h) SEQ ID NOs: 1017 and 1018; (i) SEQ ID NOs: 1161 and 1162, and (j) SEQ ID NOs: 1163 and 1164.

[0034] In some examples, the RNAi oligonucleotides are selected from the group consisting of nucleotide sequences set forth in Table A, Table B, Table C, or Table D, particularly SEQ ID NOs: 1178, 1180, 1182, 1184, 1186, 1188, 1190, 1192, 1194, 1196, 1198, 1200, 1202, 1204, 1206, 1208, 1210, 1212, 1214, 1216, 1218, 1220, 1222, 1224, 1226, 1228, 1230, 1231, 1232, 1233, 1234, 1235, 1236, 1237, 1238, 1239, 1240, 1241, 1242, 1243, 1244, 1245, 1246, 1247, 1248, 1249, 1250, 1251, 1252, 1253, 1254, 1255, 1256, 1257, 1258, 1259, 1260, 1261, 1262, 1263, 1264, 1265, 1266, 1267, 1268, 1269, 1270, 1271, 1272, 1273, 1274, 1275, 1276, 1277, 1278, 1279, 1280, 1281, 1234, 1236, 1238, 1240, 1242, 1244, 1246, 1248, 1250, 1252, 1254, 1256, 1258, 1260, 1262, 1264, 1266, 1268, 1270, 1272, 1274, 1276, 1278, 1280, 1282, 1284, 1286, 1288, 1290, 1292, 1294, 1296, 1298, or 1300. In some examples, the RNAi oligonucleotides are selected from the group consisting of nucleotide sequences set forth in Table A, Table B, Table C, or Table D, particularly SEQ ID NOs: 1179, 1181, 1183, 1185, 1187, 1189, 1191, 1193, 1195, 1197, 1199, 1202, 1203, 1205, 1207, 1209, 1211, 1213, 1215, 1217, 1219, 1221, 1223, 1225, 1227, 1229, 1231, 1232, 1233, 1234, 1235, 1236, 1237, 1238, 1239, 1240, 1241, 1242, 1243, 1244, 1245, 1246, 1247, 1248, 1249, 1250, 1251, 1252, 1253, 1254, 1255, 1256, 1257, 1258, 1259, 1260, 1261, 1262, 1263, 1264, 1265, 1266, 1267, 1268, 1269, 1270, 1271, 1272, 1273, 1274, 1275, 1276, 1277, 1278, 1279, 1280, 1281, 1282, 1235, 1237, 1239, 1241, 1243, 1245, 1247, 1249, 1251, 1253, 1255, 1257, 1259, 1261, 1263, 1265, 1267, 1269, 1271, 1273, 1275, 1277, 1279, 1281, 1283, 1285, 1287, 1289, 1291, 1293, 1295, 1297, 1299, or 1301.In particular examples, the RNAi oligonucleotides are selected from the group consisting of SEQ ID NOs: 1178, 1180, 1182, 1184, 1186, 1188, 1190, 1192, 1194, 1196, 1198, 1200, 1202, 1204, 1206, 1208, 1210, 1212, 1214, 1216, 1218, 1220, 1222, 1224, 1226, 1228, 1230, 1232, 1234, 1236, 1238, 1239, 1240, 1241, 1242, 1243, 1244, 1245, 1246, 1247, 1248, 1249, 1250, 1251, 1252, 1253, 1254, 1255, 1256, 1257, 1258, 1259, 1260, 1261, 1262, 1263, 1264, 1265, 1266, 1267, 1268, 1269, 1270, 1271, 1272, 1273, 1274, 1275, 1276, 1277, 1278, 1279, 1280, 1281, 1282, 1283, 1284, 1285, 1286, 1287, 1288, 1 1270, 1272, 1274, 1276, 1278, 1280, 1282, 1284, 1286, 1288, 1290, 1292, 1294, 1296, 1298, or 1300 nucleotide sequences. and the sense strand of SEQ ID NOs: 1179, 1181, 1183, 1185, 1187, 1189, 1191, 1193, 1195, 1197, 1199, 1201, 1203, 1205, 1207, 1209, 1211, 1213, 1215, 1217, 1219, 1221, 1223, 1225, 1227, 1229, 1231, 1233, 1235, 1237, 1239, 1241, 1243, 1 and an antisense strand having any one of the nucleotide sequences of 245, 1247, 1249, 1251, 1253, 1255, 1257, 1259, 1261, 1263, 1265, 1267, 1269, 1271, 1273, 1275, 1277, 1279, 1281, 1283, 1285, 1287, 1289, 1291, 1293, 1295, 1297, 1299, or 1301.

[0035] In particular examples, the RNAi oligonucleotide has the nucleotide sequence of any one of SEQ ID NOs: 1188, 1190, 1200, 1216, 1218, 1220, 1224, 1230, 1232, 1234, 1244, 1246, 1250, 1254, 1262, 1288, 1290, 1292, 1294, 1296, 1298, or 1300. and an antisense strand having the nucleotide sequence of any one of SEQ ID NOs: 1189, 1191, 1201, 1215, 1217, 1219, 1225, 1231, 1233, 1235, 1245, 1247, 1251, 1255, 1263, 1289, 1291, 1295, 1297, 1299, or 1301.

[0036] In particular examples, the sense and antisense strands of the RNAi oligonucleotide are each selected from the following: (a) SEQ ID NOs: 1220 and 1221; (b) SEQ ID NOs: 1224 and 1225; (c) SEQ ID NOs: 1230 and 1231; (d) SEQ ID NOs: 1232 and 1233; (e) SEQ ID NOs: 1188 and 1189; (f) SEQ ID NOs: 1190 and 1191; (g) SEQ ID NOs: 1244 and 1245; (h) SEQ ID NOs: 1250 and 1251-, (i) SEQ ID NOs: 1254 and 1255, and (j) SEQ ID NOs: 1246 and 1247.

[0037] Also described is an oligonucleotide for inhibiting or reducing PNPLA3 expression, comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double-stranded region, all nucleotides of the sense strand and the antisense strand comprise base, sugar, and / or internucleotide linkage modifications, and the antisense strand comprises a region of complementarity to one of PNPLA3 mRNA target sequences set forth in SEQ ID NOs: 1167-1176, the region of complementarity being at least about 15 contiguous nucleotides in length.

[0038] In another aspect, pharmaceutical compositions are described herein that include at least one oligonucleotide and a pharmaceutically acceptable carrier, delivery agent, or excipient. In some examples, the pharmaceutical composition includes an additional therapeutic agent, such as an antidiabetic agent or an antiobesity agent.

[0039] In another aspect, a method for reducing PNPLA3 expression in cells, cell populations, tissues, organs, or individuals is described, the method comprising at least one step of administering / contacting the oligonucleotide herein or pharmaceutical composition herein to cells, cell populations, tissues, organs, or individuals.In some examples, reducing PNPLA3 expression comprises reducing the amount or level of PNPLA3 mRNA, the amount or level of PNPLA3 protein, or both in cells, cell populations, tissues, organs, or individuals.In some examples, cells, cell populations, tissues, organs, or individuals have diseases, disorders, or conditions related to PNPLA3 expression.In certain examples, the diseases, disorders, or conditions related to PNPLA3 expression are cardiometabolic disease, AH, ALD, cirrhosis, HCC, CCA, and other cholangiopathies (such as PSC), NAFLD, and NASH.

[0040] In another aspect, a method for treating an individual who has or is suspected to have a disease, disorder, or condition associated with PNPLA3 expression is described.This method comprises at least one step of administering an effective amount of the oligonucleotide herein or the pharmaceutical composition herein to an individual in need thereof.In some examples, the disease, disorder, or condition associated with PNPLA3 expression is cardiometabolic disease, AH, ALD, CCA, cirrhosis, HCC, NAFLD, PSC, and NASH.In some examples, the oligonucleotide or pharmaceutical composition is administered subcutaneously daily, weekly, monthly, quarterly, or yearly, particularly monthly or quarterly.

[0041] In some examples, the individual has cirrhosis, diabetes, liver fibrosis, hepatitis, hyperlipidemia, AH, ALD, CCA, cirrhosis, HCC, NAFLD, PSC, NASH, obesity, and / or steatosis.

[0042] In any of the above embodiments, the method includes an additional step, such as measuring or obtaining genotype information, PNPLA3 expression, PNPLA3 protein levels, the individual's weight and / or blood glucose and / or TG levels, and comparing such obtained values ​​to one or more baseline or previously obtained values ​​to assess the effectiveness of the contact or administration. In some embodiments, the additional step includes confirming that the individual has the PNPLA3 I148M variant. In some embodiments, the additional step includes confirming that the individual does not have the PNPLA3 E434K variant. In some embodiments, the additional step includes confirming that the individual does not have the protein-cleaving HSD17B13 variant (rs72613567).

[0043] In any of the above embodiments, the method may include administering the RNAi oligonucleotide or pharmaceutical composition simultaneously, separately, or sequentially with the second composition or second therapeutic agent. In some embodiments, the second composition or second therapeutic agent is a PNPLA3 antibody or fragment thereof, an antidiabetic agent, or an antiobesity agent. In some embodiments, the second composition or second therapeutic agent is administered at the same frequency as the RNAi oligonucleotide (i.e., every other day, twice a week, or even weekly). In other embodiments, the second composition or second therapeutic agent is administered at a different frequency than the RNAi oligonucleotide. Similarly, in other embodiments, the second composition or second therapeutic agent is administered via the same route as the RNAi oligonucleotide (e.g., subcutaneously). In still other embodiments, the second composition or second therapeutic agent is administered via a different route than the RNAi oligonucleotide.

[0044] In other aspects, the use of the RNAi oligonucleotides herein is described for treating diseases, disorders, or conditions associated with PNPLA3 expression, wherein the RNAi oligonucleotides are optionally administered simultaneously, separately, or sequentially (i.e., in combination) with a second composition or a second therapeutic agent.

[0045] In another aspect, the present specification describes the use of the RNAi oligonucleotides in the manufacture of a medicament for treating a disease, disorder, or condition associated with PNPLA3 expression, the medicament optionally further comprising a second composition or a second therapeutic agent.

[0046] In another aspect, kits are described that include at least one oligonucleotide of the present invention, an optional pharmaceutically acceptable carrier, and a package insert with instructions for administering the same to an individual having a disease, disorder, or condition associated with PNPLA3 expression.

[0047] An advantage of the oligonucleotides and compositions herein is that inhibition of PNPLA3 expression, particularly PNPLA3 148M, exerts beneficial effects on all areas of NAFLD, including fibrosis.

[0048] Other benefits, advantages, features, and objects described above will become more readily apparent from a consideration of the following detailed description, which refers to the following drawing(s). [Brief explanation of the drawings]

[0049] [Figure 1] 1 is a schematic diagram showing the structure and chemical modification pattern of a typical GalNAc-conjugated PNPLA3 oligonucleotide. SEQ ID NOs: 1302-1303 are respectively disclosed in order of appearance. [Figure 2] 1 discloses a schematic diagram showing the structure and chemical modification pattern of another typical GalNAc-conjugated PNPLA3 oligonucleotide. DETAILED DESCRIPTION OF THE INVENTION

[0050] overview ALD and NAFLD are serious public health burdens. ALD and NAFLD are chronic liver disorders that begin with hepatic TG accumulation (steatosis) and progress to hepatitis and fibrosis, cirrhosis, and even liver cancer. PNPLA3 148M is a genetic factor that has been shown to be associated not only with ALD and NAFLD, but also with cirrhosis, HCC, and liver-related death.

[0051] RNA interference (RNAi) is a process in which exogenous RNA is introduced into cells to cause the specific degradation of mRNA encoding a target protein, thereby reducing the expression of the target gene.

[0052] In humans, PNPLA3 is 481 amino acids long and has a predicted molecular weight of 52.865 kD. Exemplary nucleic acid sequences of PNPLA3 can be found in NCBI reference sequence numbers NM_025225 (human), NM_054088 or XM_006520346 (mouse), NM_001282324 (rat), XM_015457081 (primate), XM_005567051 (primate), and XM_001109144 (primate). However, those skilled in the art will understand that additional examples of PNPLA3 mRNA sequences can be easily obtained using publicly available databases, such as GenBank and UniProt.

[0053] definition As used herein, "about" means within a statistically significant range of a value(s), such as a stated concentration, length, molecular weight, pH, sequence similarity, time frame, temperature, volume, etc. Such a value or range may be within an order of magnitude, typically within 20%, more typically within 10%, and even more typically within 5% of a given value or range. The acceptable variation encompassed by "about" will vary depending on the system being tested and will be readily apparent to one of ordinary skill in the art.

[0054] As used herein, "administer," "administering," "administration," and the like refer to providing a substance (e.g., an oligonucleotide herein or a composition herein) to an individual in a pharmacologically useful manner (e.g., to treat a disease, disorder, or condition of the individual).

[0055] As used herein, "antisense strand" refers to an oligonucleotide herein that is complementary to a region of a target sequence. Similarly, as used herein, "sense strand" refers to an oligonucleotide herein that is complementary to a region of the antisense strand.

[0056] As used herein, "asialoglycoprotein receptor" or "ASGPR" refers to a bipartite C-type lectin formed by a larger 48 kDa subunit (ASGPR-1) and a smaller 40 kDa subunit (ASGPR-2). ASGPR is expressed primarily on the sinusoidal surface of hepatocytes and plays a primary role in the binding, internalization, and subsequent excretion of circulating glycoproteins containing terminal galactose or GalNAc residues (asialoglycoproteins).

[0057] As used herein, "attenuate," "attenuating," "attenuating," and the like refer to reducing or effectively stopping. As a non-limiting example, one or more of the treatments herein may reduce or effectively stop the onset or progression of AH, ALD, CCA, PSC, cirrhosis, HCC, NAFLD, and NASH, and related diseases, disorders, and conditions, in an individual. This attenuation can be exemplified by, for example, a decrease in one or more aspects of AH, ALD, cirrhosis, HCC, CCA, PSC, NAFLD, and NASH, and related diseases, disorders, and conditions (e.g., symptoms, tissue characteristics, and cellular, inflammatory, or immune activity, etc.), the absence of detectable progression (worsening) of one or more aspects of AH, ALD, cirrhosis, HCC, CCA, PSC, NAFLD, and NASH, and related diseases, disorders, and conditions, or the absence of a detectable aspect of AH, ALD, cirrhosis, HCC, NAFLD, and NASH, and related diseases, disorders, and conditions in an individual when otherwise expected.

[0058] As used herein, "attenuate," "attenuating," "attenuation," and the like mean to reduce or effectively stop. As a non-limiting example, one or more of the treatments herein may reduce or effectively stop the onset or progression of dyslipidemia / hypertriglyceridemia / hyperlipidemia in a subject. This attenuation may be exemplified, for example, by an otherwise expected reduction in one or more aspects (e.g., symptoms, tissue characteristics, and cellular, inflammatory, or immune activity) of AH, ALD, cirrhosis, HCC, CCA, PSC, NAFLD, and NASH, and related diseases, disorders, and conditions in an individual.

[0059] As used herein, "complementary" refers to a structural relationship between two nucleotides (e.g., on two opposing nucleic acids or on opposing regions of a single nucleic acid strand) that allows the two nucleotides to base pair with each other. For example, purine nucleotides of one nucleic acid that are complementary to pyrimidine nucleotides of an opposing nucleic acid can base pair together by forming hydrogen bonds with each other. Complementary nucleotides can base pair via Watson-Crick or any other mechanism that allows the formation of a stable duplex. Similarly, two nucleic acids can have a region of multiple nucleotides that are complementary to each other, thereby forming a region of complementarity, as described herein.

[0060] As used herein, "contact," "contacting," and the like refer to directly or indirectly introducing or delivering RNAi to a cell, for example, by promoting or effecting uptake or absorption into the cell.

[0061] As used herein, "deoxyribonucleotide" refers to a nucleotide that, compared to a ribonucleotide, has a hydrogen atom instead of a hydroxyl at the 2' position of its pentose sugar. Modified deoxyribonucleotides have one or more modified substitutions at atoms other than the 2' position, for example, modifications or substitutions in the nucleobase, sugar, or phosphate group, or modifications or substitutions of the nucleobase, sugar, or phosphate group.

[0062] As used herein, "double-stranded oligonucleotide" or "ds oligonucleotide" refers to an oligonucleotide that is substantially in a duplex form. Complementary base pairing in the duplex region(s) of a ds oligonucleotide can be formed between antiparallel sequences of nucleotides in covalently separated nucleic acid strands. Similarly, complementary base pairing in the duplex region(s) of a ds oligonucleotide can be formed between antiparallel sequences of nucleotides in covalently linked nucleic acid strands. Furthermore, complementary base pairs in the duplex region(s) of a ds oligonucleotide can be formed from a single nucleic acid strand that folds back (e.g., via a hairpin) to provide a complementary antiparallel sequence of nucleotides that base pair together. A ds oligonucleotide can comprise two covalently separated nucleic acid strands that are fully duplexed with each other. However, a ds oligonucleotide can also comprise two covalently separated nucleic acid strands that are partially duplexed (e.g., with overhangs at one or both ends). A ds oligonucleotide can contain antiparallel sequences of partially complementary nucleotides and therefore can have one or more mismatches, which can include internal or terminal mismatches.

[0063] As used herein, with respect to nucleic acids (eg, oligonucleotides), "duplex" means the structure formed by complementary base pairing of two antiparallel sequences of nucleotides.

[0064] As used herein, "excipient" means a non-therapeutic agent that can be included in the compositions herein to, for example, impart or contribute a desired consistency or stabilizing effect.

[0065] As used herein, "hepatocyte(s)" refers to cells of the liver parenchyma. These cells comprise approximately 70% to 85% of the liver's mass and produce serum albumin, fibronectin (FBN), and the prothrombin group of clotting factors (excluding factors 3 and 4). Markers of hepatocyte-lineage cells include, but are not limited to, transthyretin (Ttr), glutamine synthetase (Glul), hepatocyte nuclear factor 1a (Hnf1a), and hepatocyte nuclear factor 4a (Hnf4a). Markers of mature hepatocytes may include, but are not limited to, cytochrome P450 (Cyp3a11), fumarylacetoacetate hydrolase (Fah), glucose 6-phosphate (G6p), albumin (Alb), and OC2-2F8. See, e.g., Huch et al. (2013) Nature 494:247-50.

[0066] As used herein, "hepatotoxic agent" means a compound, virus, or other substance that is itself toxic to the liver or can be processed to form a metabolic product that is toxic to the liver. Hepatotoxic agents may include, but are not limited to, carbon tetrachloride (CCl4), acetaminophen (paracetamol), vinyl chloride, arsenic, chloroform, nonsteroidal anti-inflammatory drugs (such as aspirin and phenylbutazone).

[0067] As used herein, a "labile linker" refers to a linker that can be cleaved (e.g., by acidic pH). Similarly, a "fairly stable linker" refers to a linker that cannot be cleaved.

[0068] As used herein, "liver inflammation" or "hepatitis" refers to a physical condition that can be caused by exposure to hepatotoxic agents, particularly as a result of injury or infection, resulting in swelling, dysfunction, and / or pain in the liver. Symptoms can include jaundice, fatigue, weakness, nausea, vomiting, loss of appetite, and weight loss. If left untreated, liver inflammation can progress to fibrosis, cirrhosis, liver failure, or liver cancer.

[0069] As used herein, "liver fibrosis," "liver fibrosis," or "liver fibrosis" refers to the excessive accumulation of extracellular matrix proteins in the liver, which may include collagens (I, III, and IV), FBN, undulin, elastin, laminin, hyaluronan, and proteoglycans, resulting from inflammation and liver cell death. If left untreated, liver fibrosis can progress to cirrhosis, liver failure, or liver cancer.

[0070] As used herein, "loop" means an unpaired region of a nucleic acid (e.g., an oligonucleotide) that is adjacent to two antiparallel regions of nucleic acid that are sufficiently complementary to each other that under appropriate hybridization conditions (e.g., in a phosphate buffer, in a cell), the two antiparallel regions adjacent to the unpaired region hybridize to form a duplex (called a "stem").

[0071] As used herein, "modified internucleotide bond" refers to an internucleotide bond that has one or more chemical modifications compared to a reference internucleotide bond that has a phosphodiester bond. Modified nucleotides can be non-naturally occurring bonds. Typically, modified internucleotide bonds impart one or more desirable properties to the nucleic acid in which the modified internucleotide bond is present. For example, modified nucleotides can improve thermal stability, resistance to degradation, nuclease resistance, solubility, bioavailability, biological activity, reduced immunogenicity, etc.

[0072] As used herein, "modified nucleotide" refers to a nucleotide having one or more chemical modifications compared to a corresponding reference nucleotide selected from adenine ribonucleotides, guanine ribonucleotides, cytosine ribonucleotides, uracil ribonucleotides, adenine deoxyribonucleotides, guanine deoxyribonucleotides, cytosine deoxyribonucleotides, and thymidine deoxyribonucleotides. The modified nucleotide may be a non-naturally occurring nucleotide. The modified nucleotide may have one or more chemical modifications in its sugar, nucleobase, and / or phosphate group. Additionally or alternatively, the modified nucleotide may have one or more chemical moieties conjugated to the corresponding reference nucleotide. Typically, the modified nucleotide confers one or more desirable properties to the nucleic acid in which the modified nucleotide is present. For example, the modified nucleotide may improve thermal stability, resistance to degradation, nuclease resistance, solubility, bioavailability, biological activity, reduced immunogenicity, etc.

[0073] As used herein, "nicked tetraloop structure" refers to an RNAi oligonucleotide structure featuring separate sense (passenger) and antisense (guide) strands, where the sense strand has a region complementary to the antisense strand, and where at least one of the strands (generally the sense strand) has a tetraloop configured to stabilize an adjacent stem region formed within said at least one strand.

[0074] As used herein, "nucleotide" means an organic molecule having a nucleoside (e.g., a nucleic acid base such as adenine, cytosine, guanine, thymine, or uracil; and a five-carbon sugar such as ribose or 2'-deoxyribose; and a phosphate group), which can function as a monomer unit of nucleic acid polymers such as deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).

[0075] As used herein, "oligonucleotide" refers to a short nucleic acid molecule (e.g., less than about 100 nucleotides in length). An oligonucleotide can be single-stranded (ss) or ds. An oligonucleotide may or may not have a double-stranded region. As a non-limiting set of examples, an oligonucleotide can be, but is not limited to, a small interfering RNA (siRNA), a microRNA (miRNA), a short hairpin RNA (shRNA), a dicer substrate interfering RNA (dsiRNA), an antisense oligonucleotide (ASO), a short siRNA, or a ss siRNA. Typically, a ds oligonucleotide is an RNAi oligonucleotide.

[0076] As used herein, "overhang" refers to the terminal non-base-paired nucleotide(s) resulting from one strand or region extending beyond the end of the complementary strand with which it forms a duplex. An overhang can include one or more non-paired nucleotides extending from the double-stranded region at the 5'-end or 3'-end of a ds oligonucleotide. An overhang can be a 3'- or 5'-overhang on the antisense strand or the sense strand of a ds oligonucleotide.

[0077] As used herein, "phosphate analog" refers to a chemical moiety that mimics the electrostatic and / or steric properties of a phosphate group. In some embodiments, a phosphate analog is placed at the 5'-terminal nucleotide of an oligonucleotide in place of the 5'-phosphate, which is susceptible to enzymatic removal. The 5'-phosphate analog may comprise a phosphatase-resistant linkage. Examples of phosphate analogs include, but are not limited to, 5'-phosphonates, such as 5'-methylene phosphonate (5'-MP) and 5'-(E)-vinyl phosphonate (5'-VP). An oligonucleotide may have a phosphate analog at the 4'-carbon position of the sugar at the 5'-terminal nucleotide (referred to as a 4'-phosphate analog). An example of a 4'-phosphate analog is an oxymethyl phosphonate, in which the oxygen atom of the oxymethyl group is attached to the sugar moiety (e.g., its 4'-carbon), or an analog thereof. See, for example, International Patent Application Publication No. WO 2018 / 045317. Other modifications to the 5' end of oligonucleotides have been developed (see, e.g., International Patent Application Publication No. WO2011 / 133871; U.S. Patent No. 8,927,513; and Prakash et al. (2015) Nucleic Acids Res. 43:2993-3011).

[0078] As used herein, "PNPLA3-associated disease," "PNPLA3-associated disorder," or "PNPLA3-associated condition" refers to a condition having increased PNPLA3 expression and / or the presence of, for example, the PNPLA3 I148M variant. Exemplary PNPLA3-associated conditions, diseases, or disorders include, but are not limited to, fat accumulation in the liver, cirrhosis, fatty liver (steatosis), hepatocellular necrosis, HCC, liver fibrosis, liver inflammation, NASH, NAFLD, or obesity.

[0079] As used herein, "reduced expression" with respect to a gene (e.g., PNPLA3) refers to a decrease in the amount or level of an RNA transcript (e.g., PNPLA3 mRNA) or protein encoded by the gene, and / or a decrease in the amount or level of the gene's activity in a cell, cell population, sample, or subject, compared to an appropriate reference (e.g., a reference cell, cell population, sample, or subject). For example, contacting a cell with an oligonucleotide herein (e.g., an oligonucleotide having an antisense strand with a nucleotide sequence complementary to a nucleotide sequence comprising PNPLA3 mRNA) can result in a decrease in the amount or level of mRNA, protein, and / or activity (e.g., due to degradation of PNPLA3 mRNA by the RNAi pathway) compared to cells not treated with the ds oligonucleotide. Similarly, as used herein, "reduced expression" refers to an act that results in a decrease in the expression of a gene (e.g., PNPLA3). Specifically, as used herein, "reduced PNPLA3 expression" means a decrease in the amount or level of PNPLA3 mRNA, PMPLA3 protein, and / or PNPLA3 activity in a cell, cell population, sample, or subject compared to an appropriate reference (e.g., a reference cell, cell population, sample, or subject).

[0080] As used herein, "region of complementarity" refers to a sequence of nucleotides of a nucleic acid (e.g., a ds oligonucleotide) that is sufficiently complementary to an antiparallel sequence of nucleotides to allow hybridization between the two sequences of nucleotides under appropriate hybridization conditions (e.g., in a phosphate buffer, in a cell, etc.). Oligonucleotides herein include target sequences that have a region complementary to an mRNA target sequence.

[0081] As used herein, "ribonucleotide" refers to a nucleotide having ribose as its pentose sugar and containing a hydroxyl group at its 2' position. Modified ribonucleotides are ribonucleotides that have one or more modifications or substitutions at atoms other than the 2' position, for example, modifications or substitutions in or of the nucleobase, sugar, or phosphate group.

[0082] As used herein, "RNAi oligonucleotide" refers to either (a) a ds oligonucleotide having a sense strand (passenger) and an antisense strand (guide), where the antisense strand or a portion of the antisense strand is used by Argonaute 2 (Ago2) endonuclease to cleave the target mRNA, or (b) a ss oligonucleotide having a single-stranded antisense strand, where the antisense strand (or a portion of the antisense strand) is used by Ago2 endonuclease to cleave the target mRNA.

[0083] As used herein, a "strand" refers to a single, continuous sequence of nucleotides linked together via internucleotide bonds (e.g., phosphodiester or phosphorothioate bonds). A strand may have two free ends (e.g., a 5' end and a 3' end).

[0084] As used herein, "subject" means any mammal, including cats, dogs, mice, rats, and primates, particularly humans. Furthermore, "individual" or "patient" may be used interchangeably with "subject."

[0085] As used herein, "synthetic" refers to a nucleic acid or other molecule that is artificially synthesized (e.g., using a machine (e.g., a solid phase nucleic acid synthesizer)) or is not otherwise derived from a natural source (e.g., a cell or organism) that normally produces nucleic acids or molecules.

[0086] As used herein, a "targeting ligand" refers to a molecule (e.g., an amino sugar, carbohydrate, cholesterol, lipid, or polypeptide) that selectively binds to a cognate molecule (e.g., a receptor) in a tissue or cell of interest and can be conjugated to another substance to target the other substance to the tissue or cell of interest. For example, a targeting ligand can be conjugated to an oligonucleotide herein to target the oligonucleotide to a specific tissue or cell of interest. The targeting ligand can selectively bind to a cell surface receptor. Thus, when conjugated to an oligonucleotide, the targeting ligand promotes delivery of the oligonucleotide to a specific cell through selective binding to a receptor expressed on the surface of the cell and endosomal internalization by the cell of a complex comprising the oligonucleotide, targeting ligand, and receptor. Furthermore, the targeting ligand can be conjugated to the oligonucleotide via a linker that is cleaved after or during cellular internalization so that the oligonucleotide is released from the targeting ligand within the cell.

[0087] As used herein, "tetraloop" refers to a loop that increases the stability of an adjacent duplex formed by hybridization of an adjacent sequence of nucleotides. The increased stability is measured by increasing the melting temperature (T) of the adjacent stem duplex. m ), which is detectable as an increase in the T of adjacent stem duplexes expected as an average from a set of loops of equivalent length composed of randomly selected nucleotide sequences. m For example, a tetraloop can be prepared by forming a hairpin comprising a duplex of at least 2 base pairs (bp) in length, which exhibits a T of at least about 50°C, at least about 55°C, at least about 56°C, at least about 58°C, at least about 60°C, at least about 65°C, or at least about 75°C in 10 mM NaHPO. mThe tetraloop can stabilize adjacent bp of the stem duplex through stacking interactions. Furthermore, interactions between nucleotides within the tetraloop include, but are not limited to, non-Watson-Crick base pairing, stacking interactions, hydrogen bonding, and contact interactions (Cheong et al. (1990) Nature 346:680-682; Heus & Pardi (1991) Science 253:191-194). As used herein, a tetraloop can contain or have about 3-6 nucleotides, typically about 4-5 nucleotides. Thus, a tetraloop can have 3, 4, 5, or 6 nucleotides, typically 4 nucleotides, which may or may not be modified (e.g., conjugated to a targeting moiety). Any nucleotide can be used in the tetraloop, and such nucleotides can use standard IUPAC-IUB symbols as described in Cornish-Bowden (1985) Nucleic Acids Res. 13:3021-30. For example, the letter "N" can be used to indicate that any base can be at that position, the letter "R" can be used to indicate that A (adenine) or G (guanine) can be at that position, and "B" can be used to indicate that C (cytosine), G (guanine), or T (thymine) can be at that position. Examples of tetraloops include the UNCG family of tetraloops (e.g., UUCG), the GNRA family of tetraloops (e.g., GAAA), and the CUUG tetraloop (Woese et al. (1990) Proc. Natl. Acad. Sci. USA 87:8467-71; Antao et al. (1991) Nucleic Acids Res. 19:5901-05).Examples of DNA tetraloops include the d(GNNA) family of tetraloops (e.g., d(GTTA)), the d(GNRA) family of tetraloops, the d(GNAB) family of tetraloops, the d(CNNG) family of tetraloops, and the d(TNCG) family of tetraloops (e.g., d(TTCG)). See, e.g., Nakano et al. (2002) Biochem. 41:4281-92; and Shinji et al. (2000) Nippon Kagakkai Koen Yokoshu 78:731. As used herein, the tetraloop may be in a nicked tetraloop structure.

[0088] As used herein, "treat" or "treating" refers to the act of providing care to an individual in need thereof, for example, by administering a therapeutic agent (e.g., an oligonucleotide herein) to the individual for the purpose of improving the individual's health and / or well-being with respect to an existing condition (e.g., disease, disorder) or to prevent or reduce the likelihood of the condition occurring. Treatment can include reducing the frequency or severity of at least one sign, symptom, or contributing factor of a condition (e.g., disease, disorder) experienced by the individual.

[0089] As used herein, "iRNA," "iRNA agent," "RNAi," "RNAi agent," and "RNA interference agent" refer to an agent that contains RNA and mediates targeted cleavage of RNA transcripts via the RNA-induced silencing complex (RISC) pathway. iRNA directs the sequence-specific degradation of mRNA through RNA interference. iRNA regulates, inhibits, or reduces PNPLA3 expression in cells.

[0090] composition According to some aspects, the present disclosure provides oligonucleotides (e.g., double-stranded RNAi oligonucleotides) that reduce, regulate, or inhibit the expression of PNPLA3 in the liver. In some embodiments, the oligonucleotides provided herein are used to treat diseases associated with PNPLA3 expression. In some aspects, the present disclosure provides methods for treating diseases associated with PNPLA3 expression by reducing, regulating, or inhibiting PNPLA3 expression in the liver (e.g., cells that constitute the liver).

[0091] Oligonucleotide inhibitors of PNPLA3 expression I. PNPLA3 Target Sequence: The oligonucleotides (e.g., RNAi oligonucleotides) herein target a target sequence (i.e., a PNPLA3 target sequence) comprising PNPLA3 mRNA. In some embodiments, the oligonucleotide or a portion, fragment, or strand thereof (e.g., the antisense strand or guide strand of a dsRNAi oligonucleotide) binds to or anneals to the PNPLA3 target sequence, thereby inhibiting PNPLA3 expression. In some embodiments, the oligonucleotide targets the PNPLA3 target sequence and inhibits PNPLA3 expression in vivo. In some embodiments, the amount or degree of PNPLA3 expression inhibition by an oligonucleotide targeting a PNPLA3 target sequence correlates with the efficacy of the oligonucleotide. In some embodiments, the amount or degree of PNPLA3 expression inhibition by an oligonucleotide targeting a PNPLA3 target sequence correlates with the amount or degree of therapeutic effect in an individual having or suspected of having a disease, disorder, or condition associated with PNPLA3 expression treated with the oligonucleotide.

[0092] Through examination and analysis of the nucleotide sequence of PNPLA3 mRNA, including mRNA from several different species (e.g., human, cynomolgus monkey, and rhesus monkey; see, e.g., Example 1), and as a result of in vitro and in vivo testing (see, e.g., Examples 2-3), it is shown herein that certain nucleotide sequences of PNPLA3 mRNA are more susceptible to oligonucleotide-based inhibition of PNPLA3 expression than other nucleotide sequences and are therefore useful as target sequences for the oligonucleotides herein. In some embodiments, the sense strand of an oligonucleotide (e.g., a dsRNAi oligonucleotide) described herein (e.g., in Table 1 or 3, or Tables A, B, C, or D) comprises a PNPLA3 target sequence. In some embodiments, a portion or region of the sense strand of an oligonucleotide described herein (e.g., in Table 1 or 3, or Tables A, B, C, or D) comprises a PNPLA3 target sequence. In some embodiments, the PNPLA3 target sequence comprises or consists of the sequence of any one of SEQ ID NOs: 1167-1176.

[0093] II. PNPLA3 mRNA Target Sequence: In some embodiments, the oligonucleotides herein have a region of complementarity to PNPLA3 mRNA (e.g., within the target sequence of PNPLA3 mRNA) to target PNPLA3 mRNA in cells and inhibit PNPLA3 expression. In some embodiments, the oligonucleotides herein comprise a PNPLA3 target sequence (e.g., the antisense strand or guide strand of a ds oligonucleotide) with a complementary region that binds or anneals to the PNPLA3 mRNA target sequence by complementary (Watson-Crick) base pairing. The target sequence or complementary region has a length and base content suitable to enable binding or annealing of the oligonucleotide (or strand thereof) to PNPLA3 mRNA and inhibit its expression. In some embodiments, the target sequence or complementary region is at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, at least about 28, at least about 29, or at least about 30 nucleotides in length. Alternatively, the target sequence or complementary region is about 12 to about 30 (e.g., 12 to 30, 12 to 22, 15 to 25, 17 to 21, 18 to 27, 19 to 27, or 15 to 30) nucleotides in length. Alternatively, the target sequence or complementary region is about 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. In certain embodiments, the target sequence or complementary region is 18 nucleotides in length. In certain embodiments, the target sequence or complementary region is 19 nucleotides in length. In certain embodiments, the target sequence or complementary region is 20 nucleotides in length. In certain embodiments, the target sequence or complementary region is 21 nucleotides in length. In certain embodiments, the target sequence or complementary region is 22 nucleotides in length. In certain embodiments, the target sequence or complementary region is 23 nucleotides in length. In certain embodiments, the target sequence or complementary region is 24 nucleotides in length.

[0094] In some embodiments, the oligonucleotides herein comprise a target sequence or complementary region that is fully complementary to the PNPLA3 target sequence (e.g., the antisense strand or guide strand of a double-stranded oligonucleotide). In some embodiments, the target sequence or complementary region is partially complementary to the PNPLA3 target sequence. In some embodiments, the oligonucleotide comprises a target sequence or complementary region that is fully complementary to any one of SEQ ID NOs: 1167-1176. In some embodiments, the oligonucleotide comprises a target sequence or complementary region that is partially complementary to any one of SEQ ID NOs: 1167-1176.

[0095] Alternatively, in some embodiments, the oligonucleotides herein comprise a target sequence or complementary region complementary to a contiguous sequence of nucleotides constituting PNPLA3 mRNA, the contiguous sequence being about 12 to about 30 nucleotides in length (e.g., 12 to 30, 12 to 28, 12 to 26, 12 to 24, 12 to 20, 12 to 18, 12 to 16, 14 to 22, 16 to 20, 18 to 20, or 18 to 19 nucleotides in length). In some embodiments, the oligonucleotides comprise a target sequence or complementary region complementary to a contiguous sequence of nucleotides constituting PNPLA3 mRNA, the contiguous sequence of nucleotides being 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides in length. In some embodiments, the oligonucleotides comprise a target sequence or complementary region complementary to a contiguous sequence of nucleotides constituting PNPLA3 mRNA, the contiguous sequence of nucleotides being 19 nucleotides in length. In some embodiments, the oligonucleotide comprises a target sequence or complementary region complementary to a contiguous sequence of nucleotides constituting PNPLA3 mRNA, the contiguous sequence of nucleotides being 20 nucleotides in length. In other embodiments, the oligonucleotide comprises a target sequence or complementary region complementary to a contiguous sequence of nucleotides in any one of SEQ ID NOs: 1167-1176, optionally, the contiguous sequence of nucleotides being 19 nucleotides in length.

[0096] With respect to the target sequence or complementary region of an oligonucleotide herein, it is complementary to consecutive nucleotides of the sequence set forth in any one of SEQ ID NOs: 1167-1176 and spans the entire length of the antisense strand. In some embodiments, the complementary region of the oligonucleotide is complementary to consecutive nucleotides of the sequence set forth in any one of SEQ ID NOs: 1167-1176 and spans a portion of the entire length of the antisense strand. In some additional embodiments, the oligonucleotide comprises a complementary region (e.g., on the antisense strand of a ds oligonucleotide) that is at least partially (e.g., fully) complementary to a consecutive stretch of nucleotides spanning nucleotides 1-20 of the sequence set forth in any one of SEQ ID NOs: 1167-1176.

[0097] Alternatively, the oligonucleotides herein comprise target sequences or complementary regions that have one or more base pair (bp) mismatches with the corresponding PNPLA3 target sequence. In some embodiments, the target sequence or complementary region has at most about 1, at most about 2, at most about 3, at most about 4, at most about 5, etc. mismatches with the corresponding PNPLA3 target sequence, so long as the ability of the target sequence or complementary region to bind or anneal to PNPLA3 mRNA and / or the ability of the oligonucleotide to reduce or inhibit PNPLA3 expression under appropriate hybridization conditions is maintained. In other words, the target sequence or complementary region has no more than 1, no more than 2, no more than 3, no more than 4, or no more than 5 mismatches with the corresponding PNPLA3 target sequence, so long as the ability of the target sequence or complementary region to bind or anneal to PNPLA3 mRNA and / or the ability of the oligonucleotide to reduce or inhibit PNPLA3 expression under appropriate hybridization conditions is maintained. In some embodiments, the oligonucleotides comprise a target sequence or complementary region with one mismatch to the corresponding target sequence. In some embodiments, the oligonucleotides comprise a target sequence or complementary region with two mismatches to the corresponding target sequence. In some embodiments, the oligonucleotides comprise a target sequence or complementary region with three mismatches to the corresponding target sequence. In some embodiments, the oligonucleotides comprise a target sequence or complementary region with four mismatches to the corresponding target sequence. In some embodiments, the oligonucleotides comprise a target sequence or complementary region with five mismatches to the corresponding target sequence. In other embodiments, the oligonucleotides comprise a target sequence or complementary region with two or more mismatches to the corresponding target sequence (e.g., 2, 3, 4, 5, or more mismatches), where at least two (e.g., all) of the mismatches are contiguous (e.g., 2, 3, 4, 5, or more mismatches in a row) or the mismatches are scattered anywhere throughout the target sequence or complementary region.In other embodiments, the oligonucleotide comprises a target sequence or complementary region with two or more mismatches (e.g., 2, 3, 4, 5 or more mismatches) with the corresponding target sequence, where at least two (e.g., all) of the mismatches are positioned consecutively (e.g., 2, 3, 4, 5 or more mismatches in a row), or where at least one or more non-mismatched base pairs are positioned between the mismatches, or a combination thereof.

[0098] III. Oligonucleotide Types: Various oligonucleotide types and / or structures are useful for targeting PNPLA3 mRNA, including, but not limited to, RNAi oligonucleotides, antisense oligonucleotides, miRNAs, etc. Any of the oligonucleotide types described herein or elsewhere is contemplated as a framework for incorporating the target sequences herein for the purpose of inhibiting PNPLA3 expression. In some embodiments, the oligonucleotides herein inhibit PNPLA3 expression by incorporating into an upstream or downstream RNAi pathway involving Dicer. For example, RNAi oligonucleotides have been developed in which each strand is approximately 19-25 nucleotides in size and has at least one 3'-end overhang of 1-5 nucleotides (see, e.g., U.S. Patent No. 8,372,968). Longer oligonucleotides that are processed by Dicer to generate active RNAi products have also been developed (see, e.g., U.S. Patent No. 8,883,996). Further work has produced extended ds oligonucleotides in which at least one end of at least one strand extends beyond the target region of the duplex, such as structures in which one strand contains a thermodynamically stable tetraloop structure (see, e.g., U.S. Pat. Nos. 8,513,207 and 8,927,705, and International Patent Application Publication No. WO2010 / 033225). Such structures include ss extensions (on one or both sides of the molecule) and ds extensions.

[0099] The oligonucleotides herein are incorporated into the RNAi pathway downstream of Dicer involvement (e.g., Dicer cleavage). In some embodiments, the oligonucleotides have an overhang (e.g., 1, 2, or 3 nucleotides in length) at the 3' end of the sense strand. In some embodiments, the oligonucleotides (e.g., siRNAs) comprise a 21-nucleotide guide strand that is antisense to the target RNA (e.g., PNPLA3 mRNA) and a complementary passenger strand, where the two strands anneal to form a 19-bp duplex and a 2-nucleotide overhang at either or both 3' ends. Longer oligonucleotide designs are also contemplated, including oligonucleotides with a 23-nucleotide guide strand and a 21-nucleotide passenger strand, where there is a blunt end on the right side of the molecule (the 3' end of the passenger strand / the 5' end of the guide strand) and a 2-nucleotide 3' guide strand overhang on the left side of the molecule (the 5' end of the passenger strand / the 3' end of the guide strand). In such molecules, there is a 21-bp double-stranded region. See, for example, U.S. Patent Nos. 9,012,138; 9,012,621; and 9,193,753.

[0100] The oligonucleotides herein comprise a sense strand and an antisense strand, both ranging from about 17 to about 26 (e.g., 17 to 26, 20 to 25, or 21 to 23) nucleotides in length. In some embodiments, the oligonucleotide comprises a sense strand and an antisense strand, both ranging from about 19 to about 22 nucleotides in length. In some embodiments, the sense and antisense strands are equal in length. In some embodiments, the oligonucleotide comprises a sense strand and an antisense strand, such that a 3' overhang is present on either the sense strand or the antisense strand, or on both the sense and antisense strands. In some examples, for oligonucleotides having a sense strand and an antisense strand, both ranging from about 21 to about 23 nucleotides in length, the 3' overhang on the sense strand, the antisense strand, or both the sense and antisense strands is 1 or 2 nucleotides in length. In some embodiments, the oligonucleotide comprises a 22-nucleotide guide strand and a 20-nucleotide passenger strand, with a blunt end on the right side of the molecule (3' end of passenger strand / 5' end of guide strand) and a 2-nucleotide 3' guide strand overhang on the left side of the molecule (5' end of passenger strand / 3' end of guide strand). In such molecules, there is a 20 bp double-stranded region.

[0101] Other oligonucleotide designs for use herein include 16-mer siRNAs (see, e.g., "Nucleic Acids in Chemistry & Biology," Blackburn (ed.), Royal Society of Chemistry, 2006), shRNAs (e.g., with stems of 19 bp or shorter; see, e.g., Moore et al. (2010) Methods Mol. Biol. 629:141-58), blunt siRNAs (e.g., 19 bp in length; see, e.g., Kraynack & Baker (2006) RNA 12:163-76), asymmetric siRNAs (aiRNAs; see, e.g., Sun et al. (2008) Nat. Biotechnol. 26:1379-82), asymmetric short duplex siRNAs (see, e.g., Chang et al. (2009) Mol. Ther. 17:725-32), forked siRNAs (see, e.g., Hohjoh (2004) FEBS Lett. 557:193-198), ss siRNA (see, e.g., Elsner (2012) Nat. Biotechnol. 30:1063), dumbbell-shaped circular siRNA (see, e.g., Abe et al. (2007) J. Am. Chem. Soc. 129:15108-09), and small internal segmented interfering RNA (sisiRNA; see, e.g., Bramsen et al. (2007) Nucleic Acids Res. 35:5886-97). Further non-limiting examples of oligonucleotide structures that can be used herein to reduce or inhibit PNPLA3 expression are miRNA, shRNA, and short siRNA (see, e.g., Hamilton et al. (2002) EMBO J. 21:4671-79; also see U.S. Patent Application Publication No. 2009 / 0099115).

[0102] Alternatively, the oligonucleotides herein are single-stranded (ss). Such structures include, but are not limited to, ssRNAi molecules. Recent efforts have demonstrated the activity of ssRNAi molecules (see, for example, Matsui et al. (2016) Mol. Ther. 24:946-55). In some embodiments, the oligonucleotide is an ASO. An ASO is an ss oligonucleotide that, when written or depicted in the 5' to 3' direction, contains the reverse complement of a specific nucleic acid target segment and is appropriately modified to induce RNase H-mediated cleavage of that target RNA in a cell (e.g., as a gapmer) or inhibit translation of a target mRNA in a cell (e.g., as a mixmer). ASOs for use in the present disclosure may be modified in any suitable manner known in the art, including, for example, those described in U.S. Pat. No. 9,567,587 (e.g., including modifications of length, sugar moieties of nucleobases (pyrimidines, purines), and heterocyclic moieties of nucleobases). Furthermore, ASOs have been used for decades to reduce the expression of specific target genes (see, e.g., Bennett et al. (2017) Annu. Rev. Pharmacol. 57:81-105).

[0103] IV. Double-stranded RNAi oligonucleotide: A ds oligonucleotide for targeting PNPLA3 mRNA and inhibiting PNPLA3 expression (e.g., via the RNAi pathway), comprising a sense strand (i.e., passenger strand) and an antisense strand (i.e., guide strand). In some embodiments, the sense strand and the antisense strand are separate strands and are not covalently linked. In some embodiments, the sense strand and the antisense strand are covalently linked.

[0104] In some embodiments, the sense strand comprises a first region (R1) and a second region (R2), wherein R2 comprises a first subregion (S1), a tetraloop (L) or a triloop (triL), and a second subregion (S2), wherein L or triL is located between S1 and S2, and S1 and S2 form a second duplex (D2). D2 can vary in length. In some embodiments, D2 is about 1 to about 6 bp in length. In some embodiments, D2 is 2 to 6, 3 to 6, 4 to 6, 5 to 6, 1 to 5, 2 to 5, 3 to 5, or 4 to 5 bp in length. In other embodiments, D2 is 1, 2, 3, 4, 5, or 6 bp in length. In certain embodiments, D2 is 6 bp in length.

[0105] In some embodiments, R1 of the sense strand and R2 of the antisense strand form a first duplex (D1). In some embodiments, D1 is at least about 15 (e.g., at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21) nucleotides in length. In some embodiments, D1 is about 12 to about 30 nucleotides in length (e.g., 12 to 30, 12 to 27, 15 to 22, 18 to 22, 18 to 25, 18 to 27, 18 to 30, or 21 to 30 nucleotides in length). In other embodiments, D1 is at least 12 nucleotides in length (e.g., at least 12, at least 15, at least 20, at least 25, or at least 30 nucleotides in length). In other embodiments, D1 is 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. In certain embodiments, D1 is 20 nucleotides in length. In some examples, D1 does not span the entire length of the sense strand and / or the antisense strand. In some examples, D1 spans the entire length of either the sense strand or the antisense strand, or both. In certain examples, D1 spans the entire length of both the sense strand and the antisense strand.

[0106] In particular examples, the ds oligonucleotides herein are selected from the group consisting of SEQ ID NOs: 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 17 5, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197 , 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 295, 297, 299, 301, 303, 305, 307, 309, 311, 313, 315, 317, 319, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 23, 325, 327, 329, 331, 333, 335, 337, 339, 341, 343, 345, 347, 349, 351, 353, 355, 357, 359, 361, 363, 365, 367, 369, 371, 373, 375, 377, 379, 381, 383, 38 5, 387, 389, 391, 393, 395, 397, 399, 401, 403, 405, 407, 409, 411, 413, 415, 417, 419, 421, 423, 425, 427, 429, 431, 433, 435, 437, 439, 441, 443, 445, 447 , 449, 451, 453, 455, 457, 459, 461, 463, 465, 467, 469, 471, 473, 475, 477, 479, 481, 483, 485, 487, 489, 491, 493, 495, 497, 499, 501, 503, 505, 507, 509,511, 513, 515, 517, 519, 521, 523, 525, 527, 529, 531, 533, 535, 537, 539, 541, 543, 545, 547, 549, 551, 553, 555, 557, 559, 561, 563, 565, 567, 569, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 73, 575, 577, 579, 581, 583, 585, 587, 589, 591, 593, 595, 597, 599, 601, 603, 605, 607, 609, 611, 613, 615, 617, 619, 621, 623, 625, 627, 629, 631, 633, 63 5, 637, 639, 641, 643, 645, 647, 649, 651, 653, 655, 657, 659, 661, 663, 665, 667, 669, 671, 673, 675, 677, 679, 681, 683, 685, 687, 689, 691, 693, 695, 697 , 699, 701, 703, 705, 707, 709, 711, 713, 715, 717, 719, 721, 723, 725, 727, 729, 731, 733, 735, 737, 739, 741, 743, 745, 747, 749, 751, 753, 755, 757, 759, 761, 763, 765, 767, 769, 771, 773, and 775, and a sense strand having any one of the sequences set forth in SEQ ID NOs: 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 8, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190 , 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252,254、256、258、260、262、264、266、268、270、272、274、276、278、280、282、284、286、288、290、292、294、296、298、300、302、304、306、308、310、312、314、316、318、320、322、324、326、328、330、332、334、336、338、340、342、344、346、348、350、352、354、356、358、360、362、364、366、368、370、372、374、376、378、380、382、384、386、388、390、392、394、396、398、400、402、404、406、408、410、412、414、416、418、420、422、424、426、428、430、432、434、436、438、440、442、444、446、448、450、452、454、456、458、460、462、464、466、468、470、472、474、476、478、480、482、484、486、488、490、492、494、496、498、500、502、504、506、508、510、512、514、516、518、520、522、524、526、528、530、532、534、536、538、540、542、544、546、548、550、552、554、556、558、560、562、564、566、568、570、572、574、576、578、580、582、584、586、588、590、592、594、596、598、600、602、604、606、608、610、612、614、616、618、620、622、624、626、628、630、632、634、636、638、640、642、644、646、648、650、652、654、656、658、660、662、664、666、668、670、672、674、676、678、680、682、684、686、688、690、692、694、696、698、700、702、704、706、708、710、712、714、716、718、720、722、724、726、728、730、732、734、736、738、740、742、744、746、748、750、752、and an antisense strand having a complementary sequence selected from 754, 756, 758, 760, 762, 764, 766, 768, 770, 772, 774, and 776. Alternatively, the ds oligonucleotides herein may be selected from the group consisting of SEQ ID NOs: 777, 779, 781, 783, 785, 787, 789, 791, 793, 795, 797, 799, 801, 803, 805, 807, 809, 811, 813, 815, 817, 819, 821, 823, 825, 827, 829, 831, 833, 835, 837, 839, 841, 843, 845, 847, 849, 851, 853, 855, 857, 859, 861, 863, 865, 867, 869, 870, 871, 872, 873, 874, 875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 9 71, 873, 875, 877, 879, 881, 883, 885, 887, 889, 891, 893, 895, 897, 899, 901, 903, 905, 907, 909, 911, 913, 915, 917, 919, 921, 923, 925, 927, 929, 931, 933, 935, 937, 939, 941, 943, 945, 947, 949, 951, 953, 955, 957, 959, 961, 963, 965, 967, 969, 971, 973, 975, 977, 979, 981, 983, 985 ,987, 989, 991, 993, 995, 997, 999, 1001, 1003, 1005, 1007, 1009, 1011, 1013, 1015, 1017, 1019, 1021, 1023, 1025, 1027, 1029, 1031, 1033, 1035, 1037, 1039, 1041, 1043, 1045, 1047, 1049, 1051, 1053, 1055, 1057, 1059, 1061, 1063, 1065, 1067, 1069, 1071, 1073, 1075, 1077, 1079, 1 a sense strand having any one of the sequences of 081, 1083, 1085, 1087, 1089, 1091, 1093, 1095, 1097, 1099, 1101, 1103, 1105, 1107, 1109, 1111, 1113, 1115, 1117, 1119, 1121, 1123, 1125, 1127, 1129, 1131, 1133, 1135, 1137, 1139, 1141, 1143, 1145, 1147, 1149, 1151, 1153, 1155, 1157, 1159, 1161, and 1163;SEQ ID NOs: 778, 780, 782, 784, 786, 788, 790, 792, 794, 796, 798, 800, 802, 804, 806, 808, 810, 812, 814, 816, 818, 820, 822, 824, 826, 828, 830, 832, 834, 836, 838, 840, 842, 844, 846, 848, 850, 852, 854, 856, 858, 860, 862, 864, 866, 868, 870, 872, 874, 876, 878, 880, 882, 884, 886 , 888, 890, 892, 894, 896, 898, 900, 902, 904, 906, 908, 910, 912, 914, 916, 918, 920, 922, 924, 926, 928, 930, 932, 934, 936, 938, 940, 942, 944, 946, 948, 950, 952, 954, 956, 958, 960, 962, 964, 966, 968, 970, 972, 974, 976, 978, 980, 982, 984, 986, 988, 990, 992, 994, 996, 99 8, 1000, 1002, 1004, 1006, 1008, 1010, 1012, 1014, 1016, 1018, 1020, 1022, 1024, 1026, 1028, 1030, 1032, 1034, 1036, 1038, 1040, 1042, 1044, 1046, 1048, 1050, 1052, 1054, 1056, 1058, 1060, 1062, 1064, 1066, 1068, 1070, 1072, 1074, 1076, 1078, 1080, 1082, 1084, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095, 1096, 1097, 1098, 1099, 2000, 2001, 2002, 2003, 2004, 2005, 2006, 2007, 2008, 2009, 2010, 2011, 2012, 2013, 2014, 2015, 2016, 2017, 2018, 2019, 2020, 2021, 2022, 2023, 2024, 2025, 2026, 202 and an antisense strand having a complementary sequence selected from the group consisting of: 1150, 1152, 1154, 1156, 1158, 1160, 1162, and 1164. In particular examples, the sense strand is any one of SEQ ID NOs: 787, 843, 867, 871, 937, 1003, 1007, 1017, 1161, or 1163, and the antisense strand is any one of SEQ ID NOs: 788, 844, 868, 872, 938,It can be one of 1004, 1008, 1018, 1162, or 1164.

[0107] In certain embodiments, the present disclosure provides a method for the production of a nucleotide sequence of a nucleotide sequence set forth in Table A, B, C, or D (e.g., SEQ ID NOs: 1178, 1180, 1182, 1184, 1186, 1188, 1190, 1192, 1194, 1196, 1198, 1200, 1202, 1204, 1206, 1208, 1210, 1212, 1214, 1216, 1218, 1220, 1222, 1224, 1226, 1228, 1230, 1232, 1234, 1236, 1238, 1240, 1242, 1243, 1244, 1245, 1246, 1247, 1248, 1249, 1250, 1251, 1252, 1253, 1254, 1255, 1256, 1257, 1258, 1259, 1260, 1261, 1262, 1263, 1264, 1265, 1266, 1267, 1268, 1269, 1270, 1271, 1272, 1273, 1274, 1275, 1276, 1277, 1278, 1279, 1280, 1281, 1282, 1283, 1284, 1285, 1286, 1 , 1244, 1246, 1248, 1250, 1252, 1254, 1256, 1258, 1260, 1262, 1264, 1266, 1268, 1270, 1272, 1274, 1276, 1278, 1280, 1282, 1284, 1286, 1288, 1290, 1292, 1294, 1296, 1298, or 1300).

[0108] In certain embodiments, the disclosure provides a method for the production of a nucleotide sequence comprising a sequence set forth in Table A, B, C, or D (e.g., SEQ ID NOs: 1179, 1181, 1183, 1185, 1187, 1189, 1191, 1193, 1195, 1197, 1199, 1201, 1203, 1205, 1207, 1209, 1211, 1213, 1215, 1217, 1219, 1221, 1223, 1225, 1227, 1229, 1231, 1233, 1235, 1237, 1239, 1241, 1243, 1245, 1247, 1249, 1251, 1253, 1255, 1257, 1259, 1261, 1263, 1265, 1267, 1269, 1271, 1273, 1275, 1277, 1279, 1281, 1283, 1285, 1287, 1289, 1291, 1293, 1295, 1297, 1299, or 1301) are described. In certain embodiments, the present disclosure provides a method for the production of a nucleotide sequence of a nucleotide sequence set forth in Table A, B, C, or D (e.g., SEQ ID NOs: 1178, 1180, 1182, 1184, 1186, 1188, 1190, 1192, 1194, 1196, 1198, 1200, 1202, 1204, 1206, 1208, 1210, 1212, 1214, 1216, 1218, 1220, 1222, 1224, 1226, 1228, 1230, 1232, 1234, 1236, 1238, 1240, 1242, 1243, 1244, 1245, 1246, 1247, 1248, 1249, 1250, 1251, 1252, 1253, 1254, 1255, 1256, 1257, 1258, 1259, 1260, 1261, 1262, 1263, 1264, 1265, 1266, 1267, 1268, 1269, 1270, 1271, 1272, 1273, 1274, 1275, 1276, 1277, 1278, 1279, 1280, 1281, 1282, 1283, 1284, 1285, 1286, 1 , 1244, 1246, 1248, 1250, 1252, 1254, 1256, 1258, 1260, 1262, 1264, 1266, 1268, 1270, 1272, 1274, 1276, 1278, 1280, 1282, 1284, 1286, 1288, 1290, 1292, 1294, 1296, 1298, or 1300).

[0109] In certain embodiments, the disclosure provides a method for the production of a nucleotide sequence comprising a sequence set forth in Table A, B, C, or D (e.g., SEQ ID NOs: 1179, 1181, 1183, 1185, 1187, 1189, 1191, 1193, 1195, 1197, 1199, 1201, 1203, 1205, 1207, 1209, 1211, 1213, 1215, 1217, 1219, 1221, 1223, 1225, 1227, 1229, 1231, 1233, 1235, 1237, 1239, 1241, 1243, 1245, 1247, 1249, 1251, 1253, 1255, 1257, 1259, 1261, 1263, 1265, 1267, 1269, 1271, 1273, 1275, 1277, 1279, 1281, 1283, 1285, 1287, 1289, 1291, 1293, 1295, 1297, 1299, or 1301) are described.

[0110] In some embodiments, RNAi oligonucleotides for reducing or inhibiting PNPLA3 expression are described, comprising an antisense strand and a sense strand, wherein the antisense strand has a sequence set forth in Table A, Table B, Table C, or Table D, and the sense strand has a sequence set forth in Table A, Table B, Table C, or Table D.

[0111] In some examples, the RNAi oligonucleotides are selected from the group consisting of nucleotide sequences set forth in Table A, Table B, Table C, or Table D, particularly SEQ ID NOs: 1178, 1180, 1182, 1184, 1186, 1188, 1190, 1192, 1194, 1196, 1198, 1200, 1202, 1204, 1206, 1208, 1210, 1212, 1214, 1216, 1218, 1220, 1222, 1224, 1226, 1228, 1230, 1231, 1232, 1233, 1234, 1235, 1236, 1237, 1238, 1239, 1240, 1241, 1242, 1243, 1244, 1245, 1246, 1247, 1248, 1249, 1250, 1251, 1252, 1253, 1254, 1255, 1256, 1257, 1258, 1259, 1260, 1261, 1262, 1263, 1264, 1265, 1266, 1267, 1268, 1269, 1270, 1271, 1272, 1273, 1274, 1275, 1276, 1277, 1278, 1279, 1280, 1281, 1234, 1236, 1238, 1240, 1242, 1244, 1246, 1248, 1250, 1252, 1254, 1256, 1258, 1260, 1262, 1264, 1266, 1268, 1270, 1272, 1274, 1276, 1278, 1280, 1282, 1284, 1286, 1288, 1290, 1292, 1294, 1296, 1298, or 1300. In some examples, the RNAi oligonucleotides are selected from the group consisting of nucleotide sequences set forth in Table A, Table B, Table C, or Table D, particularly SEQ ID NOs: 1179, 1181, 1183, 1185, 1187, 1189, 1191, 1193, 1195, 1197, 1199, 1202, 1203, 1205, 1207, 1209, 1211, 1213, 1215, 1217, 1219, 1221, 1223, 1225, 1227, 1229, 1231, 1232, 1233, 1234, 1235, 1236, 1237, 1238, 1239, 1240, 1241, 1242, 1243, 1244, 1245, 1246, 1247, 1248, 1249, 1250, 1251, 1252, 1253, 1254, 1255, 1256, 1257, 1258, 1259, 1260, 1261, 1262, 1263, 1264, 1265, 1266, 1267, 1268, 1269, 1270, 1271, 1272, 1273, 1274, 1275, 1276, 1277, 1278, 1279, 1280, 1281, 1282, 1235, 1237, 1239, 1241, 1243, 1245, 1247, 1249, 1251, 1253, 1255, 1257, 1259, 1261, 1263, 1265, 1267, 1269, 1271, 1273, 1275, 1277, 1279, 1281, 1283, 1285, 1287, 1289, 1291, 1293, 1295, 1297, 1299, or 1301.In particular examples, the RNAi oligonucleotides are selected from the group consisting of SEQ ID NOs: 1178, 1180, 1182, 1184, 1186, 1188, 1190, 1192, 1194, 1196, 1198, 1200, 1202, 1204, 1206, 1208, 1210, 1212, 1214, 1216, 1218, 1220, 1222, 1224, 1226, 1228, 1230, 1232, 1234, 1236, 1238, 1239, 1240, 1241, 1242, 1243, 1244, 1245, 1246, 1247, 1248, 1249, 1250, 1251, 1252, 1253, 1254, 1255, 1256, 1257, 1258, 1259, 1260, 1261, 1262, 1263, 1264, 1265, 1266, 1267, 1268, 1269, 1270, 1271, 1272, 1273, 1274, 1275, 1276, 1277, 1278, 1279, 1280, 1281, 1282, 1283, 1284, 1285, 1286, 1287, 1288, 1 1270, 1272, 1274, 1276, 1278, 1280, 1282, 1284, 1286, 1288, 1290, 1292, 1294, 1296, 1298, or 1300 nucleotide sequences. and the sense strand of SEQ ID NOs: 1179, 1181, 1183, 1185, 1187, 1189, 1191, 1193, 1195, 1197, 1199, 1201, 1203, 1205, 1207, 1209, 1211, 1213, 1215, 1217, 1219, 1221, 1223, 1225, 1227, 1229, 1231, 1233, 1235, 1237, 1239, 1241, 1243, 1 and an antisense strand having any one of the nucleotide sequences of 245, 1247, 1249, 1251, 1253, 1255, 1257, 1259, 1261, 1263, 1265, 1267, 1269, 1271, 1273, 1275, 1277, 1279, 1281, 1283, 1285, 1287, 1289, 1291, 1293, 1295, 1297, 1299, or 1301.

[0112] In particular examples, the RNAi oligonucleotide has the nucleotide sequence of any one of SEQ ID NOs: 1188, 1190, 1200, 1216, 1218, 1220, 1224, 1230, 1232, 1234, 1244, 1246, 1250, 1254, 1262, 1288, 1290, 1292, 1294, 1296, 1298, or 1300. and an antisense strand having the nucleotide sequence of any one of SEQ ID NOs: 1189, 1191, 1201, 1215, 1217, 1221, 1225, 1231, 1233, 1235, 1245, 1247, 1251, 1255, 1263, 1289, 1291, 1295, 1297, 1299, or 1301.

[0113] In particular examples, the RNAi oligonucleotide comprises a sense strand having the nucleotide sequence of any one of SEQ ID NOs: 1188, 1190, 1220, 1224, 1230, 1232, 1244, 1246, 1250, or 1254, and an antisense strand having the nucleotide sequence of any one of SEQ ID NOs: 1189, 1191, 1221, 1225, 1231, 1233, 1245, 1247, 1251, or 1255.

[0114] In particular examples, the sense and antisense strands of the RNAi oligonucleotide are each selected from the following: (a) SEQ ID NOs: 1220 and 1221; (b) SEQ ID NOs: 1224 and 1225; (c) SEQ ID NOs: 1230 and 1231; (d) SEQ ID NOs: 1232 and 1233; (e) SEQ ID NOs: 1188 and 1189; (f) SEQ ID NOs: 1190 and 1191; (g) SEQ ID NOs: 1244 and 1245; (h) SEQ ID NOs: 1250 and 1251-, (i) SEQ ID NOs: 1254 and 1255, and (j) SEQ ID NOs: 1246 and 1247.

[0115] Those skilled in the art will understand that in some instances, the sequences shown in the sequence listing are referenced to describe the structure of an oligonucleotide (e.g., a ds oligonucleotide) or other nucleic acid. In such instances, the actual oligonucleotide or other nucleic acid retains essentially the same or similar complementary properties as the described sequence, but has one or more alternative nucleotides (e.g., RNA counterparts of DNA nucleotides or DNA counterparts of RNA nucleotides) and / or one or more modified nucleotides and / or one or more modified internucleotide linkages and / or one or more other modifications compared to the described sequence.

[0116] In some embodiments, the ds oligonucleotide herein comprises a sense strand of 25 nucleotides and a 27 nucleotide antisense strand, which is acted upon by Dicer enzyme to generate the antisense strand that is incorporated into mature RISC.In certain examples, the sense strand of ds oligonucleotide is longer than 27 nucleotides (for example, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 nucleotides).In certain examples, the sense strand of ds oligonucleotide is longer than 25 nucleotides (for example, 26, 27, 28, 29 or 30 nucleotides).

[0117] In some examples, one 5' end of a ds oligonucleotide herein is less thermodynamically stable than the other 5' end. In some embodiments, the ds oligonucleotide is asymmetric, comprising a blunt end at the 3' end of the sense strand and a 3' overhang at the 3' end of the antisense strand. In some embodiments, the 3' overhang on the antisense strand is about 1 to about 8 nucleotides in length (e.g., 1, 2, 3, 4, 5, 6, 7, or 8 nucleotides in length). Typically, RNAi ds oligonucleotides have a 2-nucleotide overhang at the 3' end of the antisense (guide) strand. However, other overhangs are possible. In some embodiments, the overhang is about 1 to about 6 nucleotides in length, optionally 1-5, 1-4, 1-3, 1-2, 2-6, 2-5, 2-4, 2-3, 3-6, 3-5, 3-4, 4-6, 4-5, 5-6 nucleotides, or 1, 2, 3, 4, 5, or 6 nucleotides in length. However, in other examples, the overhang is a 5' overhang comprising a length of about 1 to about 6 nucleotides, optionally 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 6, 3 to 5, 3 to 4, 4 to 6, 4 to 5, 5 to 6 nucleotides, or 1, 2, 3, 4, 5, or 6 nucleotides.

[0118] In some examples, the two terminal nucleotides at the 3' end of the antisense strand are modified.In some examples, the two terminal nucleotides at the 3' end of the antisense strand are complementary to target mRNA (for example, PNPLA3 mRNA).In other examples, the two terminal nucleotides at the 3' end of the antisense strand are not complementary to target mRNA.In some examples, the two terminal nucleotides at each 3' end of the oligonucleotide in the nicked tetraloop structure are GG.Usually, one or both of the two terminal GG nucleotides at each 3' end of the ds oligonucleotide are not complementary to target mRNA.

[0119] In some examples, there are one or more (e.g., one, two, three, four, or five) mismatch(es) between the sense strand and the antisense strand. When there are two or more mismatches between the sense strand and the antisense strand, they may be arranged consecutively (e.g., two, three, or more consecutively) or may be scattered throughout the complementary region. In some examples, the 3' end of the sense strand contains one or more mismatches. In certain examples, two mismatches are incorporated into the 3' end of the sense strand. In some examples, destabilizing a base mismatch or segment at the 3' end of the sense strand of the oligonucleotide improves or increases the efficacy of the ds oligonucleotide.

[0120] A. Antisense Strand: Oligonucleotides (e.g., ds oligonucleotides) herein for targeting PNPLA3 mRNA and inhibiting PNPLA3 expression include antisense strands comprising sequences set forth in Table 1 or Table 3, or the antisense strands of Tables A, B, C, or D. In some examples, the oligonucleotide comprises an antisense strand having at least about 12 (e.g., at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23) consecutive nucleotides of the sequence set forth in any one of SEQ ID NOs: 788, 844, 868, 872, 938, 1004, 1008, 1018, 1162, or 1164, or an antisense strand having the nucleotide sequence of any one of SEQ ID NOs: 1189, 1191, 1221, 1225, 1231, 1233, 1245, 1247, 1251, or 1255.

[0121] Furthermore, oligonucleotides (e.g., ds oligonucleotides) herein can comprise an antisense strand up to about 40 nucleotides in length (e.g., up to 40, up to 35, up to 30, up to 27, up to 25, up to 21, up to 19, up to 17, or up to 12 nucleotides in length). In some examples, oligonucleotides can have an antisense strand at least about 12 nucleotides in length (e.g., at least 12, at least 15, at least 19, at least 21, at least 22, at least 25, at least 27, at least 30, at least 35, or at least 38 nucleotides in length). Alternatively, the oligonucleotide may have an antisense strand ranging from about 12 to about 40 nucleotides in length (e.g., 12-40, 12-36, 12-32, 12-28, 15-40, 15-36, 15-32, 15-28, 17-22, 17-25, 19-27, 19-30, 20-40, 22-40, 25-40, or 32-40). In particular examples, the oligonucleotide may have an antisense strand that is 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 nucleotides in length.

[0122] As mentioned above, the antisense strand of the oligonucleotide herein may be referred to as " guide strand ".For example, the antisense strand that is incorporated into RISC and binds to Argonaute protein, such as Ago2, or that is incorporated into or binds to one or more similar factors, and induces the silencing of target gene, is referred to as guide strand (or passenger strand).

[0123] B. Sense Strand: Oligonucleotides (e.g., ds oligonucleotides) herein for targeting PNPLA3 mRNA and inhibiting PNPLA3 expression comprise a sense strand sequence that includes a sequence set forth in Table 1 or Table 3, or the sense strand of Table A, B, C, or D. In some examples, the oligonucleotide comprises a sense strand having at least about 12 (e.g., at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23) consecutive nucleotides of a sequence set forth in any one of SEQ ID NOs: 787, 843, 867, 871, 937, 1003, 1007, 1017, 1161, or 1163.

[0124] Additionally, oligonucleotides herein (e.g., ds oligonucleotides) comprise a sense strand (or passenger strand) up to about 40 nucleotides in length (e.g., up to 40, up to 36, up to 30, up to 27, up to 25, up to 21, up to 19, up to 17, or up to 12 nucleotides in length). In some examples, oligonucleotides can have a sense strand at least about 12 nucleotides in length (e.g., at least 12, at least 15, at least 19, at least 21, at least 25, at least 27, at least 30, at least 36, or at least 38 nucleotides in length). Alternatively, the oligonucleotides can have a sense strand ranging from about 12 to about 40 nucleotides in length (e.g., 12-40, 12-36, 12-32, 12-28, 15-40, 15-36, 15-32, 15-28, 17-21, 17-25, 19-27, 19-30, 20-40, 22-40, 25-40, or 32-40). In particular examples, the oligonucleotides can have a sense strand that is 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 nucleotides in length.

[0125] In some embodiments, the sense strand comprises a stem-loop structure at its 3'-end. In other embodiments, the sense strand comprises a stem-loop structure at its 5'-end. In additional embodiments, the stem is a duplex about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 bp in length. In some embodiments, the stem-loop protects the oligonucleotide from degradation (e.g., enzymatic degradation) and facilitates or improves targeting and / or delivery to target cells, tissues, or organs (e.g., the liver), or both. For example, the loop of the stem-loop provides nucleotides with one or more modifications that facilitate, improve, or increase targeting to a target mRNA (e.g., PNPLA3 mRNA), inhibition of target gene expression (e.g., PNPLA3 expression), and / or delivery to a target cell, tissue, or organ (e.g., the liver), or both. In some embodiments, the stem-loop itself or modification(s) to the stem-loop do not substantially affect the intrinsic gene expression inhibitory activity of the oligonucleotide, but facilitate, improve, or increase stability (e.g., providing protection against degradation) and / or delivery of the oligonucleotide to target cells, tissues, or organs (e.g., the liver). In certain embodiments, the oligonucleotide comprises a sense strand comprising (e.g., at its 3' end) a stem-loop designated as S1-L-S2, where S1 is complementary to S2 and L forms a single-stranded loop between S1 and S2 up to about 10 nucleotides in length (e.g., 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides in length). In certain embodiments, the loop (L) is 4 nucleotides in length. Figures 1 and 2 depict non-limiting examples of such oligonucleotides. In some embodiments, the loop (L) of the stem-loop having the structure S1-L-S2 described above is a tetraloop (e.g., within a nicked tetraloop structure). In some embodiments, the tetraloop comprises a ribonucleotide, a deoxyribonucleotide, a modified nucleotide, a delivery ligand, and combinations thereof.

[0126] V. Oligonucleotide Modifications

[0127] A. Sugar Modifications: Modified sugars (also referred to herein as sugar analogs) include, for example, modified deoxyribose or ribose moieties in which one or more modifications occur at the 2', 3', 4', and / or 5' carbon positions of the sugar. Modified sugars can also include unnatural alternative carbon structures, such as those present in locked nucleic acids ("LNAs"; see, e.g., Koshkin et al. (1998) Tetrahedon 54:3607-3630), unlocked nucleic acids ("UNAs"; see, e.g., Snead et al. (2013) Mol. Ther-Nuc. Acids 2:e103), and bridged nucleic acids ("BNAs"; see, e.g., Imanishi & Obika (2002) Chem. Commun. 16:1653-1659).

[0128] In some embodiments, the modification of the nucleotide at the sugar is a 2'-modification, such as 2'-O-propargyl, 2'-O-propylamine, 2'-amino, 2'-ethyl, 2'-fluoro (2'-F), 2'-aminoethyl (EA), 2'-O-methyl (2'-OMe), 2'-O-methoxyethyl (2'-MOE), 2'-O-[2-(methylamino)-2-oxoethyl] (2'-O-NMA), or 2'-deoxy-2'-fluoro-β-d-arabinonucleic acid (2'-FANA). In certain embodiments, the modification is 2'-F, 2'-OMe, or 2'-MOE. In other embodiments, the modification at the sugar is a modification of the sugar ring, including modification of one or more carbons of the sugar ring. For example, the modification on the sugar is the 2'-oxygen of the sugar linked to the 1'-carbon or 4'-carbon of the sugar, or the 2'-oxygen attached to the 1'-carbon or 4'-carbon via an ethylene or methylene bridge. In other embodiments, the modification is an acyclic sugar lacking a bond between the 2'-carbon and the 3'-carbon. In other embodiments, the modification is a thiol group, such as a thiol group at the 4' position of the sugar.

[0129] The oligonucleotides herein comprise at least one (e.g., at least 1, at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, or more) modified nucleotide. In some embodiments, the sense strand comprises at least one (e.g., at least 1, at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, or more) modified nucleotide. In some embodiments, the antisense strand comprises at least one (e.g., at least 1, at least 5, at least 10, at least 15, at least 20, or more) modified nucleotide.

[0130] In certain embodiments, all nucleotides in the sense strand are modified. Similarly, all nucleotides in the antisense strand are modified. In some embodiments, all nucleotides in the oligonucleotides herein (i.e., both the sense and antisense strands) are modified. As described above, in some embodiments, the modified nucleotides are 2'-modified (e.g., 2'-F, 2'-OMe, 2'-MOE, and / or 2'-deoxy-2'-fluoro-β-d-arabinonucleic acid). In certain embodiments, the modified nucleotides are 2'-modified, such as 2'-F or 2'-OMe.

[0131] Additionally, the oligonucleotides herein have different modification patterns. In some embodiments, a modified oligonucleotide comprises an antisense strand having a modification pattern set forth in any one of Tables A, B, C, or D, and a sense strand sequence having a modification pattern set forth in any one of Tables A, B, C, or D (and FIG. 1). In some embodiments, one or more of positions 8, 9, 10, or 11 of the sense strand are modified with 2'-F. In other embodiments, the sugar moieties of each of the nucleotides at positions 1-7 and 12-20 of the sense strand are modified with 2'-OMe.

[0132] In some embodiments, the antisense strand comprises three nucleotides modified with 2'-F at the 2'-position of the sugar moiety. In some embodiments, the sugar moieties at positions 2, 5, and 14 of the antisense strand, and optionally up to three nucleotides at positions 1, 3, 7, and 10, are modified with 2'-F. In other embodiments, the sugar moieties at positions 2, 5, and 14 of the antisense strand are modified with 2'-F. In other embodiments, the sugar moieties at positions 1, 2, 5, and 14 of the antisense strand are modified with 2'-F. In yet other examples, the sugar moieties at positions 1, 2, 3, 5, 7, and 14 of the antisense strand are modified with 2'-F. In yet other embodiments, the sugar moieties at positions 1, 2, 3, 5, 10, and 14 of the antisense strand are modified with 2'-F. In yet other embodiments, the sugar moieties at positions 2, 3, 5, 7, 10, and 14 of the antisense strand are modified with 2'-F.

[0133] B. 5'-Terminal Phosphate: A 5'-terminal phosphate group can be used to promote the interaction of the oligonucleotides herein with Ago2. However, oligonucleotides with a 5'-phosphate group are susceptible to degradation by phosphatases or other enzymes, potentially limiting their bioavailability in vivo. In some embodiments, the oligonucleotide (e.g., a ds oligonucleotide) contains a 5'-phosphate analog that is resistant to such degradation. Examples of such phosphate analogs include, but are not limited to, oxymethylphosphonate, vinylphosphonate, malonylphosphonate, or combinations thereof. In certain embodiments, the 3'-end of the oligonucleotide chain is conjugated to a chemical moiety (a "phosphate mimetic") that mimics the electrostatic and steric properties of the natural 5'-phosphate group.

[0134] Alternatively, or in addition, the oligonucleotides herein have a phosphate analog at the 4' carbon of the sugar (referred to as a "4'-phosphate analog"). See, for example, International Patent Application Publication No. WO2018 / 045317. In some embodiments, the oligonucleotides herein include a 4'-phosphate analog at the 5'-terminal nucleotide. In some embodiments, the phosphate analog is an oxymethylphosphonate, or an analog thereof, in which the oxygen atom of the oxymethyl group is attached to the sugar moiety (e.g., at its 4'-carbon). In other embodiments, the 4'-phosphate analog is a thiomethylphosphonate or aminomethylphosphonate, or an analog thereof, in which the sulfur atom of the thiomethyl group or the nitrogen atom of the aminomethyl group is attached to the 4'-carbon of the sugar moiety. In certain embodiments, the 4'-phosphate analog is an oxymethylphosphonate and is represented by the formula -O-CH-PO(OH) or -O-CH-PO(OR), where R is independently selected from H, CH, an alkyl group, CHCHCN, CHOCOC(CH), CHOCHCHSi(CH), or a protecting group. In certain embodiments, the alkyl group is CHCH. In certain other embodiments, R is independently selected from H, CH, or CHCH.

[0135] C. Modified Internucleoside Linkages: In addition to the modifications described above, the oligonucleotides herein contain modified internucleoside linkages. In some examples, phosphate modification or substitution results in an oligonucleotide containing at least one (e.g., at least 1, at least 2, at least 3, or at least 5) modified internucleoside linkage. In some embodiments, the oligonucleotide contains from about 1 to about 10 (e.g., 1-10, 2-8, 4-6, 3-10, 5-10, 1-5, 1-3, or 1-2) modified internucleoside linkages. In certain additional embodiments, the oligonucleotide contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 modified internucleoside linkages.

[0136] The example of modified internucleotide bond includes but is not limited to phosphorodithioate bond, phosphorothioate bond, phosphotriester bond, thionoalkylphosphonate bond, thionealkylphosphotriester bond, phosphoramidite bond, phosphonate bond or boranophosphate bond.In some embodiments, at least one modified internucleotide bond of any one of the oligonucleotides disclosed herein is phosphorothioate bond.

[0137] In some embodiments, the oligonucleotides herein comprise a phosphorothioate linkage between one or more of positions 1 and 2 of the sense strand, positions 1 and 2 of the antisense strand, positions 2 and 3 of the antisense strand, positions 3 and 4 of the antisense strand, positions 20 and 21 of the antisense strand, and positions 21 and 22 of the antisense strand. In other embodiments, the oligonucleotides comprise a phosphorothioate linkage between each of positions 1 and 2 of the sense strand, positions 1 and 2 of the antisense strand, positions 2 and 3 of the antisense strand, positions 20 and 21 of the antisense strand, and positions 21 and 22 of the antisense strand.

[0138] D. Base Modification: In addition to the modifications described above, the oligonucleotides herein also contain one or more modified nucleobases. In some embodiments, the modified nucleobase (also referred to herein as a base analog) is attached to the 1'-position of the nucleotide sugar moiety. In certain embodiments, the modified nucleobase is a nitrogenous base. In certain other embodiments, the modified nucleobase does not contain a nitrogen atom. See, for example, U.S. Patent Application Publication No. 2008 / 0274462. In some embodiments, the modified nucleotide is a universal base. However, in certain embodiments, the modified nucleotide does not contain a nucleobase (abasic).

[0139] With respect to universal bases, a universal base comprises a heterocyclic moiety located at the 1' position of a nucleotide sugar moiety of a modified nucleotide, or at the equivalent position of a nucleotide sugar moiety substitute, and when present in a duplex, is arranged to pair with multiple types of bases without substantially altering the structure of the duplex. Furthermore, compared to a reference ss nucleic acid (e.g., an oligonucleotide) that is perfectly complementary to a target nucleic acid, a ss nucleic acid having a universal base has a lower T than a duplex formed with a complementary nucleic acid. m However, compared to a reference ss nucleic acid in which the universal base is replaced with a base resulting in one mismatch, the ss nucleic acid with the universal base has a higher T than the duplex formed with the nucleic acid having the mismatched base. m It forms a duplex with a target nucleic acid having the formula:

[0140] Exemplary universal-binding nucleotides include, but are not limited to, inosine, 1-β-D-ribofuranosyl-5-nitroindole, and / or 1-β-D-ribofuranosyl-3-nitropyrrole (see, e.g., U.S. Patent Application Publication No. 2007 / 0254362; Van Aerschot et al. (1995) Nucleic Acids Res. 23:4363-70; Loakes et al. (1995) Nucleic Acids Res. 23:2361-66; and Loakes & Brown (1994) Nucleic Acids Res. 22:4039-43).

[0141] E. Reversible Modifications: While certain modifications can be made to the oligonucleotides herein to protect them from the in vivo environment before they reach the target cell, these modifications may also reduce the efficacy or activity of the oligonucleotides once they reach the cytosol of the target cell. Thus, reversible modifications can be made that allow the molecule to retain the desired properties outside the cell, and then be removed once it enters the cytosolic environment of the cell. Reversible modifications can be removed, for example, by the action of intracellular enzymes or by chemical conditions inside the cell (e.g., through reduction by intracellular glutathione).

[0142] In some embodiments, the reversibly modified nucleotide comprises a glutathione-sensitive moiety. Typically, nucleic acid molecules are chemically modified with a cyclic disulfide moiety to shield the negative charge caused by the internucleotide diphosphate bond and improve cellular uptake and nuclease resistance. See U.S. Patent Application Publication No. 2011 / 0294869, International Patent Application Publication No. WO2014 / 088920, and International Patent Application Publication No. WO2015 / 188197, and Meade et al. (2014) Nat. Biotechnol. 32:1256-1263. This reversible modification of the internucleotide diphosphate bond is designed to be cleaved intracellularly by the reducing environment of the cytosol (e.g., glutathione). Earlier examples include neutralizing phosphotriester modifications, which have been reported to be cleavable inside cells (see, e.g., Dellinger et al. (2003) J. Am. Chem. Soc. 125:940-50).

[0143] Such reversible modifications protect the oligonucleotide during in vivo administration (e.g., passage through the blood and / or lysosomal / endosomal compartments of cells), which exposes the oligonucleotide to nucleases and other harsh environmental conditions (e.g., pH). Upon release into the cytosol of cells, where glutathione levels are higher compared to the extracellular space, the modification is reversed, resulting in cleavage of the oligonucleotide. The use of reversible glutathione-sensitive moieties allows for the introduction of sterically larger chemical groups into oligonucleotides compared to options available using irreversible chemical modifications. This means that these larger chemical groups will be removed in the cytosol, and therefore should not interfere with the biological activity of the oligonucleotide within the cytosol of cells. As a result, these larger chemical groups can be engineered to confer various advantages on the oligonucleotide, such as nuclease resistance, lipophilicity, charge, thermal stability, specificity, and reduced immunogenicity. In some instances, the structure of the glutathione-sensitive moiety can be manipulated to alter its release kinetics.

[0144] In some embodiments, the glutathione-sensitive moiety is attached to the sugar of the nucleotide. In certain embodiments, the glutathione-sensitive moiety is attached to the 2'-carbon of the sugar of the modified nucleotide. Additionally or alternatively, the glutathione-sensitive moiety is attached to the 5'-carbon of the sugar, particularly when the modified nucleotide is the 5'-terminal nucleotide of the oligonucleotide. Additionally or alternatively, the glutathione-sensitive moiety is attached to the 3'-carbon of the sugar, particularly when the modified nucleotide is the 3'-terminal nucleotide of the oligonucleotide. In some embodiments, the glutathione-sensitive moiety comprises a sulfonyl group (see, e.g., International Patent Application Publication No. WO2018 / 039364).

[0145] VI. Targeting Ligands

[0146] It is desirable to target the oligonucleotides herein to one or more cells or one or more organs. Such a strategy can be useful to avoid undesirable effects in other organs or to avoid excessive loss of the oligonucleotide to cells, tissues, or organs that do not benefit from the oligonucleotide. Thus, the oligonucleotide can be modified to facilitate targeting and / or delivery to a tissue, cell, or organ (e.g., to facilitate delivery of the oligonucleotide to the liver). In some embodiments, the oligonucleotide is modified to facilitate delivery of the oligonucleotide to hepatocytes in the liver. In certain embodiments, the oligonucleotide comprises at least one nucleotide (e.g., 1, 2, 3, 4, 5, 6, or more nucleotides) conjugated to one or more targeting ligand(s).

[0147] Exemplary targeting ligands include, but are not limited to, carbohydrates, amino sugars, cholesterol, peptides, polypeptides, proteins or protein parts (for example, antibodies or antibody fragments), or lipids.In some embodiments, targeting ligand is aptamer.For example, targeting ligand is RGD peptide for targeting tumor vasculature or glioma cells, CREKA peptide for targeting tumor vasculature or tumor stroma, transferrin, lactoferrin or aptamer for targeting transferrin receptor expressed on CNS vasculature, or anti-EGFR antibody for targeting EGFR on glioma cells.In certain embodiments, targeting ligand is one or more GalNAc moieties.

[0148] In some embodiments, one or more (e.g., 1, 2, 3, 4, 5, or 6) nucleotides of an oligonucleotide can each be conjugated to a separate targeting ligand. In some embodiments, 2 to 4 nucleotides of an oligonucleotide are each conjugated to a separate targeting ligand. In some embodiments, a targeting ligand can be conjugated to 2 to 4 nucleotides at either the sense or antisense strand (e.g., a targeting ligand is conjugated to a 2 to 4 nucleotide overhang or extension at the 5' or 3' end of the sense or antisense strand), resulting in a targeting ligand resembling toothbrush bristles and an oligonucleotide resembling a toothbrush. For example, an oligonucleotide can include a stem loop at either the 5' or 3' end of the sense strand, and 1, 2, 3, or 4 nucleotides of the stem loop can be individually conjugated to a targeting ligand. In some embodiments, the oligonucleotide (e.g., a ds oligonucleotide) comprises a stem-loop at the 3' end of the sense strand, the loop of the stem-loop comprises a tri-loop or a tetra-loop, and each of the three or four nucleotides of the tri-loop or tetra-loop is individually conjugated to a targeting ligand.

[0149] GalNAc is a high-affinity ligand for ASGPR, which is primarily expressed on the sinusoidal surface of hepatocytes, and plays a major role in the binding, internalization, and subsequent excretion of circulating glycoproteins containing terminal galactose or GalNAc residues (asialoglycoproteins). Conjugation (either indirectly or directly) of a GalNAc moiety to an oligonucleotide herein is used to target the oligonucleotide to an ASGPR expressed on cells. In some embodiments, the oligonucleotide is conjugated to at least one or more GalNAc moieties, and the GalNAc moiety targets the oligonucleotide to an ASGPR expressed on human liver cells (e.g., human hepatocytes).

[0150] Oligonucleotide is directly or indirectly conjugated to monovalent GalNAc.In some embodiments, oligonucleotide is directly or indirectly conjugated to two or more monovalent GalNAc (i.e., conjugated to two, three or four monovalent GalNAc moieties, typically conjugated to three or four monovalent GalNAc moieties).In some embodiments, oligonucleotide is conjugated to one or more divalent GalNAc, trivalent GalNAc or tetravalent GalNAc moieties.

[0151] In some embodiments, one or more (e.g., 1, 2, 3, 4, 5, or 6) nucleotides of the oligonucleotides herein can each be conjugated to a GalNAc moiety. In some embodiments, 2-4 nucleotides of a tetraloop are each conjugated to a distinct GalNAc. In other embodiments, 1-3 nucleotides of a triloop are each conjugated to a distinct GalNAc. In some embodiments, a targeting ligand is conjugated to 2-4 nucleotides at either the sense or antisense strand's end (e.g., the ligand is conjugated to a 2-4 nucleotide overhang or extension at the 5' or 3' end of the sense or antisense strand), resulting in GalNAc moieties resembling toothbrush bristles and giving the oligonucleotide a toothbrush-like appearance. In some embodiments, GalNAc moieties are conjugated to nucleotides of the sense strand. For example, four GalNAc moieties are conjugated to nucleotides within the tetraloop of the sense strand, with each GalNAc moiety being conjugated to one nucleotide. In certain embodiments, three GalNAc moieties are conjugated to nucleotides within the tetraloop of the sense strand, with each GalNAc moiety being conjugated to one nucleotide.

[0152] In certain embodiments, the oligonucleotide comprises a monovalent GalNAc attached to a guanine nucleotide, designated as [ademG-GalNAc] or 2'-aminodiethoxymethanol-guanine-GalNAc, as shown below. [ka]

[0153] In certain embodiments, the oligonucleotides herein comprise a monovalent GalNAc attached to an adenine nucleotide, designated as [ademA-GalNAc] or 2'-aminodiethoxymethanol-adenine-GalNAc, as shown below. [ka]

[0154] An example of such a conjugation is shown below for a loop having the nucleotide sequence GAAA in the 5' to 3' direction (L = linker, X = heteroatom), where the stem attachment point is indicated. Such a loop can be found, for example, at positions 27-30 of the sense strand listed in Table 3, A, B, C, or D, and shown in Figure 1. [ka] is used to represent the point of attachment to the oligonucleotide chain. [ka]

[0155] The targeting ligand is attached to the nucleotide using an appropriate method or chemical approach (e.g., click chemistry). One method of conjugating the targeting ligand to the nucleotide is by using a click linker. In some embodiments, the targeting ligand is conjugated to any one of the nucleotides of the oligonucleotides herein using an acetal-based linker. Acetal-based linkers are disclosed, for example, in International Patent Application Publication No. WO2016 / 100401. In some examples, the linker is a labile linker. However, in other examples, the linker is stable. An example of a loop having the nucleotides GAAA in the 5' to 3' direction, in which a GalNAc moiety is attached to the nucleotide of the loop using an acetal linker, is shown below. Such a loop can be found, for example, at positions 27-30 of any one of the sense strands listed in Table 3, A, B, C, or D. In the chemical formula: [ka] is the point of attachment to the oligonucleotide chain. [ka]

[0156] In some embodiments, a duplex extension (e.g., up to 3, 4, 5, or 6 bp in length) is provided between the targeting ligand (e.g., the GalNAc moiety) and the oligonucleotide (e.g., the ds oligonucleotide) herein. In other embodiments, the oligonucleotide does not have a GalNAc conjugated thereto.

[0157] Formulations and Pharmaceutical Compositions

[0158] The oligonucleotides herein are incorporated into formulations or pharmaceutical compositions. Various formulations have been developed to facilitate the use of oligonucleotides. For example, oligonucleotides can be delivered to a subject or cellular environment using formulations that minimize degradation, facilitate delivery and / or uptake, or impart other beneficial properties to the oligonucleotides in the formulation. In some embodiments, oligonucleotides are formulated in buffers such as phosphate-buffered saline, liposomes, micellar structures, and capsids.

[0159] Oligonucleotide formulations containing cationic lipids can be used to facilitate the transfection of oligonucleotides into cells. For example, cationic lipids such as lipofectin, cationic glycerol derivatives, and polycationic molecules (e.g., polylysine) can be used. Suitable lipids include oligofectamine, lipofectamine (Life Technologies), NC388 (Ribozyme Pharmaceuticals, Inc.), or FuGene6 (Roche), all of which are used according to the manufacturer's instructions.

[0160] Thus, in some embodiments, the formulations herein comprise liposomes, lipids, lipid complexes, microspheres, microparticles, nanospheres, or nanoparticles (e.g., lipid nanoparticles), or can be formulated in other forms for administration to the cells, tissues, organs, or body of an individual in need thereof (see, e.g., Remington, "The Science and Practice of Pharmacy" (L.V. Allen Jr., ed., 2002). nd Edition, Pharmaceutical Press, 2013).

[0161] In some embodiments, the formulations herein further comprise an excipient that can impart improved stability, improved absorption, improved solubility, and / or therapeutic enhancement effects of the active ingredient to the composition. In some embodiments, the excipient is a buffer (e.g., sodium citrate, sodium phosphate, Tris base, or sodium hydroxide) or a vehicle (e.g., buffer solution, petrolatum, dimethyl sulfoxide, or mineral oil). In some embodiments, the oligonucleotides herein are lyophilized to extend shelf life and then reconstituted into a solution prior to use (e.g., administration to an individual). Thus, the excipient in a pharmaceutical composition comprising one or more oligonucleotides is a lyoprotectant (e.g., mannitol, lactose, polyethylene glycol, or polyvinylpyrrolidone) or a disintegration temperature modifier (e.g., dextran, Ficoll™, or gelatin).

[0162] A pharmaceutical composition is formulated to be compatible with its intended route of administration, including, but not limited to, parenteral (e.g., intravenous, intramuscular, intraperitoneal, intradermal, and subcutaneous), oral (e.g., inhalation), transdermal (e.g., topical), transmucosal, and rectal administration.

[0163] Pharmaceutical compositions suitable for injection include sterile aqueous solutions (if water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include, but are not limited to, physiological saline, bacteriostatic water, Cremophor EL™ (BASF), or phosphate-buffered saline (PBS). Carriers are solvents or dispersion media containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), and suitable mixtures thereof. In many embodiments, it is preferable to include isotonic agents, such as sugars, polyalcohols (e.g., mannitol, sorbitol, and / or sodium chloride) in the composition. Sterile injectable solutions are prepared by adding the required amount of the oligonucleotides herein to the selected solvent, optionally with one or a combination of the ingredients listed above, followed by filter sterilization.

[0164] Additionally, pharmaceutical compositions contain at least about 0.1% or more of a therapeutic agent (e.g., one or more of the oligonucleotides herein), although the percentage of therapeutic agent may be from about 1% to about 80% or more by weight or volume of the total composition. Factors such as solubility, bioavailability, biological half-life, route of administration, product shelf life, and other pharmacological considerations will be contemplated by those skilled in the art of preparing such pharmaceutical formulations, and therefore, various dosages and treatment regimens may be desirable.

[0165] Some examples are directed to liver-targeted delivery of at least one of the oligonucleotides herein, although targeting of other tissues is also contemplated.

[0166] kit

[0167] The oligonucleotides herein can be incorporated into kits containing one or more oligonucleotides herein and instructions for use. In some embodiments, the kits contain one or more oligonucleotides and a package insert containing instructions for use of the kit and / or any of its components. In other embodiments, the kits contain suitable containers, one or more oligonucleotides, one or more controls, and various buffers, reagents, enzymes, and other standard components known in the art.

[0168] In some embodiments, the container may be at least one vial, well, test tube, flask, bottle, syringe, or other container means into which one or more oligonucleotides are placed, and optionally, appropriately dispensed. In other embodiments in which additional components are provided, the kit includes an additional container into which the component is placed. The kit also includes a means for tightly containing the one or more oligonucleotides and any other reagents for commercial sale. Such containers include injection-molded or blow-molded plastic containers into which the desired vials are retained. The container and / or kit includes a label bearing instructions and / or warnings.

[0169] In some embodiments, the kit comprises one or more of the oligonucleotides herein and a pharmaceutically acceptable carrier, or a pharmaceutical composition comprising one or more oligonucleotides, and instructions for treating or delaying the progression of a disease, disorder, or condition associated with PNPLA3 expression in an individual in need thereof.

[0170] method

[0171] Production method

[0172] The oligonucleotides herein are prepared using methods and / or techniques known to those skilled in the art, such as conventional solid-phase nucleic acid synthesis. The polynucleotides of the oligonucleotides are assembled on a suitable nucleic acid synthesizer using standard nucleotide or nucleoside precursors (e.g., phosphoramidites). Automated nucleic acid synthesizers, such as DNA / RNA synthesizers, are commercially available from, for example, Applied Biosystems (Foster City, CA), BioAutomation (Irving, TX), and GE Healthcare Life Sciences (Pittsburgh, PA).

[0173] As will be appreciated by those skilled in the art, other methods and / or techniques for synthesizing the oligonucleotides herein may be used. Additionally, various synthetic steps may be performed in a different order or sequence to obtain the desired compound. Other synthetic chemical transformations, protecting groups (e.g., hydroxyl, amino, etc. present on bases), and protecting group methodologies (protection and deprotection) useful in the synthesis of oligonucleotides are known in the art and are described, for example, in Larock, "Comprehensive Organic Transformations," VCH Publishers (1989); Greene & Wuts, Protective Groups in Organic Synthesis, 2000; nd Ed., John Wiley & Sons (1991); Fieser & Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley & Sons (1994); and Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley & Sons (1995).

[0174] How to use

[0175] I. Methods of reducing PNPLA3 expression in cells, tissues, organs, and organisms

[0176] The oligonucleotides herein are used to reduce PNPLA3 mRNA in cells, tissues, organs, or individuals. The method includes the steps described herein, which may, but need not necessarily, be performed in the order described. However, other orders are also contemplated. Furthermore, individual or multiple steps may be performed in parallel and / or overlapping in time, and / or repeated individually or multiple times. Furthermore, the method may include additional, unspecified steps.

[0177] The method comprises contacting or delivering an effective amount of any of the oligonucleotides (e.g., ds oligonucleotides) herein to a cell, a cell population, a tissue, an organ, or an individual to reduce PNPLA3 expression. In some embodiments, the reduction in PNPLA3 expression is determined by measuring the amount or level of PNPLA3 mRNA, PNPLA3 protein, or PNPLA3 activity in the cell.

[0178] With regard to suitable cell types, the cell type is any cell that expresses mRNA (e.g., hepatocytes, macrophages, monocyte-derived cells, prostate cancer cells, cells of the brain, endocrine tissue, bone marrow, lymph nodes, lung, gallbladder, liver, duodenum, small intestine, pancreas, kidney, gastrointestinal tract, urinary bladder, adipose and soft tissue, and skin). In some embodiments, the cell is a primary cell obtained from an individual. In some embodiments, the primary cell has undergone a limited number of passages, whereby the cell substantially maintains its native phenotypic characteristics. In some embodiments, the cell is an ex vivo, in vivo, or in vitro cell (i.e., such that one or more oligonucleotides herein can be delivered to a cell in culture or to the organism in which the cell resides).

[0179] In some embodiments, the oligonucleotides herein are delivered to cells or cell populations using nucleic acid delivery methods known in the art, including, but not limited to, injection of a solution containing the oligonucleotides, bombardment with particles coated with the oligonucleotides, exposure of cells or cell populations to a solution containing the oligonucleotides, or electroporation of cell membranes in the presence of the oligonucleotides. Other methods known in the art for delivering oligonucleotides to cells may also be used, such as lipid-mediated carrier transport, chemical-mediated transport, and cationic liposome transfection, such as calcium phosphate.

[0180] The reduction of PNPLA3 expression is determined by assays or techniques that evaluate one or more molecules, characteristics, or features of cells or cell populations related to PNPLA3 expression (e.g., using PNPLA3 expression biomarkers), or by assays or techniques that evaluate molecules that directly indicate PNPLA3 expression in cells or cell populations (e.g., PNPLA3 mRNA or PNPLA3 protein). In some embodiments, the extent to which an oligonucleotide reduces PNPLA3 expression is assessed by comparing the PNPLA3 expression in cells or cell populations contacted with the oligonucleotide with that of a control cell or cell population (e.g., cells or cell populations that have not been contacted with the oligonucleotide or that have been contacted with a control oligonucleotide). In some embodiments, the control amount or level of PNPLA3 expression in a control cell or cell population is predetermined, so that it is not necessary to measure the control amount or level in every case in which the assay or technique is performed. The predetermined level or value can take various forms, including, but not limited to, a single cutoff value, such as a median or mean value.

[0181] Contacting or delivering an oligonucleotide (e.g., a ds oligonucleotide) herein to a cell or cell population reduces PNPLA3 expression. In some embodiments, the reduction in PNPLA3 expression is compared to a control amount or level of PNPLA3 expression in a cell or cell population not contacted with the oligonucleotide or contacted with a control oligonucleotide. In some embodiments, the reduction in PNPLA3 expression is about 1% or less, about 5% or less, about 10% or less, about 15% or less, about 20% or less, about 25% or less, about 30% or less, about 35% or less, about 40% or less, about 45% or less, about 50% or less, about 55% or less, about 60% or less, about 70% or less, about 80% or less, or about 90% or less compared to the control amount or level of PNPLA3 expression. In some embodiments, the control amount or level of PNPLA3 expression is the amount or level of PNPLA3 mRNA and / or PNPLA3 protein in a cell or cell population not contacted with the oligonucleotide herein. In some embodiments, the effect of delivery of an oligonucleotide to a cell or cell population by the methods herein is evaluated after any finite period or period (e.g., minutes, hours, days, weeks, and / or months). For example, PNPLA3 expression is determined in a cell or cell population at least about 4 hours, about 8 hours, about 12 hours, about 18 hours, or about 24 hours. Alternatively, PNPLA3 expression is determined in a cell or cell population at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 21 days, about 28 days, about 35 days, about 42 days, about 49 days, about 56 days, about 63 days, about 70 days, about 77 days, or about 84 days or more after contacting or delivering an oligonucleotide to the cell or cell population. In other embodiments, PNPLA3 expression is determined in the cell or cell population at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months or more after contacting or delivering the oligonucleotide to the cell or cell population.

[0182] In some embodiments, the oligonucleotides herein are delivered in the form of a transgene engineered to express one or more oligonucleotides or strands (e.g., sense and antisense strands) in a cell. For example, the oligonucleotides are delivered using a transgene engineered to express any of the oligonucleotides herein. The transgene can be delivered using a viral vector (e.g., adenovirus, retrovirus, vaccinia virus, poxvirus, adeno-associated virus, or herpes simplex virus) or a non-viral vector (e.g., a plasmid or synthetic mRNA). In some embodiments, the transgene is directly injected into an individual.

[0183] II. Treatment method:

[0184] Methods for treating individuals suffering from, suspected of suffering from, or at risk of developing a disease, disorder, or condition associated with PNPLA3 expression include administering at least one or more oligonucleotides described herein. Furthermore, methods for treating or attenuating the onset or progression of a disease, disorder, or condition associated with PNPLA3 expression in an individual include using one or more oligonucleotides described herein. Furthermore, methods for achieving one or more therapeutic effects in a subject suffering from a disease, disorder, or condition associated with PNPLA3 expression include providing one or more oligonucleotides described herein. In some embodiments, an individual can be treated by administering a therapeutically effective amount of any one or more of the oligonucleotides described herein. In some embodiments, the treatment includes reducing PNPLA3 expression. In some embodiments, the individual is treated therapeutically. In some embodiments, the individual is treated prophylactically. In all of these embodiments, the oligonucleotide is selected from Tables A, B, C, or D.

[0185] In some embodiments, one or more oligonucleotides, or pharmaceutical compositions comprising oligonucleotides, are administered to an individual with a disease, disorder, or condition associated with PNPLA3 expression, thereby reducing PNPLA3 expression in the individual, thereby treating the individual. In some embodiments, the amount or level of PNPLA3 mRNA is reduced in the individual. In other embodiments, the amount or level of PNPLA3 protein is reduced in the individual. In still other embodiments, the amount or level of PNPLA3 activity is reduced in the individual. In still other embodiments, the amount or level of liver TG (e.g., one or more TGs or total TG in the liver) is reduced in the individual, particularly in the liver. In still other examples, the amount or level of liver inflammation can be reduced. In still other examples, the amount or level of liver fibrosis is reduced. In still other embodiments, the amount or level of plasma AST, plasma ALT, or even Pro-C3 is reduced. In any of the above disclosed embodiments, the oligonucleotide comprises a sense strand having the nucleotide sequence of any one of SEQ ID NOs: 1188, 1190, 1220, 1224, 1230, 1232, 1244, 1246, 1250, or 1254, and an antisense strand having the nucleotide sequence of any one of SEQ ID NOs: 1189, 1191, 1221, 1225, 1231, 1233, 1245, 1247, 1251, or 1255.

[0186] In some embodiments, PNPLA3 expression in the individual is reduced by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or more than 99% when compared to PNPLA3 expression before administration of one or more oligonucleotides or pharmaceutical compositions thereof. In other embodiments, PNPLA3 expression in an individual is reduced by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or more than 99% when compared to PNPLA3 expression in an individual (e.g., a reference or control subject) that has not been administered one or more oligonucleotides or pharmaceutical compositions or that has received a control oligonucleotide, pharmaceutical composition, or treatment.

[0187] In certain embodiments, the amount or level of PNPLA3 mRNA in an individual is reduced by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or more than 99% when compared to the amount or level of PNPLA3 mRNA before administration of one or more oligonucleotides or pharmaceutical compositions thereof. In some embodiments, the amount or level of PNPLA3 mRNA in an individual is reduced by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or more than 99% when compared to the amount or level of PNPLA3 mRNA in an individual (e.g., a reference or control subject) that has not been administered one or more oligonucleotides or pharmaceutical compositions or that has received a control oligonucleotide, pharmaceutical composition, or treatment.

[0188] In certain embodiments, the amount or level of PNPLA3 protein in an individual is reduced by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or more than 99% when compared to the amount or level of PNPLA3 protein before administration of one or more oligonucleotides or pharmaceutical compositions thereof. In other embodiments, the amount or level of PNPLA3 protein in an individual is reduced by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or more than 99% when compared to the amount or level of PNPLA3 protein in an individual (e.g., a reference or control subject) that has not been administered one or more oligonucleotides or pharmaceutical compositions or that has received a control oligonucleotide, pharmaceutical composition, or treatment.

[0189] In certain embodiments, the amount or level of PNPLA3 activity in an individual is reduced by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or more than 99% when compared to the amount or level of PNPLA3 activity before administration of one or more oligonucleotides or pharmaceutical compositions thereof. In some embodiments, the amount or level of PNPLA3 activity in an individual is reduced by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or more than 99% when compared to the amount or level of PNPLA3 activity in an individual (e.g., a reference or control subject) that has not been administered one or more oligonucleotides or pharmaceutical compositions or that has received a control oligonucleotide, pharmaceutical composition, or treatment.

[0190] In certain embodiments, the amount or level of TG, particularly liver TG, in an individual may be reduced by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or more than 99% when compared to the amount or level of TG before administration of one or more oligonucleotides or pharmaceutical compositions thereof. In some embodiments, the amount or level of TG in an individual is reduced by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or more than 99% when compared to the amount or level of TG in an individual (e.g., a reference or control subject) that has not been administered one or more oligonucleotides or pharmaceutical compositions or that has received a control oligonucleotide, pharmaceutical composition, or treatment.

[0191] In this specification, the amount or level of PNPLA3 expression, PNPLA3 mRNA, PNPLA3 protein, PNPLA3 activity, liver TG, or any combination thereof, is reduced in cells (e.g., hepatocytes), cell populations or cell groups (e.g., organoids), tissues (e.g., liver tissue), samples (e.g., liver biopsy samples), organs (e.g., liver), blood or its fractions (e.g., plasma) or any other biological material obtained or isolated from an individual. In some embodiments, the amount or level of PNPLA3 expression, PNPLA3 mRNA, PNPLA3 protein, PNPLA3 activity, TG, or any combination thereof, is decreased in two or more types of cells (e.g., hepatocytes and one or more other types of cells), two or more cell populations, two or more tissues (e.g., liver tissue and one or more other types of tissue), two or more samples (e.g., liver biopsy sample and one or more other types of biopsy sample), two or more organs (e.g., liver and one or more other organs), two or more blood fractions (e.g., plasma and one or more other blood fractions) obtained or isolated from a subject.

[0192] Examples of diseases, disorders, or conditions associated with PNPLA3 expression include, but are not limited to, AH, ALD, HCC, CCA, PSC, NAFLD, NASH, fatty liver (steatosis), liver inflammation, liver fibrosis, cirrhosis, or a combination thereof.

[0193] Due to their high specificity, the oligonucleotides herein specifically target the mRNA of target genes in cells, tissues, or organs (e.g., liver).In disease prevention, the target gene is a gene that is required for the onset or maintenance of disease, or a gene that has been identified as being associated with a high risk of suffering from disease.In disease treatment, one or more oligonucleotides are contacted with cells, tissues, or organs that exhibit disease or play a role in mediating disease.For example, an oligonucleotide that is substantially identical to the whole or part of the wild-type (i.e., natural type) or mutant gene associated with the disorder or condition associated with PNPLA3 expression is contacted with or introduced into target cells or tissue types, such as hepatocytes or other liver cells.

[0194] In some embodiments, the target gene is derived from any mammal, for example, a human. Any gene can be silenced according to the methods of the present invention. Furthermore, the methods of the present invention typically involve administering to an individual a therapeutically effective amount, i.e., an amount capable of producing a desired therapeutic result, of one or more of the oligonucleotides of the present invention. A therapeutically acceptable amount is an amount that therapeutically treats a disease, disorder, or condition. The appropriate dosage for any individual will depend on certain factors, including the individual's size, body surface area, age, the composition to be administered, the active ingredient(s) in the composition, the time and route of administration, overall health, and other therapeutic agents being administered at the same time.

[0195] In this method, the individual is administered any one of the oligonucleotides or compositions herein enterally (for example, orally, by gastric feeding tube, by duodenal feeding tube, through gastrostomy or rectally), parenterally (for example, subcutaneous injection, intravenous injection or infusion, intraarterial injection or infusion, intraosseous infusion, intramuscular injection, intracerebral injection, intraventricular injection or intrathecal), topically (for example, transdermally, inhalation, via eye drops or through mucous membrane), or by direct injection into target organ (for example, the liver of the subject).Typically, the oligonucleotide is administered intravenously or subcutaneously.

[0196] As a non-limiting example, the oligonucleotide or composition herein is typically administered quarterly (once every 3 months), bimonthly (once every 2 months), monthly, or weekly.For example, the oligonucleotide or composition is administered weekly, or at intervals of 2 weeks or 3 weeks.In certain embodiments, the oligonucleotide or composition is administered daily.In some embodiments, the individual is administered one or more loading doses of the oligonucleotide or composition, followed by one or more maintenance doses of the oligonucleotide or composition.

[0197] In some embodiments, the individual is a human, a non-human primate, or other mammalian subject, hi other embodiments, the individual is a domestic animal such as a dog or cat, a livestock animal such as a horse, cow, pig, sheep, goat, or chicken, and an animal such as a mouse, rat, guinea pig, or hamster.

[0198] III. Medical Use The oligonucleotides herein can be used or adapted for use to treat individuals who would benefit from reduced PNPLA3 expression (e.g., humans with diseases, disorders, or conditions associated with PNPLA3 expression). In some embodiments, oligonucleotides are provided that are used or adapted for use in treating individuals with diseases, disorders, or conditions associated with PNPLA3 expression. Also provided are oligonucleotides that are used or adapted for use in the manufacture of medicaments or pharmaceutical compositions for treating diseases, disorders, or conditions associated with PNPLA3 expression. In other embodiments, oligonucleotides are provided that target PNPLA3 mRNA and are used or adapted for use to reduce PNPLA3 expression (e.g., via the RNAi pathway). In other embodiments, oligonucleotides are provided that target PNPLA3 mRNA and are used or adapted for use to reduce the amount or level of PNPLA3 mRNA, PNPLA3 protein, and / or PNPLA3 activity.

[0199] In some embodiments, the method comprises selecting an individual for treatment based on the individual having or being predisposed to a disease, disorder, or condition associated with PNPLA3 expression, such as, but not limited to, a marker (e.g., biomarker) of PNPLA3 mRNA, PNPLA3 protein, or a combination thereof.Similarly, as described in more detail below, the method also comprises an additional step, such as measuring or obtaining a baseline value of a marker of PNPLA3 expression (e.g., PNPLA3 protein), and then comparing the value thus obtained with one or more other baseline values, or with a value obtained after administering one or more oligonucleotides to the individual, to evaluate the effectiveness of treatment. [Example]

[0200] The following non-limiting examples are offered by way of illustration and not by way of limitation.

[0201] Oligonucleotide synthesis

[0202] Example 1: Preparation of dsRNAi oligonucleotides

[0203] Oligonucleotide synthesis and purification: In the examples, dsRNAi oligonucleotides are chemically synthesized using methods described herein. Generally, dsRNAi oligonucleotides are synthesized using solid-phase oligonucleotide synthesis methods described for 19-23mer siRNAs (see, e.g., Scaringe et al. (1990) Nucleic Acids Res. 18:5433-41 and Usman et al. (1987) J. Am. Chem. Soc. 109:7845-45; see also U.S. Patent Nos. 5,804,683; 5,831,071; 5,998,203; 6,008,400; 6,111,086; 6,117,657; 6,353,098; 6,362,323; 6,437,117; and 6,469,158).

[0204] Individual RNA strands are synthesized and HPLC-purified according to standard methods (Integrated DNA Technologies). For example, RNA oligonucleotides are synthesized using solid-phase phosphoramidite chemistry, deprotected, and desalted on a NAP-5 column (Amersham Pharmacia Biotech; Piscataway, NJ) using standard techniques (Damha & Olgivie (1993) Methods Mol. Biol. 20:81-114; Wincott et al. (1995) Nucleic Acids Res. 23:2677-84). Oligomers are purified using ion-exchange high-performance liquid chromatography (IE-HPLC) on an Amersham Source 15Q column (1.0 cm x 25 cm; Amersham Pharmacia Biotech) using a 15-minute linear step gradient. The gradient varies from 90:10 buffer A:B to 52:48 buffer A:B, where buffer A is 100 mM Tris, pH 8.5, and buffer B is 100 mM Tris, pH 8.5, 1 M NaCl. Samples are monitored at 260 nm, and peaks corresponding to full-length oligonucleotide species are collected, pooled, desalted on a NAP-5 column, and lyophilized.

[0205] The purity of each oligomer is determined by capillary electrophoresis (CE) on a Beckman PACE 5000 (Beckman Coulter, Inc.). The CE capillary has an inner diameter of 100 μm and contains ssDNA 100R Gel (Beckman-Coulter). Typically, approximately 0.6 nmoles of oligonucleotide is injected into the capillary, run at an electric field of 444 V / cm, and detected by UV absorbance at 260 nm. A denaturing Tris-borate-7 M-urea running buffer is purchased from Beckman-Coulter. Oligoribonucleotides of at least 90% purity, as assessed by CE, are obtained for use in the experiments described below. The identity of the compounds is verified by matrix-assisted laser desorption / ionization time-of-flight (MALDI-TOF) mass spectrometry on a Voyager DE™ Biospectometry Work Station (Applied Biosystems) according to the manufacturer's recommended protocol. The relative molecular weights of all oligomers are obtained, often within 0.2% of the predicted molecular weight.

[0206] Preparation of duplexes: Resuspend ssRNA oligomers (e.g., at a concentration of 100 μM) in duplex buffer containing 100 mM potassium acetate, 30 mM HEPES, pH 7.5. Mix the complementary sense and antisense strands in equimolar amounts to obtain a final solution of, e.g., 50 μM duplex. Heat the sample to 100°C for 5 minutes in RNA buffer (IDT) and cool to room temperature before use. dsRNA oligonucleotides are stored at -20°C. ssRNA oligomers are stored lyophilized or in nuclease-free water at -80°C.

[0207] In vitro function

[0208] Example 2: RNAi oligonucleotide inhibition of PNPLA3 expression in vitro

[0209] Identification of PNPLA3 target sequences: To identify RNAi oligonucleotide inhibitors of PNPLA3 expression, a computer-based algorithm was used to generate PNPLA3 target sequences suitable for assaying inhibition of PNPLA3 expression via the RNAi pathway. The algorithm provided RNAi oligonucleotide guide (antisense) strand sequences complementary to the appropriate PNPLA3 target sequence in human PNPLA3 mRNA (e.g., SEQ ID NO: 1). Some of the guide strand sequences identified by the algorithm were also complementary to the corresponding PNPLA3 target sequence in monkey PNPLA3 mRNA. Some of the antisense (guide) strand sequences identified by the algorithm were also complementary to the corresponding PNPLA3 target sequence in monkey PNPLA3 mRNA (e.g., SEQ ID NO: 5). From this, 384 dsRNAi oligonucleotides (formatted as DsiRNA oligonucleotides) were generated, each with a unique antisense strand that had a region of complementarity to the PNPLA3 target sequence identified by the algorithm.

[0210] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14]

[0211] In vitro cell-based assay: The ability of each of the 384 DsiRNAs listed in Table 1 to inhibit PNPLA3 expression was determined using an in vitro cell-based assay. Furthermore, the nucleotide sequences of the passenger and guide strands of the DsiRNAs contain unique patterns of modified nucleotides and phosphorothioate linkages (see, e.g., Figure 2). Briefly, HuH-7 human liver cells stably expressing PNPLA3 were transfected with each DsiRNA (0.5 nM) in separate wells of a multi-well cell culture plate. The cells were maintained for 24 hours after transfection, and then the remaining PNPLA3 mRNA levels from the transfected cells were determined using a TAQMAN®-based qPCR assay. Two qPCR assays, a 3' assay and a 5' assay, were used to determine mRNA levels measured by a HEX probe and a FAM probe, respectively.

[0212] The results of HuH-7 cell-based assays using DsiRNAs are shown in Table 2. Table 2 shows the results of HuH-7 cell-based assays using 384 DsiRNAs with guide strands complementary to human and monkey PNPLA3 mRNA ("double common"). Transfections of double common DsiRNAs that result in 30% or less of PNPLA3 mRNA remaining in cells compared to negative controls are considered candidate PNPLA3 expression inhibitors (referred to herein as "hits"). [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9]

[0213] These results demonstrate that DsiRNAs designed to target human PNPLA3 mRNA inhibit PNPLA3 expression in cells (as determined by a reduction in PNPLA3 mRNA levels in DsiRNA-transfected cells), and that nucleotide sequences containing DsiRNA hits are useful for generating RNAi oligonucleotides that inhibit PNPLA3 expression.Furthermore, these results demonstrate that multiple PNPLA3 target sequences are suitable for RNAi-mediated inhibition of PNPLA3 expression.

[0214] In vivo function Example 3: RNAi oligonucleotide inhibition of PNPLA3 expression in vivo Of the 384 DsiRNAs screened in the HuH-7 cell-based assay described in Example 2, the nucleotide sequences of 192 DsiRNA hits (Table 3) were selected for further in vivo evaluation. Briefly, the nucleotide sequences of the selected DsiRNAs were used to generate 194 corresponding dsRNAi oligonucleotides containing a nicked tetraloop GalNAc-conjugated structure (referred to herein as "GalNAc-conjugated PNPLA3 oligonucleotides") with a 36-mer sense (passenger) strand and a 22-mer antisense (guide) strand. Furthermore, the nucleotide sequences of the passenger and guide strands of the GalNAc-conjugated PNPLA3 oligonucleotides have a unique pattern of modified nucleotides and phosphorothioate linkages (see, e.g., Figure 1 for a schematic diagram of the general structure and chemical modification pattern of GalNAc-conjugated PNPLA3 oligonucleotides). Each of the three adenosine nucleotides in the tetraloop is conjugated to a GalNAc moiety (CAS number: 14131-60-3). [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5]

[0215] Mouse Study: Various GalNAc-conjugated PNPLA3 oligonucleotides (some of which are listed in Table 3) are evaluated in a hydrodynamic injection (HDI) mouse model. Additional HDI studies are listed in Tables 4, 5, and 6. In these HDI studies, mice are engineered to transiently express human PNPLA3 mRNA in hepatocytes. GalNAc-conjugated PNPLA3 oligonucleotide controls (SEQ ID NOs: 1165 and 1166) are used as benchmark controls. Briefly, 6-8 week-old female CD-1 mice are subcutaneously treated with GalNAc-conjugated PNPLA3 oligonucleotides at a dose level of 1 mg / kg. Three days (72 hours) later, the mice are hydrodynamically injected with a DNA plasmid encoding the complete human PNPLA3 gene under the control of the ubiquitous cytomegalovirus (CMV) promoter sequence. Liver samples are harvested one day after plasmid transfer. Total RNA from these mice was subjected to qRT-PCR analysis for PNPLA3 mRNA and compared with mice treated with the same volume of PBS alone. Values ​​were normalized for transfection efficiency using the NeoR gene contained in the plasmid.

[0216] As shown in Tables 4, 5, and 6, the number of GalNAc-conjugated PNPLA3 oligonucleotides tested that inhibited PNPLA3 expression, as determined by a reduction in PNPLA3 mRNA levels in liver samples from oligonucleotide-treated mice, is compared with mice treated with PBS. The average percent remaining PNPLA3 mRNA in liver samples from mice treated with the benchmark GalNAc-conjugated PNPLA3 oligonucleotide control is compared with mice treated with PBS. Table 4 shows that 18 of the 21 GalNAc-conjugated PNPLA3 oligonucleotides inhibited PNPLA3 expression to a greater extent than the reference GalNAc-conjugated PNPLA3 oligonucleotide used as a control. The sequences of these oligonucleotides, along with their modification patterns and SEQ ID NOs, are disclosed in Table A. [Table 4]

[0217] Tables 5 and 6 show two additional sets of HDI studies, each using 18 GalNAc-conjugated PNPLA3 oligonucleotides and the same reference oligonucleotide, the sequences of which, along with their modification patterns and SEQ ID NOs, are disclosed in Tables B and C, respectively.

[0218] Based on these results, 10 GalNAc-conjugated PNPLA3 oligonucleotides were selected for evaluation of their ability to inhibit PNPLA3 expression in non-human primates (NHPs). The GalNAc-conjugated PNPLA3 oligonucleotides have the pattern of chemically modified nucleotides shown in Figure 1. [Table 5] [Table 6]

[0219] Table 7 discloses additional HDI studies using the best GalNAc-conjugated PNPLA3 oligonucleotides (hits) based on the results obtained from the previous studies and three previous HDI screens disclosed in Tables 4, 5, and 6. The sequences of the oligonucleotides used in this HDI screen are disclosed in Table D, along with the modification patterns and SEQ ID NOs. [Table 7]

[0220] NHP Study: Ten GalNAc-conjugated PNPLA3 oligonucleotides selected from Table 7 were evaluated in cynomolgus monkeys (Macaca fascicularis). In this study, NHPs were grouped so that the average body weight (approximately 5.4 kg) of NHPs was comparable between the control and experimental groups. Each cohort included two male and three female subjects. GalNAc-conjugated PNPLA3 oligonucleotides were administered subcutaneously on study day 0. Blood samples were collected on study days -8, -5, and 0, and weekly thereafter. Ultrasound-guided core needle liver biopsies were obtained on study days -7, 28, and 56. At each time point, total RNA from the liver biopsy samples was subjected to qRT-PCR analysis to measure PNPLA3 mRNA in oligonucleotide-treated monkeys and compare it to monkeys treated with an equivalent volume of PBS. To normalize the data, measurements were performed relative to the geometric mean of two reference genes, PPIB and 18S rRNA. As shown in Table 8 (day -7), Table 9 (day 28), and Table 10 (day 56), treatment of NHPs with GalNAc-conjugated PNPLA3 oligonucleotides inhibits PNPLA3 expression in the liver, as determined by reduced PNPLA3 mRNA levels in liver samples from oligonucleotide-treated NHPs compared with PBS-treated NHPs. At all time points evaluated, PNPLA3 oligonucleotides 34, 81, and 121 inhibit PNPLA3 expression to a greater extent than the benchmark PBS time-matched control. From the same NHP study, inhibition of PNPLA3 expression was also determined by measuring PNPLA3 protein by ELISA in serum prepared from pre-dose and weekly blood samples. Collectively, these results demonstrate that treatment of NHPs with GalNAc-conjugated PNPLA3 oligonucleotides reduces PNPLA3 mRNA levels in the liver and concomitantly reduces PNPLA3 protein levels in serum.

[0221] [Table 8]

[0222] [Table 9] [Table 10]

[0223] Taken together, these results demonstrate that GalNAc-conjugated PNPLA3 oligonucleotides designed to target human PNPLA3 mRNA inhibit PNPLA3 expression in vivo (as determined by reduced PNPLA3 mRNA and PNPLA3 protein levels in treated animals).

[0224] array The following nucleic acid and / or amino acid sequences are referred to in this disclosure and are provided below for reference.

[0225] SEQ ID NO:1 - Wild-type human PNPLA3 (2753 bp; NCBI reference sequence NM_025225.3)

[0226] SEQ ID NO:2—Wild type human PNPLA3 (481 aa; NCBI reference sequence number NP_079501.2) MYDAERGWSLSFAGCGFLGFYHVGATRCLSEHAPHLLRDARMLFGASAGALHCVGVLSGIPLEQTLQVLSDLVRKARSRNIGIFHPSFNLSKFLRQGLCKCLPANVHQLISGKIGISLTR VSDGENVLVSDFRSKDEVVDALVCSCFIPFYSGLIPPSFRGVRYVDGGVSDNVPFIDAKTTITVSPFYGEYDICPKVKSTNFLHVDITKLSLRLCTGNLYLLSRAFVPPDLKVLGEICLR GYLDAFRFLEEKGICNRPQPGLKSSSEGMDPEVAMPSWANMSLDSSSPESAALAVRLEGDELLDHLRLSILPWDESILDTLSPRLATALSEEMKDKGGYMSKICNLLPIRIMSYVMLPCTL PVESAIAIVQRLVTWLPDMPDDVLWLQWVTSQVFTRVLMCLLPASRSQMPVSSQQASPCTPEQDWPCWTPCSPKGCPAETKAEATPRSILRSSLNFFLGNKVPAGAEGLSTFPSFSLEKSL

[0227] SEQ ID NO:3 - Human PNPLA3 I148M (variant) mRNA

[0228] SEQ ID NO:4 - Human PNPLA3 I148M (variant) MYDAERGWSLSFAGCGFLGFYHVGATRCLSEHAPHLLRDARMLFGASAGALHCVGVLSGIPLEQTLQVLSDLVRKARSRNIGIFHPSFNLSKFLRQGLCKCLPANVHQLISGKIGISLTR VSDGENVLVSDFRSKDEVVDALVCSCFMPFYSGLIPPSFRGVRYVDGGVSDNVPFIDAKTTITVSPFYGEYDICPKVKSTNFLHVDITKLSLRLCTGNLYLLSRAFVPPDLKVLGEICLR GYLDAFRFLEEKGICNRPQPGLKSSSEGMDPEVAMPSWANMSLDSSSPESAALAVRLEGDELLDHLRLSILPWDESILDTLSPRLATALSEEMKDKGGYMSKICNLLPIRIMSYVMLPCTL PVESAIAIVQRLVTWLPDMPDDVLWLQWVTSQVFTRVLMCLLPASRSQMPVSSQQASPCTPEQDWPCWTPCSPKGCPAETKAEATPRSILRSSLNFFLGNKVPAGAEGLSTFPSFSLEKSL

[0229] SEQ ID NO:5 - Primate PNPLA3 (2291 bp; NCBI reference sequence number XM_015457081.1)

[0230] SEQ ID NO: 6 - Primate PNPLA3 (480 aa; NCBI reference sequence number XP_015312567.1) MYDAERGWSLSFAGCGFLGFYHVGATRCLSEHAPHLLRDARMLFGASAGALHCVGVLSGIPLEQTLQVLSDLVRKARSRNIGIFHPSFNIGKFLRQDLYKYLPANVHQLISGKICVSLTR VSDGENVLVSDFQSKDEVVDALICSCFIPFYSGLIPPSFRGVRYVDGGASDNVPFIDAKTTITVSPFYGEYDICPKVKSTNFLHVDITKLSLRLCTGNLYLLSRAFVPPDLKVLGEICLR GYLDAFRFLEEKGICNKPQRGLKSSSEGMDSEVTAPGWENTSLDSSPEPAALAMRLDGDELLDHLRLSILPWDESILDTLSPELATVSEAMKDKGGYMSKICNLLPIRIISYVMLPCTLP VESAIAIVQRLVTWLPDMPDDVQWLQWVTSQVFTRALMCLLPASRSQMPVSSEQASPCKPEQDWHCWTPCSPEDCPAEAKAEATPRSILRSSLNFFWGNKVPAGAEGLSTFPSFSLEKNL

[0231] SEQ ID NO:7 - Mouse PNPLA3 (4675 bp; NCBI reference sequence number XM_006520346.5)

[0232] SEQ ID NO:8 - Mouse PNPLA3 (367 aa; NCBI reference sequence number XP_006520409.1) MEILMDLVRKARSRNIGTLHPFFNINKCIRDGLQESLPDNVHQVISGKVHISLTRVSDGENVLVSEFHSKDEVVDALVCSCFIPLFSGLIPPSFRGERYVDGGVSDNVPVLDAKTTITVSPFYGEHDICPKVKSTNFFHVNITNLSLRLCTGNLQLLTRALFPSDVKVMGELCYQGYLDAFRF LEENGICNGPQRSLSLLVAPEACLENGKLVGDKVPVSLCFTDENIWETLSPELSTALSEAIKDREGYLSKVCNLLPVRILSYIMLPCSLPVESAIAAVHRLVTWLPDIQDDIQWLQWATSQVCARMTMCLLPSTSMRFLGQSQFLGLHCIKGLKTKGKAQLSLQHASSARTTARFGAQAVQTF

[0233] SEQ ID NO: 9 - DsiRNA 1 passenger (sense) strand UCUGCAGGUCCUCUCAGAUCUUGUG

[0234] SEQ ID NO: 10 - DsiRNA 1 guide (antisense) strand CACAAGAUCUGAGAGGACCUGCAGAGU

[0235] SEQ ID NO: 11 - DsiRNA 2 passenger (sense) strand AGGUCCUCUCAGAUCUUGUGCGGAA

[0236] SEQ ID NO: 12 - DsiRNA 2 guide (antisense) strand UUCCGCACAAGAUCUGAGAGGACCUGC

[0237] SEQ ID NO: 13 - DsiRNA 3 passenger (sense) strand AUUGGCAUCUUCCAUCCAUCCUUCA

[0238] SEQ ID NO: 14 - DsiRNA 3 guide (antisense) strand UGAAGGAUGGAUGGAAGAUGCCAAUGU

[0239] SEQ ID NO: 15 - DsiRNA 4 passenger (sense) strand AUCUUCCAUCCAUCCUUCAACUUAA

[0240] SEQ ID NO: 16 - DsiRNA 4 guide (antisense) strand UUAAGUUGAAGGAUGGAUGGAAGAUGC

[0241] SEQ ID NO: 17 - DsiRNA 5 passenger (sense) strand UCUUCCAUCCAUCCUUCAACUUAAG

[0242] SEQ ID NO: 18 - DsiRNA 5 guide (antisense) strand CUUAAGUUGAAGGAUGGAUGGAAGAUG

[0243] SEQ ID NO: 19 - DsiRNA 6 passenger (sense) strand CCAGAGUGUCUGAUGGGGAAAACGU

[0244] SEQ ID NO: 20 - DsiRNA 6 guide (antisense) strand ACGUUUUCCCCAUCAGACACUCUGGUA

[0245] SEQ ID NO: 21 - DsiRNA 7 passenger (sense) strand GAGUGUCUGAUGGGGAAAACGUUCU

[0246] SEQ ID NO: 22 - DsiRNA 7 guide (antisense) strand AGAACGUUUUCCCCAUCAGACACUCUG

[0247] SEQ ID NO: 23 - DsiRNA 8 passenger (sense) strand AUGGGGAAAACGUUCUGGUGUCUGA

[0248] SEQ ID NO: 24 - DsiRNA 8 guide (antisense) strand UCAGACACCAGAACGUUUUCCCCAUCA

[0249] SEQ ID NO: 25 - DsiRNA 9 passenger (sense) strand GGGGAAAACGUUCUGGUGUCUGACU

[0250] SEQ ID NO: 26 - DsiRNA 9 guide (antisense) strand AGUCAGACACCAGAACGUUUUCCCCAU

[0251] SEQ ID NO: 27 - DsiRNA 10 passenger (sense) strand GGGAAAACGUUCUGGUGUCUGACUU

[0252] SEQ ID NO: 28 - DsiRNA 10 guide (antisense) strand AAGUCAGACACCAGAACGUUUUCCCCA

[0253] SEQ ID NO: 29 - DsiRNA 11 passenger (sense) strand GGAAAACGUUCUGGUGUCUGACUUU

[0254] SEQ ID NO: 30 - DsiRNA 11 guide (antisense) strand AAAGUCAGACACCAGAACGUUUUCCCC

[0255] SEQ ID NO: 31 - DsiRNA 12 passenger (sense) strand GAAAACGUUCUGGUGUCUGACUUUC

[0256] SEQ ID NO: 32 - DsiRNA 12 guide (antisense) strand GAAAGUCAGACACCAGAACGUUUUCCC

[0257] SEQ ID NO: 33 - DsiRNA 13 passenger (sense) strand AAAACGUUCUGGUGUCUGACUUUCG

[0258] SEQ ID NO: 34 - DsiRNA 13 guide (antisense) strand CGAAAGUCAGACACCAGAACGUUUUCC

[0259] SEQ ID NO: 35 - DsiRNA 14 passenger (sense) strand AAACGUUCUGGUGUCUGACUUUCGG

[0260] SEQ ID NO: 36 - DsiRNA 14 guide (antisense) strand CCGAAAGUCAGACACCAGAACGUUUUC

[0261] SEQ ID NO: 37 - DsiRNA 15 passenger (sense) strand AACGUUCUGGUGUCUGACUUUCGGU

[0262] SEQ ID NO: 38 - DsiRNA 15 guide (antisense) strand ACCGAAAGUCAGACACCAGAACGUUUU

[0263] SEQ ID NO: 39 - DsiRNA 16 passenger (sense) strand ACGUUCUGGUGUCUGACUUUCGGUC

[0264] SEQ ID NO: 40 - DsiRNA 16 guide (antisense) strand GACCGAAAGUCAGACACCAGAACGUUU

[0265] SEQ ID NO: 41 - DsiRNA 17 passenger (sense) strand GUUCUGGUGUCUGACUUUCGGUCCA

[0266] SEQ ID NO: 42 - DsiRNA 17 guide (antisense) strand UGGACCGAAAGUCAGACACCAGAACGU

[0267] SEQ ID NO: 43 - DsiRNA 18 passenger (sense) strand GACGAAGUCGUGGAUGCCUUGGUAU

[0268] SEQ ID NO: 44 - DsiRNA 18 guide (antisense) strand AUACCAAGGCAUCCACGACUUCGUCUU

[0269] SEQ ID NO: 45 - DsiRNA 19 passenger (sense) strand ACGAAGUCGUGGAUGCCUUGGUAUG

[0270] SEQ ID NO: 46 - DsiRNA 19 guide (antisense) strand CAUACCAAGGCAUCCACGACUUCGUCU

[0271] SEQ ID NO: 47 - DsiRNA 20 passenger (sense) strand CGAAGUCGUGGAUGCCUUGGUAUGU

[0272] SEQ ID NO: 48 - DsiRNA 20 guide (antisense) strand ACAUACCAAGGCAUCCACGACUUCGUC

[0273] SEQ ID NO: 49 - DsiRNA 21 passenger (sense) strand CAGAGGCGUGCGAUAUGUGGAUGGA

[0274] SEQ ID NO: 50 - DsiRNA 21 guide (antisense) strand UCCAUCCACAUAUCGCACGCCUCUGAA

[0275] SEQ ID NO: 51 - DsiRNA 22 passenger (sense) strand GCGAUAUGUGGAUGGAGGAGUGAGU

[0276] SEQ ID NO: 52 - DsiRNA 22 guide (antisense) strand ACUCACUCCUCCAUCCACAUAUCGCAC

[0277] SEQ ID NO: 53 - DsiRNA 23 passenger (sense) strand GAUGGAGGAGUGAGUGACAACGUAC

[0278] SEQ ID NO: 54 - DsiRNA 23 guide (antisense) strand GUACGUUGUCACUCACUCCUCCAUCCA

[0279] SEQ ID NO: 55 - DsiRNA 24 passenger (sense) strand GAGGAGUGAGUGACAACGUACCCUU

[0280] SEQ ID NO: 56 - DsiRNA 24 guide (antisense) strand AAGGGUACGUUGUCACUCACUCCUCCA

[0281] SEQ ID NO: 57 - DsiRNA 25 passenger (sense) strand GAGUGAGUGACAACGUACCCUUCAU

[0282] SEQ ID NO: 58 - DsiRNA 25 guide (antisense) strand AUGAAGGGUACGUUGUCACUCACUCCU

[0283] SEQ ID NO: 59 - DsiRNA 26 passenger (sense) strand AGUGAGUGACAACGUACCCUUCAUU

[0284] SEQ ID NO: 60 - DsiRNA 26 guide (antisense) strand AAUGAAGGGUACGUUGUCACUCACUCC

[0285] SEQ ID NO: 61 - DsiRNA 27 passenger (sense) strand GUGAGUGACAACGUACCCUUCAUUG

[0286] SEQ ID NO: 62 - DsiRNA 27 guide (antisense) strand CAAUGAAGGGUACGUUGUCACUCACUC

[0287] SEQ ID NO: 63 - DsiRNA 28 passenger (sense) strand UGAGUGACAACGUACCCUUCAUUGA

[0288] SEQ ID NO: 64 - DsiRNA 28 guide (antisense) strand UCAAUGAAGGGUACGUUGUCACUCACU

[0289] SEQ ID NO: 65 - DsiRNA 29 passenger (sense) strand GAGUGACAACGUACCCUUCAUUGAU

[0290] SEQ ID NO: 66 - DsiRNA 29 guide (antisense) strand AUCAAUGAAGGGUACGUUGUCACUCAC

[0291] SEQ ID NO: 67 - DsiRNA 30 passenger (sense) strand AGUGACAACGUACCCUUCAUUGAUG

[0292] SEQ ID NO: 68 - DsiRNA 30 guide (antisense) strand CAUCAAUGAAGGGUACGUUGUCACUCA

[0293] SEQ ID NO: 69 - DsiRNA 31 passenger (sense) strand GUGACAACGUACCCUUCAUUGAUGC

[0294] SEQ ID NO: 70 - DsiRNA 31 guide (antisense) strand GCAUCAAUGAAGGGUACGUUGUCACUC

[0295] SEQ ID NO: 71 - DsiRNA 32 passenger (sense) strand UGACAACGUACCCUUCAUUGAUGCC

[0296] SEQ ID NO: 72 - DsiRNA 32 guide (antisense) strand GGCAUCAAUGAAGGGUACGUUGUCACU

[0297] SEQ ID NO: 73 - DsiRNA 33 passenger (sense) strand GACAACGUACCCUUCAUUGAUGCCA

[0298] SEQ ID NO: 74 - DsiRNA 33 guide (antisense) strand UGGCAUCAAUGAAGGGUACGUUGUCAC

[0299] SEQ ID NO: 75 - DsiRNA 34 passenger (sense) strand CAACGUACCCUUCAUUGAUGCCAAA

[0300] SEQ ID NO: 76 - DsiRNA 34 guide (antisense) strand UUUGGCAUCAAUGAAGGGUACGUUGUC

[0301] SEQ ID NO: 77 - DsiRNA 35 passenger (sense) strand AACGUACCCUUCAUUGAUGCCAAAA

[0302] SEQ ID NO: 78 - DsiRNA 35 guide (antisense) strand UUUUGGCAUCAAUGAAGGGUACGUUGU

[0303] SEQ ID NO: 79 - DsiRNA 36 passenger (sense) strand ACGUACCCUUCAUUGAUGCCAAAAC

[0304] SEQ ID NO: 80 - DsiRNA 36 guide (antisense) strand GUUUUGGCAUCAAUGAAGGGUACGUUG

[0305] SEQ ID NO: 81 - DsiRNA 37 passenger (sense) strand CGUACCCUUCAUUGAUGCCAAAACA

[0306] SEQ ID NO: 82 - DsiRNA 37 guide (antisense) strand UGUUUUGGCAUCAAUGAAGGGUACGUU

[0307] SEQ ID NO: 83 - DsiRNA 38 passenger (sense) strand UACCCUUCAUUGAUGCCAAAACAAC

[0308] SEQ ID NO: 84 - DsiRNA 38 guide (antisense) strand GUUGUUUUGGCAUCAAUGAAGGGUACG

[0309] SEQ ID NO: 85 - DsiRNA 39 passenger (sense) strand UUGAUGCCAAAACAACCAUCACCGU

[0310] SEQ ID NO: 86 - DsiRNA 39 guide (antisense) strand ACGGUGAUGGUUGUUUUGGCAUCAAUG

[0311] SEQ ID NO: 87 - DsiRNA 40 passenger (sense) strand GAUGCCAAAACAACCAUCACCGUGU

[0312] SEQ ID NO: 88 - DsiRNA 40 guide (antisense) strand ACACGGUGAUGGUUGUUUUGGCAUCAA

[0313] SEQ ID NO: 89 - DsiRNA 41 passenger (sense) strand AUGGGGAGUACGACAUCUGCCCUAA

[0314] SEQ ID NO: 90 - DsiRNA 41 guide (antisense) strand UUAGGGCAGAUGUCGUACUCCCCAUAG

[0315] SEQ ID NO: 91 - DsiRNA 42 passenger (sense) strand GUACGACAUCUGCCCUAAAGUCAAG

[0316] SEQ ID NO: 92 - DsiRNA 42 guide (antisense) strand CUUGACUUUAGGGCAGAUGUCGUACUC

[0317] SEQ ID NO: 93 - DsiRNA 43 passenger (sense) strand GACAUCUGCCCUAAAGUCAAGUCCA

[0318] SEQ ID NO: 94 - DsiRNA 43 guide (antisense) strand UGGACUUGACUUUAGGGCAGAUGUCGU

[0319] SEQ ID NO: 95 - DsiRNA 44 passenger (sense) strand ACAUCUGCCCUAAAGUCAAGUCCAC

[0320] SEQ ID NO: 96 - DsiRNA 44 guide (sense) strand GUGGACUUGACUUUAGGGCAGAUGUCG

[0321] SEQ ID NO: 97 - DsiRNA 45 passenger (sense) strand GUCAAGUCCACGAACUUUCUUCAUG

[0322] SEQ ID NO: 98 - DsiRNA 45 guide (antisense) strand CAUGAAGAAAGUUCGUGGACUUGACUU

[0323] SEQ ID NO: 99 - DsiRNA 46 passenger (sense) strand UCAAGUCCACGAACUUUCUUCAUGU

[0324] SEQ ID NO: 100 - DsiRNA 46 guide (antisense) strand ACAUGAAGAAAGUUCGUGGACUUGACU

[0325] SEQ ID NO: 101 - DsiRNA 47 passenger (sense) strand CAAGUCCACGAACUUUCUUCAUGUG

[0326] SEQ ID NO: 102 - DsiRNA 47 guide (antisense) strand CACAUGAAGAAAGUUCGUGGACUUGAC

[0327] SEQ ID NO: 103 - DsiRNA 48 passenger (sense) strand GUCCACGAACUUUCUUCAUGUGGAC

[0328] SEQ ID NO: 104 - DsiRNA 48 guide (antisense) strand GUCCACAUGAAGAAAGUUCGUGGACUU

[0329] SEQ ID NO: 105 - DsiRNA 49 passenger (sense) strand CCACGAACUUUCUUCAUGUGGACAU

[0330] SEQ ID NO: 106 - DsiRNA 49 guide (antisense) strand AUGUCCACAUGAAGAAAGUUCGUGGAC

[0331] SEQ ID NO: 107 - DsiRNA 50 passenger (sense) strand CACGAACUUUCUUCAUGUGGACAUC

[0332] SEQ ID NO: 108 - DsiRNA 50 guide (antisense) strand GAUGUCCACAUGAAGAAAGUUCGUGGA

[0333] SEQ ID NO: 109 - DsiRNA 51 passenger (sense) strand ACGAACUUUCUUCAUGUGGACAUCA

[0334] SEQ ID NO: 110 - DsiRNA 51 guide (antisense) strand UGAUGUCCACAUGAAGAAAGUUCGUGG

[0335] SEQ ID NO: 111 - DsiRNA 52 passenger (sense) strand CGAACUUUCUUCAUGUGGACAUCAC

[0336] SEQ ID NO: 112 - DsiRNA 52 guide (antisense) strand GUGAUGUCCACAUGAAGAAAGUUCGUG

[0337] SEQ ID NO: 113 - DsiRNA 53 passenger (sense) strand GAACUUUCUUCAUGUGGACAUCACC

[0338] SEQ ID NO: 114 - DsiRNA 53 guide (antisense) strand GGUGAUGUCCACAUGAAGAAAGUUCGU

[0339] SEQ ID NO: 115 - DsiRNA 54 passenger (sense) strand AACUUUCUUCAUGUGGACAUCACCA

[0340] SEQ ID NO: 116 - DsiRNA 54 guide (antisense) strand UGGUGAUGUCCACAUGAAGAAAGUUCG

[0341] SEQ ID NO: 117 - DsiRNA 55 passenger (sense) strand ACUUUCUUCAUGUGGACAUCACCAA

[0342] SEQ ID NO: 118 - DsiRNA 55 guide (antisense) strand UUGGUGAUGUCCACAUGAAGAAAGUUC

[0343] SEQ ID NO: 119 - DsiRNA 56 passenger (sense) strand CUUUCUUCAUGUGGACAUCACCAAG

[0344] SEQ ID NO: 120 - DsiRNA 56 guide (antisense) strand CUUGGUGAUGUCCACAUGAAGAAAGUU

[0345] SEQ ID NO: 121 - DsiRNA 57 passenger (sense) strand UUUCUUCAUGUGGACAUCACCAAGC

[0346] SEQ ID NO: 122 - DsiRNA 57 guide (antisense) strand GCUUGGUGAUGUCCACAUGAAGAAAGU

[0347] SEQ ID NO: 123 - DsiRNA 58 passenger (sense) strand UUCUUCAUGUGGACAUCACCAAGCU

[0348] SEQ ID NO: 124 - DsiRNA 58 guide (antisense) strand AGCUUGGUGAUGUCCACAUGAAGAAAG

[0349] SEQ ID NO: 125 - DsiRNA 59 passenger (sense) strand CUUCAUGUGGACAUCACCAAGCUCA

[0350] SEQ ID NO: 126 - DsiRNA 59 guide (antisense) strand UGAGCUUGGUGAUGUCCACAUGAAGAA

[0351] SEQ ID NO: 127 - DsiRNA 60 passenger (sense) strand UUCAUGUGGACAUCACCAAGCUCAG

[0352] SEQ ID NO: 128 - DsiRNA 60 guide (antisense) strand CUGAGCUUGGUGAUGUCCACAUGAAGA

[0353] SEQ ID NO: 129 - DsiRNA 61 passenger (sense) strand UCAUGUGGACAUCACCAAGCUCAGU

[0354] SEQ ID NO: 130 - DsiRNA 61 guide (antisense) strand ACUGAGCUUGGUGAUGUCCACAUGAAG

[0355] SEQ ID NO: 131 - DsiRNA 62 passenger (sense) strand CAUGUGGACAUCACCAAGCUCAGUC

[0356] SEQ ID NO: 132 - DsiRNA 62 guide (antisense) strand GACUGAGCUUGGUGAUGUCCACAUGAA

[0357] SEQ ID NO: 133 - DsiRNA 63 passenger (sense) strand AUGUGGACAUCACCAAGCUCAGUCU

[0358] SEQ ID NO: 134 - DsiRNA 63 guide (antisense) strand AGACUGAGCUUGGUGAUGUCCACAUGA

[0359] SEQ ID NO: 135 - DsiRNA 64 passenger (sense) strand UGUGGACAUCACCAAGCUCAGUCUA

[0360] SEQ ID NO: 136 - DsiRNA 64 guide (antisense) strand UAGACUGAGCUUGGUGAUGUCCACAUG

[0361] SEQ ID NO: 137 - DsiRNA 65 passenger (sense) strand GUGGACAUCACCAAGCUCAGUCUAC

[0362] SEQ ID NO: 138 - DsiRNA 65 guide (antisense) strand GUAGACUGAGCUUGGUGAUGUCCACAU

[0363] SEQ ID NO: 139 - DsiRNA 66 passenger (sense) strand UGGACAUCACCAAGCUCAGUCUACG

[0364] SEQ ID NO: 140 - DsiRNA 66 guide (antisense) strand CGUAGACUGAGCUUGGUGAUGUCCACA

[0365] SEQ ID NO: 141 - DsiRNA 67 passenger (sense) strand AGCUUUUGUCCCCCCGGAUCUCAAG

[0366] SEQ ID NO: 142 - DsiRNA 67 guide (antisense) strand CUUGAGAUCCGGGGGGACAAAAGCUCU

[0367] SEQ ID NO: 143 - DsiRNA 68 passenger (sense) strand AAGGUGCUGGGAGAGAUAUGCCUUC

[0368] SEQ ID NO: 144 - DsiRNA 68 guide (antisense) strand GAAGGCAUAUCUCUCCCAGCACCUUGA

[0369] SEQ ID NO: 145 - DsiRNA 69 passenger (sense) strand GGGAGAGAUAUGCCUUCGAGGAUAU

[0370] SEQ ID NO: 146 - DsiRNA 69 guide (antisense) strand AUAUCCUCGAAGGCAUAUCUCUCCCAG

[0371] SEQ ID NO: 147 - DsiRNA 70 passenger (sense) strand GGAGAGAUAUGCCUUCGAGGAUAUU

[0372] SEQ ID NO: 148 - DsiRNA 70 guide (antisense) strand AAUAUCCUCGAAGGCAUAUCUCUCCCA

[0373] SEQ ID NO: 149 - DsiRNA 71 passenger (sense) strand AGAGAUAUGCCUUCGAGGAUAUUUG

[0374] SEQ ID NO: 150 - DsiRNA 71 guide (antisense) strand CAAAUAUCCUCGAAGGCAUAUCUCUCC

[0375] SEQ ID NO: 151 - DsiRNA 72 passenger (sense) strand GAGAUAUGCCUUCGAGGAUAUUUGG

[0376] SEQ ID NO: 152 - DsiRNA 72 guide (antisense) strand CCAAAUAUCCUCGAAGGCAUAUCUCUC

[0377] SEQ ID NO: 153 - DsiRNA 73 passenger (sense) strand AGAUAUGCCUUCGAGGAUAUUUGGA

[0378] SEQ ID NO: 154 - DsiRNA 73 guide (antisense) strand UCCAAAUAUCCUCGAAGGCAUAUCUCU

[0379] SEQ ID NO: 155 - DsiRNA 74 passenger (sense) strand GAUAUGCCUUCGAGGAUAUUUGGAU

[0380] SEQ ID NO: 156 - DsiRNA 74 guide (antisense) strand AUCCAAAUAUCCUCGAAGGCAUAUCUC

[0381] SEQ ID NO: 157 - DsiRNA 75 passenger (sense) strand AUAUGCCUUCGAGGAUAUUUGGAUG

[0382] SEQ ID NO: 158 - DsiRNA 75 guide (antisense) strand CAUCCAAAUAUCCUCGAAGGCAUAUCU

[0383] SEQ ID NO: 159 - DsiRNA 76 passenger (sense) strand AUGCCUUCGAGGAUAUUUGGAUGCA

[0384] SEQ ID NO: 160 - DsiRNA 76 guide (antisense) strand UGCAUCCAAAUAUCCUCGAAGGCAUAU

[0385] SEQ ID NO: 161 - DsiRNA 77 passenger (sense) strand UGCCUUCGAGGAUAUUUGGAUGCAU

[0386] SEQ ID NO: 162 - DsiRNA 77 guide (antisense) strand AUGCAUCCAAAUAUCCUCGAAGGCAUA

[0387] SEQ ID NO: 163 - DsiRNA 78 passenger (sense) strand GCCUUCGAGGAUAUUUGGAUGCAUU

[0388] SEQ ID NO: 164 - DsiRNA 78 guide (antisense) strand AAUGCAUCCAAAUAUCCUCGAAGGCAU

[0389] SEQ ID NO: 165 - DsiRNA 79 passenger (sense) strand UCAGGUUCUUGGAAGAGAAGGGCAU

[0390] SEQ ID NO: 166 - DsiRNA 79 guide (antisense) strand AUGCCCUUCUCUUCCAAGAACCUGAAU

[0391] SEQ ID NO: 167 - DsiRNA 80 passenger (sense) strand CAGGUUCUUGGAAGAGAAGGGCAUC

[0392] SEQ ID NO: 168 - DsiRNA 80 guide (antisense) strand GAUGCCCUUCUCUUCCAAGAACCUGAA

[0393] SEQ ID NO: 169 - DsiRNA 81 passenger (sense) strand AGGUUCUUGGAAGAGAAGGGCAUCU

[0394] SEQ ID NO: 170 - DsiRNA 81 guide (antisense) strand AGAUGCCCUUCUCUUCCAAGAACCUGA

[0395] SEQ ID NO: 171 - DsiRNA 82 passenger (sense) strand GGUUCUUGGAAGAGAAGGGCAUCUG

[0396] SEQ ID NO: 172 - DsiRNA 82 guide (antisense) strand CAGAUGCCCUUCUCUUCCAAGAACCUG

[0397] SEQ ID NO: 173 - DsiRNA 83 passenger (sense) strand UGGAAGAGAAGGGCAUCUGCAACAG

[0398] SEQ ID NO: 174 - DsiRNA 83 guide (antisense) strand CUGUUGCAGAUGCCCUUCUCUUCCAAG

[0399] SEQ ID NO: 175 - DsiRNA 84 passenger (sense) strand UGAAGUCAUCCUCAGAAGGGAUGGA

[0400] SEQ ID NO: 176 - DsiRNA 84 guide (antisense) strand UCCAUCCCUUCUGAGGAUGACUUCAGG

[0401] SEQ ID NO: 177 - DsiRNA 85 passenger (sense) strand GAAGUCAUCCUCAGAAGGGAUGGAU

[0402] SEQ ID NO: 178 - DsiRNA 85 guide (antisense) strand AUCCAUCCCUUCUGAGGAUGACUUCAG

[0403] SEQ ID NO: 179 - DsiRNA 86 passenger (sense) strand AAGUCAUCCUCAGAAGGGAUGGAUC

[0404] SEQ ID NO: 180 - DsiRNA 86 guide (antisense) strand GAUCCAUCCCUUCUGAGGAUGACUUCA

[0405] SEQ ID NO: 181 - DsiRNA 87 passenger (sense) strand GUCAUCCUCAGAAGGGAUGGAUCCU

[0406] SEQ ID NO: 182 - DsiRNA 87 guide (antisense) strand AGGAUCCAUCCCUUCUGAGGAUGACUU

[0407] SEQ ID NO: 183 - DsiRNA 88 passenger (sense) strand CAUCCUCAGAAGGGAUGGAUCCUGA

[0408] SEQ ID NO: 184 - DsiRNA 88 guide (antisense) strand UCAGGAUCCAUCCCUUCUGAGGAUGAC

[0409] SEQ ID NO: 185 - DsiRNA 89 passenger (sense) strand AUCCUCAGAAGGGAUGGAUCCUGAG

[0410] SEQ ID NO: 186 - DsiRNA 89 guide (antisense) strand) CUCAGGAUCCAUCCCUUCUGAGGAUGA

[0411] SEQ ID NO: 187 - DsiRNA 90 passenger (sense) strand CUAGACCACCUGCGUCUCAGCAUCC

[0412] SEQ ID NO: 188 - DsiRNA 90 guide (antisense) strand GGAUGCUGAGACGCAGGUGGUCUAGCA

[0413] SEQ ID NO: 189 - DsiRNA 91 passenger (sense) strand AGUGAAGAAAUGAAAGACAAAGGUG

[0414] SEQ ID NO: 190 - DsiRNA 91 guide (antisense) strand CACCUUUGUCUUUCAUUUCUUCACUCA

[0415] SEQ ID NO: 191 - DsiRNA 92 passenger (sense) strand GUGAAGAAAUGAAAGACAAAGGUGG

[0416] SEQ ID NO: 192 - DsiRNA 92 guide (antisense) strand CCACCUUUGUCUUUCAUUUCUUCACUC

[0417] SEQ ID NO: 193 - DsiRNA 93 passenger (sense) strand UGAAGAAAUGAAAGACAAAGGUGGA

[0418] SEQ ID NO: 194 - DsiRNA 93 guide (antisense) strand UCCACCUUUGUCUUUCAUUUCUUCACU

[0419] SEQ ID NO: 195 - DsiRNA 94 passenger (sense) strand GAAGAAAUGAAAGACAAAGGUGGAU

[0420] SEQ ID NO: 196 - DsiRNA 94 guide (antisense) strand AUCCACCUUUGUCUUUCAUUUCUUCAC

[0421] SEQ ID NO: 197 - DsiRNA 95 passenger (sense) strand AAGAAAUGAAAGACAAAGGUGGAUA

[0422] SEQ ID NO: 198 - DsiRNA 95 guide (antisense) strand UAUCCACCUUUGUCUUUCAUUUCUUCA

[0423] SEQ ID NO: 199 - DsiRNA 96 passenger (sense) strand AGAAAUGAAAGACAAAGGUGGAUAC

[0424] SEQ ID NO: 200 - DsiRNA 96 guide (antisense) strand GUAUCCACCUUUGUCUUUCAUUUCUUC

[0425] SEQ ID NO: 201 - DsiRNA 97 passenger (sense) strand GAAAUGAAAGACAAAGGUGGAUACA

[0426] SEQ ID NO: 202 - DsiRNA 97 guide (antisense) strand UGUAUCCACCUUUGUCUUUCAUUUCUU

[0427] SEQ ID NO: 203 - DsiRNA 98 passenger (sense) strand AAAUGAAAGACAAAGGUGGAUACAU

[0428] SEQ ID NO: 204 - DsiRNA 98 guide (antisense) strand AUGUAUCCACCUUUGUCUUUCAUUUCU

[0429] SEQ ID NO: 205 - DsiRNA 99 passenger (sense) strand AAUGAAAGACAAAGGUGGAUACAUG

[0430] SEQ ID NO: 206 - DsiRNA 99 guide (antisense) strand CAUGUAUCCACCUUUGUCUUUCAUUUC

[0431] SEQ ID NO: 207 - DsiRNA 100 passenger (sense) strand AUGAAAGACAAAGGUGGAUACAUGA

[0432] SEQ ID NO: 208 - DsiRNA 100 guide (antisense) strand UCAUGUAUCCACCUUUGUCUUUCAUUU

[0433] SEQ ID NO: 209 - DsiRNA 101 passenger (sense) strand UGAAAGACAAAGGUGGAUACAUGAG

[0434] SEQ ID NO: 210 - DsiRNA 101 guide (antisense) strand CUCAUGUAUCCACCUUUGUCUUUCAUU

[0435] SEQ ID NO: 211 - DsiRNA 102 passenger (sense) strand GAAAGACAAAGGUGGAUACAUGAGC

[0436] SEQ ID NO: 212 - DsiRNA 102 guide (antisense) strand GCUCAUGUAUCCACCUUUGUCUUUCAU

[0437] SEQ ID NO: 213 - DsiRNA 103 passenger (sense) strand AAGACAAAGGUGGAUACAUGAGCAA

[0438] SEQ ID NO: 214 - DsiRNA 103 guide (antisense) strand UUGCUCAUGUAUCCACCUUUGUCUUUC

[0439] SEQ ID NO: 215 - DsiRNA 104 passenger (sense) strand AGACAAAGGUGGAUACAUGAGCAAG

[0440] SEQ ID NO: 216 - DsiRNA 104 guide (antisense) strand CUUGCUCAUGUAUCCACCUUUGUCUUU

[0441] SEQ ID NO: 217 - DsiRNA 105 passenger (sense) strand GACAAAGGUGGAUACAUGAGCAAGA

[0442] SEQ ID NO: 218 - DsiRNA 105 guide (antisense) strand UCUUGCUCAUGUAUCCACCUUUGUCUU

[0443] SEQ ID NO: 219 - DsiRNA 106 passenger (sense) strand ACAAAGGUGGAUACAUGAGCAAGAU

[0444] SEQ ID NO: 220 - DsiRNA 106 guide (antisense) strand AUCUUGCUCAUGUAUCCACCUUUGUCU

[0445] SEQ ID NO: 221 - DsiRNA 107 passenger (sense) strand AAGGUGGAUACAUGAGCAAGAUUUG

[0446] SEQ ID NO: 222 - DsiRNA 107 guide (antisense) strand CAAAUCUUGCUCAUGUAUCCACCUUUG

[0447] SEQ ID NO: 223 - DsiRNA 108 passenger (sense) strand AGGUGGAUACAUGAGCAAGAUUUGC

[0448] SEQ ID NO: 224 - DsiRNA 108 guide (antisense) strand GCAAAUCUUGCUCAUGUAUCCACCUUU

[0449] SEQ ID NO: 225 - DsiRNA 109 passenger (sense) strand UGGAUACAUGAGCAAGAUUUGCAAC

[0450] SEQ ID NO: 226 - DsiRNA 109 guide (antisense) strand GUUGCAAAUCUUGCUCAUGUAUCCACC

[0451] SEQ ID NO: 227 - DsiRNA 110 passenger (sense) strand GGAUACAUGAGCAAGAUUUGCAACU

[0452] SEQ ID NO: 228 - DsiRNA 110 guide (antisense) strand AGUUGCAAAUCUUGCUCAUGUAUCCAC

[0453] SEQ ID NO: 229 - DsiRNA 111 passenger (sense) strand GAUACAUGAGCAAGAUUUGCAACUU

[0454] SEQ ID NO: 230 - DsiRNA 111 guide (antisense) strand AAGUUGCAAAUCUUGCUCAUGUAUCCA

[0455] SEQ ID NO: 231 - DsiRNA 112 passenger (sense) strand AUACAUGAGCAAGAUUUGCAACUUG

[0456] SEQ ID NO: 232 - DsiRNA 112 guide (antisense) strand CAAGUUGCAAAUCUUGCUCAUGUAUCC

[0457] SEQ ID NO: 233 - DsiRNA 113 passenger (sense) strand UACAUGAGCAAGAUUUGCAACUUGC

[0458] SEQ ID NO: 234 - DsiRNA 113 guide (antisense) strand GCAAGUUGCAAAUCUUGCUCAUGUAUC

[0459] SEQ ID NO: 235 - DsiRNA 114 passenger (sense) strand ACAUGAGCAAGAUUUGCAACUUGCU

[0460] SEQ ID NO: 236 - DsiRNA 114 guide (antisense) strand AGCAAGUUGCAAAUCUUGCUCAUGUAU

[0461] SEQ ID NO: 237 - DsiRNA 115 passenger (sense) strand CAUGAGCAAGAUUUGCAACUUGCUA

[0462] SEQ ID NO: 238 - DsiRNA 115 guide (antisense) strand UAGCAAGUUGCAAAUCUUGCUCAUGUA

[0463] SEQ ID NO: 239: DsiRNA 116 passenger (sense) strand AUGAGCAAGAUUUGCAACUUGCUAC

[0464] SEQ ID NO: 240 - DsiRNA 116 guide (antisense) strand GUAGCAAGUUGCAAAUCUUGCUCAUGU

[0465] SEQ ID NO: 241 - DsiRNA 117 passenger (sense) strand UGAGCAAGAUUUGCAACUUGCUACC

[0466] SEQ ID NO: 242 - DsiRNA 117 guide (antisense) strand GGUAGCAAGUUGCAAAUCUUGCUCAUG

[0467] SEQ ID NO: 243 - DsiRNA 118 passenger (sense) strand GAGCAAGAUUUGCAACUUGCUACCC

[0468] SEQ ID NO: 244 - DsiRNA 118 guide (antisense) strand GGGUAGCAAGUUGCAAAUCUUGCUCAU

[0469] SEQ ID NO: 245 - DsiRNA 119 passenger (sense) strand AGCAAGAUUUGCAACUUGCUACCCA

[0470] SEQ ID NO: 246 - DsiRNA 119 guide (antisense) strand UGGGUAGCAAGUUGCAAAUCUUGCUCA

[0471] SEQ ID NO: 247 - DsiRNA 120 passenger (sense) strand GCAAGAUUUGCAACUUGCUACCCAU

[0472] SEQ ID NO: 248 - DsiRNA 120 guide (antisense) strand AUGGGUAGCAAGUUGCAAAUCUUGCUC

[0473] SEQ ID NO: 249 - DsiRNA 121 passenger (sense) strand CAAGAUUUGCAACUUGCUACCCAUU

[0474] SEQ ID NO: 250 - DsiRNA 121 guide (antisense) strand AAUGGGUAGCAAGUUGCAAAUCUUGCU

[0475] SEQ ID NO: 251 - DsiRNA 122 passenger (sense) strand AAGAUUUGCAACUUGCUACCCAUUA

[0476] SEQ ID NO: 252 - DsiRNA 122 guide (antisense) strand UAAUGGGUAGCAAGUUGCAAAUCUUGC

[0477] SEQ ID NO: 253 - DsiRNA 123 passenger (sense) strand AGAUUUGCAACUUGCUACCCAUUAG

[0478] SEQ ID NO: 254 - DsiRNA 123 guide (antisense) strand CUAAUGGGUAGCAAGUUGCAAAUCUUG

[0479] SEQ ID NO: 255 - DsiRNA 124 passenger (sense) strand GAUUUGCAACUUGCUACCCAUUAGG

[0480] SEQ ID NO: 256 - DsiRNA 124 guide (antisense) strand CCUAAUGGGUAGCAAGUUGCAAAUCUU

[0481] SEQ ID NO: 257 - DsiRNA 125 passenger (sense) strand AUUUGCAACUUGCUACCCAUUAGGA

[0482] SEQ ID NO: 258 - DsiRNA 125 guide (antisense) strand UCCUAAUGGGUAGCAAGUUGCAAAUCU

[0483] SEQ ID NO: 259 - DsiRNA 126 passenger (sense) strand UUUGCAACUUGCUACCCAUUAGGAU

[0484] SEQ ID NO: 260 - DsiRNA 126 guide (antisense) strand AUCCUAAUGGGUAGCAAGUUGCAAAUC

[0485] SEQ ID NO: 261 - DsiRNA 127 passenger (sense) strand UUGCAACUUGCUACCCAUUAGGAUA

[0486] SEQ ID NO: 262 - DsiRNA 127 guide (antisense) strand UAUCCUAAUGGGUAGCAAGUUGCAAAU

[0487] SEQ ID NO: 263 - DsiRNA 128 passenger (sense) strand UGCAACUUGCUACCCAUUAGGAUAA

[0488] SEQ ID NO: 264 - DsiRNA 128 guide (antisense) strand UUAUCCUAAUGGGUAGCAAGUUGCAAA

[0489] SEQ ID NO: 265 - DsiRNA 129 - passenger (sense) strand GCAACUUGCUACCCAUUAGGAUAAU

[0490] SEQ ID NO: 266 - DsiRNA 129 guide (antisense) strand AUUAUCCUAAUGGGUAGCAAGUUGCAA

[0491] SEQ ID NO: 267 - DsiRNA 130 passenger (sense) strand CAACUUGCUACCCAUUAGGAUAAUG

[0492] SEQ ID NO: 268 - DsiRNA 130 guide (antisense) strand CAUUAUCCUAAUGGGUAGCAAGUUGCA

[0493] SEQ ID NO: 269 - DsiRNA 131 passenger (sense) strand CUUGCUACCCAUUAGGAUAAUGUCU

[0494] SEQ ID NO: 270 - DsiRNA 131 guide (antisense) strand AGACAUUAUCCUAAUGGGUAGCAAGUU

[0495] SEQ ID NO: 271 - DsiRNA 132 passenger (sense) strand UUGCUACCCAUUAGGAUAAUGUCUU

[0496] SEQ ID NO: 272 - DsiRNA 132 guide (antisense) strand AAGACAUUAUCCUAAUGGGUAGCAAGU

[0497] SEQ ID NO: 273 - DsiRNA 133 passenger (sense) strand UGCUACCCAUUAGGAUAAUGUCUUA

[0498] SEQ ID NO: 274 - DsiRNA 133 guide (antisense) strand UAAGACAUUAUCCUAAUGGGUAGCAAG

[0499] SEQ ID NO: 275 - DsiRNA 134 passenger (sense) strand AUUAGGAUAAUGUCUUAUGUAAUGC

[0500] SEQ ID NO: 276 - DsiRNA 134 guide (antisense) strand GCAUUACAUAAGACAUUAUCCUAAUGG

[0501] SEQ ID NO: 277 - DsiRNA 135 passenger (sense) strand UUAGGAUAAUGUCUUAUGUAAUGCU

[0502] SEQ ID NO: 278 - DsiRNA 135 guide (antisense) strand AGCAUUACAUAAGACAUUAUCCUAAUG

[0503] SEQ ID NO: 279 - DsiRNA 136 passenger (sense) strand CUGUGGAAUCUGCCAUUGCGAUUGU

[0504] SEQ ID NO: 280 - DsiRNA 136 guide (antisense) strand ACAAUCGCAAUGGCAGAUUCCACAGGC

[0505] SEQ ID NO: 281 - DsiRNA 137 passenger (sense) strand GGAAUCUGCCAUUGCGAUUGUCCAG

[0506] SEQ ID NO: 282 - DsiRNA 137 guide (antisense) strand CUGGACAAUCGCAAUGGCAGAUUCCAC

[0507] SEQ ID NO: 283 - DsiRNA 138 passenger (sense) strand GAAUCUGCCAUUGCGAUUGUCCAGA

[0508] SEQ ID NO: 284 - DsiRNA 138 guide (antisense) strand UCUGGACAAUCGCAAUGGCAGAUUCCA

[0509] SEQ ID NO: 285 - DsiRNA 139 passenger (sense) strand AAUCUGCCAUUGCGAUUGUCCAGAG

[0510] SEQ ID NO: 286 - DsiRNA 139 guide (antisense) strand CUCUGGACAAUCGCAAUGGCAGAUUCC

[0511] SEQ ID NO: 287 - DsiRNA 140 passenger (sense) strand AUCUGCCAUUGCGAUUGUCCAGAGA

[0512] SEQ ID NO: 288 - DsiRNA 140 guide (antisense) strand UCUCUGGACAAUCGCAAUGGCAGAUUC

[0513] SEQ ID NO: 289 - DsiRNA 141 passenger (sense) strand CCAUUGCGAUUGUCCAGAGACUGGU

[0514] SEQ ID NO: 290 - DsiRNA 141 guide (antisense) strand ACCAGUCUCUGGACAAUCGCAAUGGCA

[0515] SEQ ID NO: 291 - DsiRNA 142 passenger (sense) strand CAUUGCGAUUGUCCAGAGACUGGUG

[0516] SEQ ID NO: 292 - DsiRNA 142 guide (antisense) strand CACCAGUCUCUGGACAAUCGCAAUGGC

[0517] SEQ ID NO: 293 - DsiRNA 143 passenger (sense) strand AUUGCGAUUGUCCAGAGACUGGUGA

[0518] SEQ ID NO: 294 - DsiRNA 143 guide (antisense) strand UCACCAGUCUCUGGACAAUCGCAAUGG

[0519] SEQ ID NO: 295 - DsiRNA 144 passenger (sense) strand UUGCGAUUGUCCAGAGACUGGUGAC

[0520] SEQ ID NO: 296 - DsiRNA 144 guide (antisense) strand GUCACCAGUCUCUGGACAAUCGCAAUG

[0521] SEQ ID NO: 297 - DsiRNA 145 passenger (sense) strand UGCGAUUGUCCAGAGACUGGUGACA

[0522] SEQ ID NO: 298 - DsiRNA 145 guide (antisense) strand UGUCACCAGUCUCUGGACAAUCGCAAU

[0523] SEQ ID NO: 299 - DsiRNA 146 passenger (sense) strand GCGAUUGUCCAGAGACUGGUGACAU

[0524] SEQ ID NO: 300 - DsiRNA 146 guide (antisense) strand AUGUCACCAGUCUCUGGACAAUCGCAA

[0525] SEQ ID NO: 301 - DsiRNA 147 passenger (sense) strand CGAUUGUCCAGAGACUGGUGACAUG

[0526] SEQ ID NO: 302 - DsiRNA 147 guide (antisense) strand CAUGUCACCAGUCUCUGGACAAUCGCA

[0527] SEQ ID NO: 303 - DsiRNA 148 passenger (sense) AUUGUCCAGAGACUGGUGACAUGGC

[0528] SEQ ID NO: 304 - DsiRNA 148 guide (antisense) strand GCCAUGUCACCAGUCUCUGGACAAUCG

[0529] SEQ ID NO: 305 - DsiRNA 149 passenger (sense) strand GUCCAGAGACUGGUGACAUGGCUUC

[0530] SEQ ID NO: 306 - DsiRNA 149 guide (antisense) strand GAAGCCAUGUCACCAGUCUCUGGACAA

[0531] SEQ ID NO: 307 - DsiRNA 150 passenger (sense) strand CCAGAGACUGGUGACAUGGCUUCCA

[0532] SEQ ID NO: 308 - DsiRNA 150 guide (antisense) strand UGGAAGCCAUGUCACCAGUCUCUGGAC

[0533] SEQ ID NO: 309 - DsiRNA 151 passenger (sense) CAGAGACUGGUGACAUGGCUUCCAG

[0534] SEQ ID NO: 310 - DsiRNA 151 guide (antisense) strand CUGGAAGCCAUGUCACCAGUCUCUGGA

[0535] SEQ ID NO: 311 - DsiRNA 152 passenger (sense) strand AGAGACUGGUGACAUGGCUUCCAGA

[0536] SEQ ID NO: 312 - DsiRNA 152 guide (antisense) strand UCUGGAAGCCAUGUCACCAGUCUCUGG

[0537] SEQ ID NO: 313 - DsiRNA 153 passenger (sense) strand GAGACUGGUGACAUGGCUUCCAGAU

[0538] SEQ ID NO: 314 - DsiRNA 153 guide (antisense) strand AUCUGGAAGCCAUGUCACCAGUCUCUG

[0539] SEQ ID NO: 315 - DsiRNA 154 passenger (sense) strand AGACUGGUGACAUGGCUUCCAGAUA

[0540] SEQ ID NO: 316 - DsiRNA 154 guide (antisense) strand UAUCUGGAAGCCAUGUCACCAGUCUCU

[0541] SEQ ID NO: 317 - DsiRNA 155 passenger (sense) strand GACUGGUGACAUGGCUUCCAGAUAU

[0542] SEQ ID NO: 318 - DsiRNA 155 guide (antisense) strand AUAUCUGGAAGCCAUGUCACCAGUCUC

[0543] SEQ ID NO: 319 - DsiRNA 156 passenger (sense) strand ACUGGUGACAUGGCUUCCAGAUAUG

[0544] SEQ ID NO: 320 - DsiRNA 156 guide (antisense) strand CAUAUCUGGAAGCCAUGUCACCAGUCU

[0545] SEQ ID NO: 321 - DsiRNA 157 passenger (sense) strand CUGGUGACAUGGCUUCCAGAUAUGC

[0546] SEQ ID NO: 322 - DsiRNA 157 guide (antisense) strand GCAUAUCUGGAAGCCAUGUCACCAGUC

[0547] SEQ ID NO: 323 - DsiRNA 158 passenger (sense) strand GACAUGGCUUCCAGAUAUGCCCGAC

[0548] SEQ ID NO: 324 - DsiRNA 158 guide (antisense) strand GUCGGGCAUAUCUGGAAGCCAUGUCAC

[0549] SEQ ID NO: 325 - DsiRNA 159 passenger (sense) strand CAUGGCUUCCAGAUAUGCCCGACGA

[0550] SEQ ID NO: 326 - DsiRNA 159 guide (antisense) strand UCGUCGGGCAUAUCUGGAAGCCAUGUC

[0551] SEQ ID NO: 327 - DsiRNA 160 passenger (sense) strand CAGAUAUGCCCGACGAUGUCCUGUG

[0552] SEQ ID NO: 328 - DsiRNA 160 guide (antisense) strand CACAGGACAUCGUCGGGCAUAUCUGGA

[0553] SEQ ID NO: 329 - DsiRNA 161 passenger (sense) strand CUCACAGGUGUUCACUCGAGUGCUG

[0554] SEQ ID NO: 330 - DsiRNA 161 guide (antisense) strand CAGCACUCGAGUGAACACCUGUGAGGU

[0555] SEQ ID NO: 331 - DsiRNA 162 passenger (sense) strand CACUCGAGUGCUGAUGUGUCUGCUC

[0556] SEQ ID NO: 332 - DsiRNA 162 guide (antisense) strand GAGCAGACACAUCAGCACUCGAGUGAA

[0557] SEQ ID NO: 333 - DsiRNA 163 passenger (sense) strand CUCGAGUGCUGAUGUGUCUGCUCCC

[0558] SEQ ID NO: 334 - DsiRNA 163 guide (antisense) strand GGGAGCAGACACAUCAGCACUCGAGUG

[0559] SEQ ID NO: 335 - DsiRNA 164 passenger (sense) strand CCCAAAUGCCAGUGAGCAGCCAACA

[0560] SEQ ID NO: 336 - DsiRNA 164 guide (antisense) strand UGUUGGCUGCUCACUGGCAUUUGGGAC

[0561] SEQ ID NO: 337 - DsiRNA 165 passenger (sense) strand UCAGGUCCAGCCUGAACUUCUUCUU

[0562] SEQ ID NO: 338 - DsiRNA 165 guide (antisense) strand AAGAAGAAGUUCAGGCUGGACCUGAGG

[0563] SEQ ID NO: 339 - DsiRNA 166 passenger (sense) strand CAGGUCCAGCCUGAACUUCUUCUUG

[0564] SEQ ID NO: 340 - DsiRNA 166 guide (antisense) strand CAAGAAGAAGUUCAGGCUGGACCUGAG

[0565] SEQ ID NO: 341 - DsiRNA 167 passenger (sense) strand AGGUCCAGCCUGAACUUCUUCUUGG

[0566] SEQ ID NO: 342 - DsiRNA 167 guide (antisense) strand CCAAGAAGAAGUUCAGGCUGGACCUGA

[0567] SEQ ID NO: 343 - DsiRNA 168 passenger (sense) strand CAAUAAAGUACCUGCUGGUGCUGAG

[0568] SEQ ID NO: 344 - DsiRNA 168 guide (antisense) strand CUCAGCACCAGCAGGUACUUUAUUGCC

[0569] SEQ ID NO: 345 - DsiRNA 169 passenger (sense) strand AAUAAAGUACCUGCUGGUGCUGAGG

[0570] SEQ ID NO: 346 - DsiRNA 169 guide (antisense) strand CCUCAGCACCAGCAGGUACUUUAUUGC

[0571] SEQ ID NO: 347 - DsiRNA 170 passenger (sense) strand AUAAAGUACCUGCUGGUGCUGAGGG

[0572] SEQ ID NO: 348 - DsiRNA 170 guide (antisense) strand CCCUCAGCACCAGCAGGUACUUUAUUG

[0573] SEQ ID NO: 349 - DsiRNA 171 passenger (sense) strand CUCUCCACCUUUCCCAGUUUUUCAC

[0574] SEQ ID NO: 350 - DsiRNA 171 guide (antisense) strand GUGAAAAACUGGGAAAGGUGGAGAGCC

[0575] SEQ ID NO: 351 - DsiRNA 172 passenger (sense) strand CUCCACCUUUCCCAGUUUUUCACUA

[0576] SEQ ID NO: 352 - DsiRNA 172 guide (antisense) strand UAGUGAAAAACUGGGAAAGGUGGAGAG

[0577] SEQ ID NO: 353 - DsiRNA 173 passenger (sense) strand UCCACCUUUCCCAGUUUUUCACUAG

[0578] SEQ ID NO: 354 - DsiRNA 173 guide (antisense) strand CUAGUGAAAAACUGGGAAAGGUGGAGA

[0579] SEQ ID NO: 355 - DsiRNA 174 passenger (sense) strand CCACCUUUCCCAGUUUUUCACUAGA

[0580] SEQ ID NO: 356 - DsiRNA 174 guide (antisense) strand UCUAGUGAAAAACUGGGAAAGGUGGAG

[0581] SEQ ID NO: 357 - DsiRNA 175 passenger (sense) strand CACCUUUCCCAGUUUUUCACUAGAG

[0582] SEQ ID NO: 358 - DsiRNA 175 guide (antisense) strand CUCUAGUGAAAAACUGGGAAAGGUGGA

[0583] SEQ ID NO: 359 - DsiRNA 176 passenger (sense) strand ACCUUUCCCAGUUUUUCACUAGAGA

[0584] SEQ ID NO: 360 - DsiRNA 176 guide (antisense) strand UCUCUAGUGAAAAACUGGGAAAGGUGG

[0585] SEQ ID NO: 361 - DsiRNA 177 passenger (sense) strand CCUUUCCCAGUUUUUCACUAGAGAA

[0586] SEQ ID NO: 362 - DsiRNA 177 guide (antisense) strand UUCUCUAGUGAAAAACUGGGAAAGGUG

[0587] SEQ ID NO: 363 - DsiRNA 178 passenger (sense) strand AGUUUUUCACUAGAGAAGAGUCUGU

[0588] SEQ ID NO: 364 - DsiRNA 178 guide (antisense) strand ACAGACUCUUCUCUAGUGAAAAACUGG

[0589] SEQ ID NO: 365 - DsiRNA 179 passenger (sense) strand UCUAGCAGAUUCUUUCAGAGGUGCU

[0590] SEQ ID NO: 366 - DsiRNA 179 guide (antisense) strand AGCACCUCUGAAAGAAUCUGCUAGACU

[0591] SEQ ID NO: 367 - DsiRNA 180 passenger (sense) strand AGCAGAUUCUUUCAGAGGUGCUAAA

[0592] SEQ ID NO: 368 - DsiRNA 180 guide (antisense) strand UUUAGCACCUCUGAAAGAAUCUGCUAG

[0593] SEQ ID NO: 369 - DsiRNA 181 passenger (sense) strand GCAGAUUCUUUCAGAGGUGCUAAAG

[0594] SEQ ID NO: 370 - DsiRNA 181 guide (antisense) strand CUUUAGCACCUCUGAAAGAAUCUGCUA

[0595] SEQ ID NO: 371 - DsiRNA 182 passenger (sense) strand CAGAUUCUUUCAGAGGUGCUAAAGU

[0596] SEQ ID NO: 372 - DsiRNA 182 guide (antisense) strand ACUUUAGCACCUCUGAAAGAAUCUGCU

[0597] SEQ ID NO: 373 - DsiRNA 183 passenger (sense) strand AGAUUCUUUCAGAGGUGCUAAAGUU

[0598] SEQ ID NO: 374 - DsiRNA 183 guide (antisense) strand AACUUUAGCACCUCUGAAAGAAUCUGC

[0599] SEQ ID NO: 375 - DsiRNA 184 passenger (sense) strand GAUUCUUUCAGAGGUGCUAAAGUUU

[0600] SEQ ID NO: 376 - DsiRNA 184 guide (antisense) strand AAACUUUAGCACCUCUGAAAGAAUCUG

[0601] SEQ ID NO: 377 - DsiRNA 185 passenger (sense) strand AUUCUUUCAGAGGUGCUAAAGUUUC

[0602] SEQ ID NO: 378 - DsiRNA 185 guide (antisense) strand GAAACUUUAGCACCUCUGAAAGAAUCU

[0603] SEQ ID NO: 379 - DsiRNA 186 passenger (sense) strand AGGUGCUAAAGUUUCCCAUCUUUGU

[0604] SEQ ID NO: 380 - DsiRNA 186 guide (antisense) strand ACAAAGAUGGGAAACUUUAGCACCUCU

[0605] SEQ ID NO: 381 - DsiRNA 187 passenger (sense) strand GGUGCUAAAGUUUCCCAUCUUUGUG

[0606] SEQ ID NO: 382 - DsiRNA 187 guide (antisense) strand CACAAAGAUGGGAAACUUUAGCACCUC

[0607] SEQ ID NO: 383 - DsiRNA 188 passenger (sense) strand GUGCUAAAGUUUCCCAUCUUUGUGC

[0608] SEQ ID NO: 384 - DsiRNA 188 guide (antisense) strand GCACAAAGAUGGGAAACUUUAGCACCU

[0609] SEQ ID NO: 385 - DsiRNA 189 passenger (sense) strand GCUAAAGUUUCCCAUCUUUGUGCAG

[0610] SEQ ID NO: 386 - DsiRNA 189 guide (antisense) strand CUGCACAAAGAUGGGAAACUUUAGCAC

[0611] SEQ ID NO: 387 - DsiRNA 190 passenger (sense) strand CUAAAGUUUCCCAUCUUUGUGCAGC

[0612] SEQ ID NO: 388 - DsiRNA 190 guide (antisense) strand GCUGCACAAAGAUGGGAAACUUUAGCA

[0613] SEQ ID NO: 389 - DsiRNA 191 passenger (sense) strand UAAAGUUUCCCAUCUUUGUGCAGCU

[0614] SEQ ID NO: 390 - DsiRNA 191 guide (antisense) strand AGCUGCACAAAGAUGGGAAACUUUAGC

[0615] SEQ ID NO: 391 - DsiRNA 192 passenger (sense) strand AAAGUUUCCCAUCUUUGUGCAGCUA

[0616] SEQ ID NO: 392 - DsiRNA 192 guide (antisense) strand UAGCUGCACAAAGAUGGGAAACUUUAG

[0617] SEQ ID NO: 393 - DsiRNA 193 passenger (sense) strand AAGUUUCCCAUCUUUGUGCAGCUAC

[0618] SEQ ID NO: 394 - DsiRNA 193 guide (antisense) strand GUAGCUGCACAAAGAUGGGAAACUUUA

[0619] SEQ ID NO: 395 - DsiRNA 194 passenger (sense) strand AGUUUCCCAUCUUUGUGCAGCUACC

[0620] SEQ ID NO: 396 - DsiRNA 194 guide (antisense) strand GGUAGCUGCACAAAGAUGGGAAACUUU

[0621] SEQ ID NO: 397 - DsiRNA 195 passenger (sense) strand GUUUCCCAUCUUUGUGCAGCUACCU

[0622] SEQ ID NO: 398 - DsiRNA 195 guide (antisense) strand AGGUAGCUGCACAAAGAUGGGAAACUU

[0623] SEQ ID NO: 399 - DsiRNA 196 passenger (sense) strand AUCUUUGUGCAGCUACCUCCGCAUU

[0624] SEQ ID NO: 400 - DsiRNA 196 guide (antisense) strand AAUGCGGAGGUAGCUGCACAAAGAUGG

[0625] SEQ ID NO: 401 - DsiRNA 197 passenger (sense) strand GUGCAGCUACCUCCGCAUUGCUGUG

[0626] SEQ ID NO: 402 - DsiRNA 197 guide (antisense) strand CACAGCAAUGCGGAGGUAGCUGCACAA

[0627] SEQ ID NO: 403 - DsiRNA 198 passenger (sense) strand CCAGCCUCUGAGCUGAGUUGGUUUU

[0628] SEQ ID NO: 404 - DsiRNA 198 guide (antisense) strand AAAACCAACUCAGCUCAGAGGCUGGGA

[0629] SEQ ID NO: 405 - DsiRNA 199 passenger (sense) strand CAGCCUCUGAGCUGAGUUGGUUUUA

[0630] SEQ ID NO: 406 - DsiRNA 199 guide (antisense) strand UAAAACCAACUCAGCUCAGAGGCUGGG

[0631] SEQ ID NO: 407 - DsiRNA 200 passenger (sense) strand AGCCUCUGAGCUGAGUUGGUUUUAU

[0632] SEQ ID NO: 408 - DsiRNA 200 guide (antisense) strand AUAAAACCAACUCAGCUCAGAGGCUGG

[0633] SEQ ID NO: 409 - DsiRNA 201 passenger (sense) strand GCCUCUGAGCUGAGUUGGUUUUAUG

[0634] SEQ ID NO: 410 - DsiRNA 201 guide (antisense) strand CAUAAAACCAACUCAGCUCAGAGGCUG

[0635] SEQ ID NO: 411 - DsiRNA 202 passenger (sense) strand CCUCUGAGCUGAGUUGGUUUUAUGA

[0636] SEQ ID NO: 412 - DsiRNA 202 guide (antisense) strand UCAUAAAACCAACUCAGCUCAGAGGCU

[0637] SEQ ID NO: 413 - DsiRNA 203 passenger (sense) strand CUCUGAGCUGAGUUGGUUUUAUGAA

[0638] SEQ ID NO: 414 - DsiRNA 203 guide (antisense) strand UUCAUAAAACCAACUCAGCUCAGAGGC

[0639] SEQ ID NO: 415 - DsiRNA 204 passenger (sense) strand UCUGAGCUGAGUUGGUUUUAUGAAA

[0640] SEQ ID NO: 416 - DsiRNA 204 guide (antisense) strand UUUCAUAAAACCAACUCAGCUCAGAGG

[0641] SEQ ID NO: 417 - DsiRNA 205 passenger (sense) strand UGAGCUGAGUUGGUUUUAUGAAAAG

[0642] SEQ ID NO: 418 - DsiRNA 205 guide (antisense) strand CUUUUCAUAAAACCAACUCAGCUCAGA

[0643] SEQ ID NO: 419 - DsiRNA 206 passenger (sense) strand UGAGUUGGUUUUAUGAAAAGCUAGG

[0644] SEQ ID NO: 420 - DsiRNA 206 guide (antisense) strand CCUAGCUUUUCAUAAAACCAACUCAGC

[0645] SEQ ID NO: 421 - DsiRNA 207 passenger (sense) strand GAGUUGGUUUUAUGAAAAGCUAGGA

[0646] SEQ ID NO: 422 - DsiRNA 207 guide (antisense) strand UCCUAGCUUUUCAUAAAACCAACUCAG

[0647] SEQ ID NO: 423 - DsiRNA 208 passenger (sense) strand UUGGUUUUAUGAAAAGCUAGGAAGC

[0648] SEQ ID NO: 424 - DsiRNA 208 guide (antisense) strand GCUUCCUAGCUUUUCAUAAAACCAACU

[0649] SEQ ID NO: 425 - DsiRNA 209 passenger (sense) strand UGGUUUUAUGAAAAGCUAGGAAGCA

[0650] SEQ ID NO: 426 - DsiRNA 209 guide (antisense) strand UGCUUCCUAGCUUUUCAUAAAACCAAC

[0651] SEQ ID NO: 427 - DsiRNA 210 passenger (sense) strand GGUUUUAUGAAAAGCUAGGAAGCAA

[0652] SEQ ID NO: 428 - DsiRNA 210 guide (antisense) strand UUGCUUCCUAGCUUUUCAUAAAACCAA

[0653] SEQ ID NO: 429 - DsiRNA 211 passenger (sense) strand UUUUAUGAAAAGCUAGGAAGCAACC

[0654] SEQ ID NO: 430 - DsiRNA 211 guide (antisense) strand GGUUGCUUCCUAGCUUUUCAUAAAACC

[0655] SEQ ID NO: 431 - DsiRNA 212 passenger (sense) strand UUAUGAAAAGCUAGGAAGCAACCUU

[0656] SEQ ID NO: 432 - DsiRNA 212 guide (antisense) strand AAGGUUGCUUCCUAGCUUUUCAUAAA

[0657] SEQ ID NO: 433 - DsiRNA 213 passenger (sense) strand UAUGAAAAGCUAGGAAGCAACCUUU

[0658] SEQ ID NO: 434 - DsiRNA 213 guide (antisense) strand AAAGGUUGCUUCCUAGCUUUUCAUAAA

[0659] SEQ ID NO: 435 - DsiRNA 214 passenger (sense) strand AUGAAAAGCUAGGAAGCAACCUUUC

[0660] SEQ ID NO: 436 - DsiRNA 214 guide (antisense) strand GAAAGGUUGCUUCCUAGCUUUUCAUAA

[0661] SEQ ID NO: 437 - DsiRNA 215 passenger (sense) strand CCAGCACUUAACUCUAAUACAUCAG

[0662] SEQ ID NO: 438 - DsiRNA 215 guide (antisense) strand CUGAUGUAUUAGAGUUAAGUGCUGGAC

[0663] SEQ ID NO: 439 - DsiRNA 216 passenger (sense) strand CAGCACUUAACUCUAAUACAUCAGC

[0664] SEQ ID NO: 440 - DsiRNA 216 guide (antisense) strand GCUGAUGUAUUAGAGUUAAGUGCUGGA

[0665] SEQ ID NO: 441 - DsiRNA 217 passenger (sense) strand UAAUACAUCAGCAUGCGUUAAUUCA

[0666] SEQ ID NO: 442 - DsiRNA 217 guide (antisense) strand UGAAUUAACGCAUGCUGAUGUAUUAGA

[0667] SEQ ID NO: 443 - DsiRNA 218 passenger (sense) strand AAUACAUCAGCAUGCGUUAAUUCAG

[0668] SEQ ID NO: 444 - DsiRNA 218 guide (antisense) strand CUGAAUUAACGCAUGCUGAUGUAUUAG

[0669] SEQ ID NO: 445 - DsiRNA 219 passenger (sense) strand AGCAUGCGUUAAUUCAGCUGGUUGG

[0670] SEQ ID NO: 446 - DsiRNA 219 guide (antisense) strand CCAACCAGCUGAAUUAACGCAUGCUGA

[0671] SEQ ID NO: 447 - DsiRNA 220 passenger (sense) strand GCAUGCGUUAAUUCAGCUGGUUGGG

[0672] SEQ ID NO: 448 - DsiRNA 220 guide (antisense) strand CCCAACCAGCUGAAUUAACGCAUGCUG

[0673] SEQ ID NO: 449 - DsiRNA 221 passenger (sense) strand UGCGUUAAUUCAGCUGGUUGGGAAA

[0674] SEQ ID NO: 450 - DsiRNA 221 guide (antisense) strand UUUCCCAACCAGCUGAAUUAACGCAUG

[0675] SEQ ID NO: 451 - DsiRNA 222 passenger (sense) strand GCGUUAAUUCAGCUGGUUGGGAAAU

[0676] SEQ ID NO: 452 - DsiRNA 222 guide (antisense) strand AUUUCCCAACCAGCUGAAUUAACGCAU

[0677] SEQ ID NO: 453 - DsiRNA 223 passenger (sense) strand CGUUAAUUCAGCUGGUUGGGAAAUG

[0678] SEQ ID NO: 454 - DsiRNA 223 guide (antisense) strand CAUUUCCCAACCAGCUGAAUUAACGCA

[0679] SEQ ID NO: 455 - DsiRNA 224 passenger (sense) strand GUUAAUUCAGCUGGUUGGGAAAUGA

[0680] SEQ ID NO: 456 - DsiRNA 224 guide (antisense) strand UCAUUUCCCAACCAGCUGAAUUAACGC

[0681] SEQ ID NO: 457 - DsiRNA 225 passenger (sense) strand UUAAUUCAGCUGGUUGGGAAAUGAC

[0682] SEQ ID NO: 458 - DsiRNA 225 guide (antisense) strand GUCAUUUCCCAACCAGCUGAAUUAACG

[0683] SEQ ID NO: 459 - DsiRNA 226 passenger (sense) strand UAAUUCAGCUGGUUGGGAAAUGACA

[0684] SEQ ID NO: 460 - DsiRNA 226 guide (antisense) strand UGUCAUUUCCCAACCAGCUGAAUUAAC

[0685] SEQ ID NO: 461 - DsiRNA 227 passenger (sense) strand AUUCAGCUGGUUGGGAAAUGACACC

[0686] SEQ ID NO: 462 - DsiRNA 227 guide (antisense) strand GGUGUCAUUUCCCAACCAGCUGAAUUA

[0687] SEQ ID NO: 463 - DsiRNA 228 passenger (sense) strand UUCAGCUGGUUGGGAAAUGACACCA

[0688] SEQ ID NO: 464 - DsiRNA 228 guide (antisense) strand UGGUGUCAUUUCCCAACCAGCUGAAUU

[0689] SEQ ID NO: 465 - DsiRNA 229 passenger (sense) strand UCAGCUGGUUGGGAAAUGACACCAG

[0690] SEQ ID NO: 466 - DsiRNA 229 guide (antisense) strand CUGGUGUCAUUUCCCAACCAGCUGAAU

[0691] SEQ ID NO: 467 - DsiRNA 230 passenger (sense) strand CAGCUGGUUGGGAAAUGACACCAGG

[0692] SEQ ID NO: 468 - DsiRNA 230 guide (antisense) strand CCUGGUGUCAUUUCCCAACCAGCUGAA

[0693] SEQ ID NO: 469 - DsiRNA 231 passenger (sense) strand AGCUGGUUGGGAAAUGACACCAGGA

[0694] SEQ ID NO: 470 - DsiRNA 231 guide (antisense) strand UCCUGGUGUCAUUUCCCAACCAGCUGA

[0695] SEQ ID NO: 471 - DsiRNA 232 passenger (sense) strand GCUGGUUGGGAAAUGACACCAGGAA

[0696] SEQ ID NO: 472 - DsiRNA 232 guide (antisense) strand UUCCUGGUGUCAUUUCCCAACCAGCUG

[0697] SEQ ID NO: 473 - DsiRNA 233 passenger (sense) strand GCAGAGGGUCCCUUACUGACUGUUU

[0698] SEQ ID NO: 474 - DsiRNA 233 guide (antisense) strand AAACAGUCAGUAAGGGACCCUCUGCAC

[0699] SEQ ID NO: 475 - DsiRNA 234 passenger (sense) strand CAGAGGGUCCCUUACUGACUGUUUC

[0700] SEQ ID NO: 476 - DsiRNA 234 guide (antisense) strand GAAACAGUCAGUAAGGGACCCUCUGCA

[0701] SEQ ID NO: 477 - DsiRNA 235 passenger (sense) strand AGAGGGUCCCUUACUGACUGUUUCG

[0702] SEQ ID NO: 478 - DsiRNA 235 guide (antisense) strand CGAAACAGUCAGUAAGGGACCCUCUGC

[0703] SEQ ID NO: 479 - DsiRNA 236 passenger (sense) strand CCUAUUAAUGGUCAGACUGUUCCAG

[0704] SEQ ID NO: 480 - DsiRNA 236 guide (antisense) strand CUGGAACAGUCUGACCAUUAAUAGGGC

[0705] SEQ ID NO: 481 - DsiRNA 237 passenger (sense) strand CUAUUAAUGGUCAGACUGUUCCAGC

[0706] SEQ ID NO: 482 - DsiRNA 237 guide (antisense) strand GCUGGAACAGUCUGACCAUUAAUAGGG

[0707] SEQ ID NO: 483 - DsiRNA 238 passenger (sense) strand UAUUAAUGGUCAGACUGUUCCAGCA

[0708] SEQ ID NO: 484 - DsiRNA 238 guide (antisense) strand UGCUGGAACAGUCUGACCAUUAAUAGG

[0709] SEQ ID NO: 485 - DsiRNA 239 passenger (sense) strand AUUAAUGGUCAGACUGUUCCAGCAU

[0710] SEQ ID NO: 486 - DsiRNA 239 guide (antisense) strand AUGCUGGAACAGUCUGACCAUUAAUAG

[0711] SEQ ID NO: 487 - DsiRNA 240 passenger (sense) strand UUAAUGGUCAGACUGUUCCAGCAUG

[0712] SEQ ID NO: 488 - DsiRNA 240 guide (antisense) strand CAUGCUGGAACAGUCUGACCAUUAAUA

[0713] SEQ ID NO: 489 - DsiRNA 241 passenger (sense) strand UAAUGGUCAGACUGUUCCAGCAUGA

[0714] SEQ ID NO: 490 - DsiRNA 241 guide (antisense) strand UCAUGCUGGAACAGUCUGACCAUUAAU

[0715] SEQ ID NO: 491 - DsiRNA 242 passenger (sense) strand AAUGGUCAGACUGUUCCAGCAUGAG

[0716] SEQ ID NO: 492 - DsiRNA 242 guide (antisense) strand CUCAUGCUGGAACAGUCUGACCAUUAA

[0717] SEQ ID NO: 493 - DsiRNA 243 passenger (sense) strand AGAACGACACUGCCUGUCAGGUGGU

[0718] SEQ ID NO: 494 - DsiRNA 243 guide (antisense) strand ACCACCUGACAGGCAGUGUCGUUCUUG

[0719] SEQ ID NO: 495 - DsiRNA 244 passenger (sense) strand CGACACUGCCUGUCAGGUGGUCUGC

[0720] SEQ ID NO: 496 - DsiRNA 244 guide (antisense) strand GCAGACCACCUGACAGGCAGUGUCGUU

[0721] SEQ ID NO: 497 - DsiRNA 245 passenger (sense) strand AACCUUGACUACUAAAAACGUCUCC

[0722] SEQ ID NO: 498 - DsiRNA 245 guide (antisense) strand GGAGACGUUUUUAGUAGUCAAGGUUAU

[0723] SEQ ID NO: 499 - DsiRNA 246 passenger (sense) strand UUUAGAACACCUUUUUCACCUAACU

[0724] SEQ ID NO: 500 - DsiRNA 246 guide (antisense) strand AGUUAGGUGAAAAAGGUGUUCUAAAAU

[0725] SEQ ID NO: 501 - DsiRNA 247 passenger (sense) strand UUAGAACACCUUUUUCACCUAACUA

[0726] SEQ ID NO: 502 - DsiRNA 247 guide (antisense) strand UAGUUAGGUGAAAAAGGUGUUCUAAAA

[0727] SEQ ID NO: 503 - DsiRNA 248 passenger (sense) strand UAGAACACCUUUUUCACCUAACUAA

[0728] SEQ ID NO: 504 - DsiRNA 248 guide (antisense) strand UUAGUUAGGUGAAAAAGGUGUUCUAAA

[0729] SEQ ID NO: 505 - DsiRNA 249 passenger (sense) strand AGAACACCUUUUUCACCUAACUAAA

[0730] SEQ ID NO: 506 - DsiRNA 249 guide (antisense) strand UUUAGUUAGGUGAAAAAGGUGUUCUAA

[0731] SEQ ID NO: 507 - DsiRNA 250 passenger (sense) strand GAACACCUUUUUCACCUAACUAAAA

[0732] SEQ ID NO: 508 - DsiRNA 250 guide (antisense) strand UUUUAGUUAGGUGAAAAAGGUGUUCUA

[0733] SEQ ID NO: 509 - DsiRNA 251 passenger (sense) strand AACACCUUUUUCACCUAACUAAAAU

[0734] SEQ ID NO: 510 - DsiRNA 251 guide (antisense) strand AUUUUAGUUAGGUGAAAAAGGUGUUCU

[0735] SEQ ID NO:511 - DsiRNA 252 passenger (sense) strand ACACCUUUUUCACCUAACUAAAAUA

[0736] SEQ ID NO: 512 - DsiRNA 252 guide (antisense) strand UAUUUUAGUUAGGUGAAAAAGGUGUUC

[0737] SEQ ID NO: 513 - DsiRNA 253 passenger (sense) strand CACCUUUUUCACCUAACUAAAAUAA

[0738] SEQ ID NO: 514 - DsiRNA 253 guide (antisense) strand UUAUUUUAGUUAGGUGAAAAAGGUGUU

[0739] SEQ ID NO: 515 - DsiRNA 254 passenger (sense) strand ACCUUUUUCACCUAACUAAAAUAAU

[0740] SEQ ID NO: 516 - DsiRNA 254 guide (antisense) strand AUUAUUUUAGUUAGGUGAAAAAGGUGU

[0741] SEQ ID NO: 517 - DsiRNA 255 passenger (sense) strand CUUUUUCACCUAACUAAAAUAAUGU

[0742] SEQ ID NO: 518 - DsiRNA 255 guide (antisense) strand ACAUUAUUUUAGUUAGGUGAAAAAGGU

[0743] SEQ ID NO: 519 - DsiRNA 256 passenger (sense) strand UUUUCACCUAACUAAAAUAAUGUUU

[0744] SEQ ID NO: 520 - DsiRNA 256 guide (antisense) strand AAACAUUAUUUUAGUUAGGUGAAAAAG

[0745] SEQ ID NO: 521 - DsiRNA 257 passenger (sense) strand UUCACCUAACUAAAAUAAUGUUUAA

[0746] SEQ ID NO: 522 - DsiRNA 257 guide (antisense) strand UUAAACAUUAUUUUAGUUAGGUGAAAA

[0747] SEQ ID NO: 523 - DsiRNA 258 passenger (sense) strand UCACCUAACUAAAAUAAUGUUUAAA

[0748] SEQ ID NO: 524 - DsiRNA 258 guide (antisense) strand UUUAAACAUUAUUUUAGUUAGGUGAAA

[0749] SEQ ID NO: 525 - DsiRNA 259 passenger (sense) strand CACCUAACUAAAAUAAUGUUUAAAG

[0750] SEQ ID NO: 526 - DsiRNA 259 guide (antisense) strand CUUUAAACAUUAUUUUAGUUAGGUGAA

[0751] SEQ ID NO: 527 - DsiRNA 260 passenger (sense) strand ACCUAACUAAAAUAAUGUUUAAAGA

[0752] SEQ ID NO: 528 - DsiRNA 260 guide (antisense) strand UCUUUAAACAUUAUUUUAGUUAGGUGA

[0753] SEQ ID NO: 529 - DsiRNA 261 passenger (sense) strand CCUAACUAAAAUAAUGUUUAAAGAG

[0754] SEQ ID NO: 530 - DsiRNA 261 guide (antisense) strand CUCUUUAAACAUUAUUUUAGUUAGGUG

[0755] SEQ ID NO: 531 - DsiRNA 262 passenger (sense) strand CUAACUAAAAUAAUGUUUAAAGAGU

[0756] SEQ ID NO: 532 - DsiRNA 262 guide (antisense) strand ACUCUUUAAACAUUAUUUUAGUUAGGU

[0757] SEQ ID NO: 533 - DsiRNA 263 passenger (sense) strand UAACUAAAAUAAUGUUUAAAGAGUU

[0758] SEQ ID NO: 534 - DsiRNA 263 guide (antisense) strand AACUCUUUAAACAUUAUUUUAGUUAGG

[0759] SEQ ID NO: 535 - DsiRNA 264 passenger (sense) strand AACUAAAAUAAUGUUUAAAGAGUUU

[0760] SEQ ID NO: 536 - DsiRNA 264 guide (antisense) strand AAACUCUUUAAACAUUAUUUUAGUUAG

[0761] SEQ ID NO: 537 - DsiRNA 265 passenger (sense) strand ACUAAAAUAAUGUUUAAAGAGUUUU

[0762] SEQ ID NO: 538 - DsiRNA 265 guide (antisense) strand AAAACUCUUUAAACAUUAUUUUAGUUA

[0763] SEQ ID NO: 539 - DsiRNA 266 passenger (sense) strand CUAAAAUAAUGUUUAAAGAGUUUUG

[0764] SEQ ID NO: 540 - DsiRNA 266 guide (antisense) strand CAAAACUCUUUAAACAUUAUUUUAGUU

[0765] SEQ ID NO: 541 - DsiRNA 267 passenger (sense) strand UAAAAUAAUGUUUAAAGAGUUUUGU

[0766] SEQ ID NO: 542 - DsiRNA 267 guide (antisense) strand ACAAAACUCUUUAAACAUUAUUUUAGU

[0767] SEQ ID NO: 543 - DsiRNA 268 passenger (sense) strand AAGAGUUUUGUAUAAAAAUGUAAGG

[0768] SEQ ID NO: 544 - DsiRNA 268 guide (antisense) strand CCUUACAUUUUUAUACAAAACUCUUUA

[0769] SEQ ID NO: 545 - DsiRNA 269 passenger (sense) strand GUUUUGUAUAAAAAUGUAAGGAAGC

[0770] SEQ ID NO: 546 - DsiRNA 269 guide (antisense) strand GCUUCCUUACAUUUUUAUACAAAACUC

[0771] SEQ ID NO: 547 - DsiRNA 270 passenger (sense) strand UUUUGUAUAAAAAUGUAAGGAAGCG

[0772] SEQ ID NO: 548 - DsiRNA 270 guide (antisense) strand CGCUUCCUUACAUUUUUAUACAAAACU

[0773] SEQ ID NO: 549 - DsiRNA 271 passenger (sense) strand UUUGUAUAAAAAUGUAAGGAAGCGU

[0774] SEQ ID NO: 550 - DsiRNA 271 guide (antisense) strand ACGCUUCCUUACAUUUUUAUACAAAAC

[0775] SEQ ID NO: 551 - DsiRNA 272 passenger (sense) strand UUGUAUAAAAAUGUAAGGAAGCGUU

[0776] SEQ ID NO: 552 - DsiRNA 272 guide (antisense) strand AACGCUUCCUUACAUUUUUAUACAAAA

[0777] SEQ ID NO: 553 - DsiRNA 273 passenger (sense) strand UGUAUAAAAAUGUAAGGAAGCGUUG

[0778] SEQ ID NO: 554 - DsiRNA 273 guide (antisense) strand CAACGCUUCCUUACAUUUUUAUACAAA

[0779] SEQ ID NO: 555 - DsiRNA 274 passenger (sense) strand GUAUAAAAAUGUAAGGAAGCGUUGU

[0780] SEQ ID NO: 556 - DsiRNA 274 guide (antisense) strand ACAACGCUUCCUUACAUUUUUAUACAA

[0781] SEQ ID NO: 557 - DsiRNA 275 passenger (sense) strand AUGUAAGGAAGCGUUGUUACCUGUU

[0782] SEQ ID NO: 558 - DsiRNA 275 guide (antisense) strand AACAGGUAACAACGCUUCCUUACAUUU

[0783] SEQ ID NO: 559 - DsiRNA 276 passenger (sense) strand UUUUGUAUUAUGUGAAUCAGUGAGA

[0784] SEQ ID NO: 560 - DsiRNA 276 guide (antisense) strand UCUCACUGAUUCACAUAAUACAAAAUU

[0785] SEQ ID NO: 561 - DsiRNA 277 passenger (sense) strand UUUGUAUUAUGUGAAUCAGUGAGAU

[0786] SEQ ID NO: 562 - DsiRNA 277 guide (antisense) strand AUCUCACUGAUUCACAUAAUACAAAAU

[0787] SEQ ID NO: 563 - DsiRNA 278 passenger (sense) strand UUGUAUUAUGUGAAUCAGUGAGAUG

[0788] SEQ ID NO: 564 - DsiRNA 278 guide (antisense) strand CAUCUCACUGAUUCACAUAAUACAAAA

[0789] SEQ ID NO: 565 - DsiRNA 279 passenger (sense) strand UGUAUUAUGUGAAUCAGUGAGAUGU

[0790] SEQ ID NO: 566 - DsiRNA 279 guide (antisense) strand ACAUCUCACUGAUUCACAUAAUACAAA

[0791] SEQ ID NO: 567 - DsiRNA 280 passenger (sense) strand GUAUUAUGUGAAUCAGUGAGAUGUU

[0792] SEQ ID NO: 568 - DsiRNA 280 guide (antisense) strand AACAUCUCACUGAUUCACAUAAUACAA

[0793] SEQ ID NO: 569 - DsiRNA 281 passenger (sense) strand UAUUAUGUGAAUCAGUGAGAUGUUA

[0794] SEQ ID NO: 570 - DsiRNA 281 guide (antisense) strand UAACAUCUCACUGAUUCACAUAAUACA

[0795] SEQ ID NO: 571 - DsiRNA 282 passenger (sense) strand AUUAUGUGAAUCAGUGAGAUGUUAG

[0796] SEQ ID NO: 572 - DsiRNA 282 guide (antisense) strand CUAACAUCUCACUGAUUCACAUAAUAC

[0797] SEQ ID NO: 573 - DsiRNA 283 passenger (sense) strand UUAUGUGAAUCAGUGAGAUGUUAGU

[0798] SEQ ID NO: 574 - DsiRNA 283 guide (antisense) strand ACUAACAUCUCACUGAUUCACAUAAUA

[0799] SEQ ID NO: 575 - DsiRNA 284 passenger (sense) strand UAUGUGAAUCAGUGAGAUGUUAGUA

[0800] SEQ ID NO: 576 - DsiRNA 284 guide (antisense) strand UACUAACAUCUCACUGAUUCACAUAAU

[0801] SEQ ID NO: 577 - DsiRNA 285 passenger (sense) strand AUGUGAAUCAGUGAGAUGUUAGUAG

[0802] SEQ ID NO: 578 - DsiRNA 285 guide (antisense) strand CUACUAACAUCUCACUGAUUCACAUAA

[0803] SEQ ID NO: 579 - DsiRNA 286 passenger (sense) strand UGUGAAUCAGUGAGAUGUUAGUAGA

[0804] SEQ ID NO: 580 - DsiRNA 286 guide (antisense) strand UCUACUAACAUCUCACUGAUUCACAUA

[0805] SEQ ID NO: 581 - DsiRNA 287 passenger (sense) strand GUGAAUCAGUGAGAUGUUAGUAGAA

[0806] SEQ ID NO: 582 - DsiRNA 287 guide (antisense) strand UUCUACUAACAUCUCACUGAUUCACAU

[0807] SEQ ID NO: 583 - DsiRNA 288 passenger (sense) strand GUGAGAUGUUAGUAGAAUAAGCCUU

[0808] SEQ ID NO: 584 - DsiRNA 288 guide (antisense) strand AAGGCUUAUUCUACUAACAUCUCACUG

[0809] SEQ ID NO: 585 - DsiRNA 289 passenger (sense) strand UUUUCUAUUUAUGCAUUUGAGUACA

[0810] SEQ ID NO: 586 - DsiRNA 289 guide (antisense) strand UGUACUCAAAUGCAUAAAUAGAAAAAA

[0811] SEQ ID NO: 587 - DsiRNA 290 passenger (sense) strand UUUCUAUUUAUGCAUUUGAGUACAG

[0812] SEQ ID NO: 588 - DsiRNA 290 guide (antisense) strand CUGUACUCAAAUGCAUAAAUAGAAAAA

[0813] SEQ ID NO: 589 - DsiRNA 291 passenger (sense) strand UUCUAUUUAUGCAUUUGAGUACAGT

[0814] SEQ ID NO: 590 - DsiRNA 291 guide (antisense) strand ACUGUACUCAAAUGCAUAAAUAGAAAA

[0815] SEQ ID NO: 591 - DsiRNA 292 passenger (sense) strand CUAUUUAUGCAUUUGAGUACAGUAC

[0816] SEQ ID NO: 592 - DsiRNA 292 guide (antisense) strand GUACUGUACUCAAAUGCAUAAAUAGAA

[0817] SEQ ID NO: 593 - DsiRNA 293 passenger (sense) strand UGCUCAAACUGUUAAAUGUUGGAAA

[0818] SEQ ID NO: 594 - DsiRNA 293 guide (antisense) strand UUUCCAACAUUUAACAGUUUGAGCACA

[0819] SEQ ID NO:-DsiRNA 294 passenger (sense) strand GCUCAAACUGUUAAAUGUUGGAAAA595

[0820] SEQ ID NO: 596 - DsiRNA 294 guide (antisense) strand UUUUCCAACAUUUAACAGUUUGAGCAC

[0821] SEQ ID NO: 597 - DsiRNA 295 passenger (sense) strand CUCAAACUGUUAAAUGUUGGAAAAG

[0822] SEQ ID NO: 598 - DsiRNA 295 guide (antisense) strand CUUUUCCAACAUUUAACAGUUUGAGCA

[0823] SEQ ID NO: 599 - DsiRNA 296 passenger (sense) strand UCAAACUGUUAAAUGUUGGAAAAGA

[0824] SEQ ID NO: 600 - DsiRNA 296 guide (antisense) strand UCUUUUCCAACAUUUAACAGUUUGAGC

[0825] SEQ ID NO: 601 - DsiRNA 297 passenger (sense) strand CAAACUGUUAAAUGUUGGAAAAGAA

[0826] SEQ ID NO: 602 - DsiRNA 297 guide (antisense) strand UUCUUUUCCAACAUUUAACAGUUUGAG

[0827] SEQ ID NO: 603 - DsiRNA 298 passenger (sense) strand AAACUGUUAAAUGUUGGAAAAGAAA

[0828] SEQ ID NO: 604 - DsiRNA 298 guide (antisense) strand UUUCUUUUCCAACAUUUAACAGUUUGA

[0829] SEQ ID NO: 605 - DsiRNA 299 passenger (sense) strand AACUGUUAAAUGUUGGAAAAGAAAG

[0830] SEQ ID NO: 606 - DsiRNA 299 guide (antisense) strand CUUUCUUUUCCAACAUUUAACAGUUUG

[0831] SEQ ID NO: 607 - DsiRNA 300 passenger (sense) strand ACUGUUAAAUGUUGGAAAAGAAAGA

[0832] SEQ ID NO: 608 - DsiRNA 300 guide (antisense) strand UCUUUCUUUUCCAACAUUUAACAGUUU

[0833] SEQ ID NO: 609 - DsiRNA 301 passenger (sense) strand CUGUUAAAUGUUGGAAAAGAAAGAT

[0834] SEQ ID NO: 610 - DsiRNA 301 guide (antisense) strand AUCUUUCUUUUCCAACAUUUAACAGUU

[0835] SEQ ID NO: 611 - DsiRNA 302 passenger (sense) strand UGUUAAAUGUUGGAAAAGAAAGATA

[0836] SEQ ID NO: 612 - DsiRNA 302 guide (antisense) strand UAUCUUUCUUUUCCAACAUUUAACAGU

[0837] SEQ ID NO: 613 - DsiRNA 303 passenger (sense) strand GUUAAAUGUUGGAAAAGAAAGAUAC

[0838] SEQ ID NO: 614 - DsiRNA 303 guide (antisense) strand GUAUCUUUCUUUUCCAACAUUUAACAG

[0839] SEQ ID NO: 615 - DsiRNA 304 passenger (sense) strand UUAAAUGUUGGAAAAGAAAGAUACA

[0840] SEQ ID NO: 616 - DsiRNA 304 guide (antisense) strand UGUAUCUUUCUUUUCCAACAUUUAACA

[0841] SEQ ID NO: 617 - DsiRNA 305 passenger (sense) strand UAAAUGUUGGAAAAGAAAGAUACAA

[0842] SEQ ID NO: 618 - DsiRNA 305 guide (antisense) strand UUGUAUCUUUCUUUUCCAACAUUUAAC

[0843] SEQ ID NO: 619 - DsiRNA 306 passenger (sense) strand GCACUUGACUGAGAAGACAGACCCT

[0844] SEQ ID NO: 620 - DsiRNA 306 guide (antisense) strand AGGGUCUGUCUUCUCAGUCAAGUGCUU

[0845] SEQ ID NO: 621 - DsiRNA 307 passenger (sense) strand GAGAAAAGAGGCUACUUGUGAAAAT

[0846] SEQ ID NO: 622 - DsiRNA 307 guide (antisense) strand AUUUUCACAAGUAGCCUCUUUUCUCAA

[0847] SEQ ID NO: 623 - DsiRNA 308 passenger (sense) strand AGAAAAGAGGCUACUUGUGAAAATA

[0848] SEQ ID NO: 624 - DsiRNA 308 guide (antisense) strand UAUUUUCACAAGUAGCCUCUUUUCUCA

[0849] SEQ ID NO: 625 - DsiRNA 309 passenger (sense) strand GAAAAGAGGCUACUUGUGAAAAUAA

[0850] SEQ ID NO: 626 - DsiRNA 309 guide (antisense) strand UUAUUUUCACAAGUAGCCUCUUUUCUC

[0851] SEQ ID NO: 627 - DsiRNA 310 passenger (sense) strand AAAAGAGGCUACUUGUGAAAAUAAT

[0852] SEQ ID NO: 628 - DsiRNA 310 guide (antisense) strand AUUAUUUUCACAAGUAGCCUCUUUUCU

[0853] SEQ ID NO: 629 - DsiRNA 311 passenger (sense) strand AAAGAGGCUACUUGUGAAAAUAATG

[0854] SEQ ID NO: 630 - DsiRNA 311 guide (antisense) strand CAUUAUUUUCACAAGUAGCCUCUUUUC

[0855] SEQ ID NO: 631 - DsiRNA 312 passenger (sense) strand AAGAGGCUACUUGUGAAAAUAAUGA

[0856] SEQ ID NO: 632 - DsiRNA 312 guide (antisense) strand UCAUUAUUUUCACAAGUAGCCUCUUUU

[0857] SEQ ID NO: 633 - DsiRNA 313 passenger (sense) strand AGAGGCUACUUGUGAAAAUAAUGAG

[0858] SEQ ID NO: 634 - DsiRNA 313 guide (antisense) strand CUCAUUAUUUUCACAAGUAGCCUCUUU

[0859] SEQ ID NO: 635 - DsiRNA 314 passenger (sense) strand GAGGCUACUUGUGAAAAUAAUGAGC

[0860] SEQ ID NO: 636 - DsiRNA 314 guide (antisense) strand GCUCAUUAUUUUCACAAGUAGCCUCUU

[0861] SEQ ID NO: 637 - DsiRNA 315 passenger (sense) strand GGCUACUUGUGAAAAUAAUGAGCCC

[0862] SEQ ID NO: 638 - DsiRNA 315 guide (antisense) strand GGGCUCAUUAUUUUCACAAGUAGCCUC

[0863] SEQ ID NO: 639 - DsiRNA 316 passenger (sense) strand CUACUUGUGAAAAUAAUGAGCCCCC

[0864] SEQ ID NO: 640 - DsiRNA 316 guide (antisense) strand GGGGGCUCAUUAUUUUCACAAGUAGCC

[0865] SEQ ID NO: 641 - DsiRNA 317 passenger (sense) strand UGAACCUGCCUUCUUACAUCUUGAG

[0866] SEQ ID NO: 642 - DsiRNA 317 guide (antisense) strand CUCAAGAUGUAAGAAGGCAGGUUCAAA

[0867] SEQ ID NO: 643 - DsiRNA 318 passenger (sense) strand AAAGUUACAAGUUUCUUUUCCCAAG

[0868] SEQ ID NO: 644 - DsiRNA 318 guide (antisense) strand CUUGGGAAAAGAAACUUGUAACUUUCC

[0869] SEQ ID NO: 645 - DsiRNA 319 passenger (sense) strand AAGUUACAAGUUUCUUUUCCCAAGT

[0870] SEQ ID NO: 646 - DsiRNA 319 guide (antisense) strand ACUUGGGAAAAGAAACUUGUAACUUUC

[0871] SEQ ID NO: 647 - DsiRNA 320 passenger (sense) strand AGUUACAAGUUUCUUUUCCCAAGTT

[0872] SEQ ID NO: 648 - DsiRNA 320 guide (antisense) strand AACUUGGGAAAAGAAACUUGUAACUUU

[0873] SEQ ID NO: 649 - DsiRNA 321 passenger (sense) strand AGUUUCUUUUCCCAAGUUUCCCAGT

[0874] SEQ ID NO: 650 - DsiRNA 321 guide (antisense) strand ACUGGGAAACUUGGGAAAAGAAACUUG

[0875] SEQ ID NO: 651 - DsiRNA 322 passenger (sense) strand CAACAGUAUUUUCUAAUAACCAGTA

[0876] SEQ ID NO: 652 - DsiRNA 322 guide (antisense) strand UACUGGUUAUUAGAAAAUACUGUUGGC

[0877] SEQ ID NO: 653 - DsiRNA 323 passenger (sense) strand AACAGUAUUUUCUAAUAACCAGUAT

[0878] SEQ ID NO: 654 - DsiRNA 323 guide (antisense) strand AUACUGGUUAUUAGAAAAUACUGUUGG

[0879] SEQ ID NO: 655 - DsiRNA 324 passenger (sense) strand ACAGUAUUUUCUAAUAACCAGUATA

[0880] SEQ ID NO: 656 - DsiRNA 324 guide (antisense) strand UAUACUGGUUAUUAGAAAAUACUGUUG

[0881] SEQ ID NO: 657 - DsiRNA 325 passenger (sense) strand CAGUAUUUUCUAAUAACCAGUAUAT

[0882] SEQ ID NO: 658 - DsiRNA 325 guide (antisense) strand AUAUACUGGUUAUUAGAAAAUACUGUU

[0883] SEQ ID NO: 659 - DsiRNA 326 passenger (sense) strand UUGUGAUUGUUAUCAGGAAAAAATA

[0884] SEQ ID NO: 660 - DsiRNA 326 guide (antisense) strand UAUUUUUUCCUGAUAACAAUCACAAUA

[0885] SEQ ID NO: 661 - DsiRNA 327 passenger (sense) strand UGUGAUUGUUAUCAGGAAAAAAUAT

[0886] SEQ ID NO: 662 - DsiRNA 327 guide (antisense) strand AUAUUUUUUCCUGAUAACAAUCACAAU

[0887] SEQ ID NO: 663 - DsiRNA 328 passenger (sense) strand GUGAUUGUUAUCAGGAAAAAAUATA

[0888] SEQ ID NO: 664 - DsiRNA 328 guide (antisense) strand UAUAUUUUUUCCUGAUAACAAUCACAA

[0889] SEQ ID NO: 665 - DsiRNA 329 passenger (sense) strand UGAUUGUUAUCAGGAAAAAAUAUAT

[0890] SEQ ID NO: 666 - DsiRNA 329 guide (antisense) strand AUAUAUUUUUUCCUGAUAACAAUCACA

[0891] SEQ ID NO: 667 - DsiRNA 330 passenger (sense) strand GAUUGUUAUCAGGAAAAAAUAUATT

[0892] SEQ ID NO: 668 - DsiRNA 330 guide (antisense) strand AAUAUAUUUUUUCCUGAUAACAAUCAC

[0893] SEQ ID NO: 669 - DsiRNA 331 passenger (sense) strand AUUGUUAUCAGGAAAAAAUAUAUTA

[0894] SEQ ID NO: 670 - DsiRNA 331 guide (antisense) strand UAAUAUAUUUUUUCCUGAUAACAAUCA

[0895] SEQ ID NO: 671 - DsiRNA 332 passenger (sense) strand UUGUUAUCAGGAAAAAAUAUAUUAA

[0896] SEQ ID NO: 672 - DsiRNA 332 guide (antisense) strand UUAAUAUAUUUUUUCCUGAUAACAAUC

[0897] SEQ ID NO: 673 - DsiRNA 333 passenger (sense) strand UGUUAUCAGGAAAAAAUAUAUUAAA

[0898] SEQ ID NO: 674 - DsiRNA 333 guide (antisense) strand UUUAAUAUAUUUUUUUCCUGAUAACAAU

[0899] SEQ ID NO: 675 - DsiRNA 334 passenger (sense) strand GUUAUCAGGAAAAAAUAUAUUAAAT

[0900] SEQ ID NO: 676 - DsiRNA 334 guide (antisense) strand AUUUAAUAUAUUUUUUCCUGAUAACAA

[0901] SEQ ID NO: 677 - DsiRNA 335 passenger (sense) strand UUAUCAGGAAAAAAUAUAUUAAATG

[0902] SEQ ID NO: 678 - DsiRNA 335 guide (antisense) strand CAUUUAAUAUAUUUUUUCCUGAUAACA

[0903] SEQ ID NO: 679 - DsiRNA 336 passenger (sense) strand UAUCAGGAAAAAAUAUAUUAAAUGG

[0904] SEQ ID NO: 680 - DsiRNA 336 guide (antisense) strand CCAUUUAAUAUAUUUUUUCCUGAUAAC

[0905] SEQ ID NO: 681 - DsiRNA 337 passenger (sense) strand AUCAGGAAAAAAUAUAUUAAAUGGC

[0906] SEQ ID NO: 682 - DsiRNA 337 guide (antisense) strand GCCAUUUAAUAUAUUUUUUCCUGAUAA

[0907] SEQ ID NO: 683 - DsiRNA 338 passenger (sense) strand AGGAAAAAAUAUAUUAAAUGGCUGA

[0908] SEQ ID NO: 684 - DsiRNA 338 guide (antisense) strand UCAGCCAUUUAAUAUAUUUUUUCCUGA

[0909] SEQ ID NO: 685 - DsiRNA 339 passenger (sense) strand GGAAAAAAUAUAUUAAAUGGCUGAT

[0910] SEQ ID NO: 686 - DsiRNA 339 guide (antisense) strand AUCAGCCAUUUAAUAUAUUUUUUCCUG

[0911] SEQ ID NO: 687 - DsiRNA 340 passenger (sense) strand GAAAAAAUAUAUUAAAUGGCUGATA

[0912] SEQ ID NO: 688 - DsiRNA 340 guide (antisense) strand UAUCAGCCAUUUAAUAUAUUUUUUCCU

[0913] SEQ ID NO: 689 - DsiRNA 341 passenger (sense) strand AAAAAAUAUAUUAAAUGGCUGAUAG

[0914] SEQ ID NO: 690 - DsiRNA 341 guide (antisense) strand CUAUCAGCCAUUUAAUAUAUUUUUUCC

[0915] SEQ ID NO: 691 - DsiRNA 342 passenger (sense) strand UAUUUUCUUUCUGCUUUUAAAAATT

[0916] SEQ ID NO: 692 - DsiRNA 342 guide (antisense) strand AAUUUUUAAAAGCAGAAAGAAAAUACG

[0917] SEQ ID NO: 693 - DsiRNA 343 passenger (sense) strand AUUUUCUUUCUGCUUUUAAAAAUTA

[0918] SEQ ID NO: 694 - DsiRNA 343 guide (antisense) strand UAAUUUUUAAAAGCAGAAAGAAAAUAC

[0919] SEQ ID NO: 695 - DsiRNA 344 passenger (sense) strand UCUUUCUGCUUUUAAAAAUUAUUCA

[0920] SEQ ID NO: 696 - DsiRNA 344 guide (antisense) strand UGAAUAAUUUUUAAAAGCAGAAAGAAA

[0921] SEQ ID NO: 697 - DsiRNA 345 passenger (sense) strand CUUUCUGCUUUUAAAAAUUAUUCAG

[0922] SEQ ID NO: 698 - DsiRNA 345 guide (antisense) strand CUGAAUAAUUUUUAAAAGCAGAAAGAA

[0923] SEQ ID NO: 699 - DsiRNA 346 passenger (sense) strand UUUCUGCUUUUAAAAAUUAUUCAGG

[0924] SEQ ID NO: 700 - DsiRNA 346 guide (antisense) strand CCUGAAUAAUUUUUAAAAGCAGAAAGA

[0925] SEQ ID NO: 701 - DsiRNA 347 passenger (sense) strand CUACUAAAAACACAAAAAUUAGCCA

[0926] SEQ ID NO: 702 - DsiRNA 347 guide (antisense) strand UGGCUAAUUUUUGUGUUUUUAGUAGAG

[0927] SEQ ID NO: 703 - DsiRNA 348 passenger (sense) strand CAAGAUAAGGAAAUCAGGAAGUGTA

[0928] SEQ ID NO: 704 - DsiRNA 348 guide (antisense) strand UACACUUCCUGAUUUCCUUAUCUUGAU

[0929] SEQ ID NO: 705 - DsiRNA 349 passenger (sense) strand AAGAUAAGGAAAUCAGGAAGUGUAA

[0930] SEQ ID NO: 706 - DsiRNA 349 guide (antisense) strand UUACACUUCCUGAUUUCCUUAUCUUGA

[0931] SEQ ID NO: 707 - DsiRNA 350 passenger (sense) strand AGAUAAGGAAAUCAGGAAGUGUAAT

[0932] SEQ ID NO: 708 - DsiRNA 350 guide (antisense) strand AUUACACUUCCUGAUUUCCUUAUCUUG

[0933] SEQ ID NO: 709 - DsiRNA 351 passenger (sense) strand GAUAAGGAAAUCAGGAAGUGUAATA

[0934] SEQ ID NO: 710 - DsiRNA 351 guide (antisense) strand UAUUACACUUCCUGAUUUCCUUAUCUU

[0935] SEQ ID NO: 711 - DsiRNA 352 passenger (sense) strand AUAAGGAAAUCAGGAAGUGUAAUAT

[0936] SEQ ID NO: 712 - DsiRNA 352 guide (antisense) strand AUAUUACACUUCCUGAUUUCCUUAUCU

[0937] SEQ ID NO: 713 - DsiRNA 353 passenger (sense) strand UAAGGAAAUCAGGAAGUGUAAUATT

[0938] SEQ ID NO: 714 - DsiRNA 353 guide (antisense) strand AAUAUUACACUUCCUGAUUUCCUUAUC

[0939] SEQ ID NO: 715 - DsiRNA 354 passenger (sense) strand AAGGAAAUCAGGAAGUGUAAUAUTC

[0940] SEQ ID NO: 716 - DsiRNA 354 guide (antisense) strand GAAUAUUACACUUCCUGAUUUCCUUAU

[0941] SEQ ID NO: 717 - DsiRNA 355 passenger (sense) strand AGGAAAUCAGGAAGUGUAAUAUUCT

[0942] SEQ ID NO: 718 - DsiRNA 355 guide (antisense) strand AGAAUAUUACACUUCCUGAUUUCCUUA

[0943] SEQ ID NO: 719 - DsiRNA 356 passenger (sense) strand GGAAAUCAGGAAGUGUAAUAUUCTT

[0944] SEQ ID NO: 720 - DsiRNA 356 guide (antisense) strand AAGAAUAUUACACUUCCUGAUUUCCUU

[0945] SEQ ID NO: 721 - DsiRNA 357 passenger (sense) strand GAAAUCAGGAAGUGUAAUAUUCUTA

[0946] SEQ ID NO: 722 - DsiRNA 357 guide (antisense) strand UAAGAAUAUUACACUUCCUGAUUUCCU

[0947] SEQ ID NO: 723 - DsiRNA 358 passenger (sense) strand CUAUGAAUGCAUUCUUAUUUCUUCT

[0948] SEQ ID NO: 724 - DsiRNA 358 guide (antisense) strand AGAAGAAAUAAGAAUGCAUUCAUAGGC

[0949] SEQ ID NO: 725 - DsiRNA 359 passenger (sense) strand UAUGAAUGCAUUCUUAUUUCUUCTT

[0950] SEQ ID NO: 726 - DsiRNA 359 guide (antisense) strand AAGAAGAAAUAAGAAUGCAUUCAUAGG

[0951] SEQ ID NO: 727 - DsiRNA 360 passenger (sense) strand CUACCACACCCAGCUAGUUUUUUTT

[0952] SEQ ID NO: 728 - DsiRNA 360 guide (antisense) strand AAAAAAAAACUAGCUGGGUGUGGUAGUG

[0953] SEQ ID NO: 729 - DsiRNA 361 passenger (sense) strand CCACACCCAGCUAGUUUUUUUUUGT

[0954] SEQ ID NO: 730 - DsiRNA 361 guide (antisense) strand ACAAAAAAAAACUAGCUGGGUGUGGUA

[0955] SEQ ID NO: 731 - DsiRNA 362 passenger (sense) strand CACACCCAGCUAGUUUUUUUUUGTA

[0956] SEQ ID NO: 732 - DsiRNA 362 guide (antisense) strand UACAAAAAAAAACUAGCUGGGUGUGGU

[0957] SEQ ID NO: 733 - DsiRNA 363 passenger (sense) strand GCUAGGAUUACAGGUGUGAGCUACC

[0958] SEQ ID NO: 734 - DsiRNA 363 guide (antisense) strand GGUAGCUCACACCUGUAAUCCUAGCAC

[0959] SEQ ID NO: 735 - DsiRNA 364 passenger (sense) strand CUAGGAUUACAGGUGUGAGCUACCA

[0960] SEQ ID NO: 736 - DsiRNA 364 guide (antisense) strand UGGUAGCUCACACCUGUAAUCCUAGCA

[0961] SEQ ID NO: 737 - DsiRNA 365 passenger (sense) strand CCAUGCCUGGUCCAACAUUCUUCAT

[0962] SEQ ID NO: 738 - DsiRNA 365 guide (antisense) strand AUGAAGAAUGUUGGACCAGGCAUGGUA

[0963] SEQ ID NO: 739 - DsiRNA 366 passenger (sense) strand UGCAGAGUAUGAGCCUGAUUUUGTT

[0964] SEQ ID NO: 740 - DsiRNA 366 guide (antisense) strand AACAAAAUCAGGCUCAUACUCUGCACU

[0965] SEQ ID NO: 741 - DsiRNA 367 passenger (sense) strand GCAGAGUAUGAGCCUGAUUUUGUTT

[0966] SEQ ID NO: 742 - DsiRNA 367 guide (antisense) strand AAACAAAAUCAGGCUCAUACUCUGCAC

[0967] SEQ ID NO: 743 - DsiRNA 368 passenger (sense) strand CAGAGUAUGAGCCUGAUUUUGUUTA

[0968] SEQ ID NO: 744 - DsiRNA 368 guide (antisense) strand UAAACAAAAUCAGGCUCAUACUCUGCA

[0969] SEQ ID NO: 745 - DsiRNA 369 passenger (sense) strand AGAGUAUGAGCCUGAUUUUGUUUAA

[0970] SEQ ID NO: 746 - DsiRNA 369 guide (antisense) strand UUAAACAAAAUCAGGCUCAUACUCUGC

[0971] SEQ ID NO: 747 - DsiRNA 370 passenger (sense) strand GAGUAUGAGCCUGAUUUUGUUUAAA

[0972] SEQ ID NO: 748 - DsiRNA 370 guide (antisense) strand UUUAAACAAAAUCAGGCUCAUACUCUG

[0973] SEQ ID NO: 749 - DsiRNA 371 passenger (sense) GGGUGAAACCCCAUCUCUACUAAAA

[0974] SEQ ID NO: 750 - DsiRNA 371 guide (antisense) strand UUUUAGUAGAGAUGGGGUUUCACCCAG

[0975] SEQ ID NO: 751 - DsiRNA 372 passenger (sense) strand GUGAAACCCCAUCUCUACUAAAAAA

[0976] SEQ ID NO: 752 - DsiRNA 372 guide (antisense) strand UUUUUUAGUAGAGAUGGGGUUUCACCC

[0977] SEQ ID NO: 753 - DsiRNA 373 passenger (sense) strand UGAAACCCCAUCUCUACUAAAAAAT

[0978] SEQ ID NO: 754 - DsiRNA 373 guide (antisense) strand AUUUUUUAGUAGAGAUGGGGUUUCACC

[0979] SEQ ID NO: 755 - DsiRNA 374 passenger (sense) strand GAAACCCCAUCUCUACUAAAAAATG

[0980] SEQ ID NO: 756 - DsiRNA 374 guide (antisense) strand CAUUUUUUAGUAGAGAUGGGGUUUCAC

[0981] SEQ ID NO: 757 - DsiRNA 375 guide (antisense) strand AAACCCCAUCUCUACUAAAAAAUGC

[0982] SEQ ID NO: 758 - DsiRNA 375 guide (antisense) strand GCAUUUUUUAGUAGAGAUGGGGUUUCA

[0983] SEQ ID NO: 759 - DsiRNA 376 passenger (sense) strand AACCCCAUCUCUACUAAAAAAUGCA

[0984] SEQ ID NO: 760 - DsiRNA 376 guide (antisense) strand UGCAUUUUUUAGUAGAGAUGGGGUUUC

[0985] SEQ ID NO: 761 - DsiRNA 377 passenger (sense) strand CCCAUCUCUACUAAAAAAUGCAAAA

[0986] SEQ ID NO: 762 - DsiRNA 377 guide (antisense) strand UUUUGCAUUUUUUAGUAGAGAUGGGGU

[0987] SEQ ID NO: 763 - DsiRNA 378 passenger (sense) strand AUCAAAACCCUUAUGGCAGACUGTT

[0988] SEQ ID NO: 764 - DsiRNA 378 guide (antisense) strand AACAGUCUGCCAUAAGGGUUUUGAUAU

[0989] SEQ ID NO: 765 - DsiRNA 379 passenger (sense) strand UAUUUUAUUUGUCGUGCUUAUAUGT

[0990] SEQ ID NO: 766 - DsiRNA 379 guide (antisense) strand ACAUAUAAGCACGACAAAUAAAAUACA

[0991] SEQ ID NO: 767 - DsiRNA 380 passenger (sense) strand GUGUUGCCCAAGUUUCUAUGGUGAA

[0992] SEQ ID NO: 768 - DsiRNA 380 guide (antisense) strand UUCACCAUAGAAACUUGGGCAACACAU

[0993] SEQ ID NO: 769 - DsiRNA 381 passenger (sense) strand GCCCAAGUUUCUAUGGUGAACGGTA

[0994] SEQ ID NO: 770 - DsiRNA 381 guide (antisense) strand UACCGUUCACCAUAGAAACUUGGGCAA

[0995] SEQ ID NO: 771 - DsiRNA 382 passenger (sense) strand CCCAAGUUUCUAUGGUGAACGGUAT

[0996] SEQ ID NO: 772 - DsiRNA 382 guide (antisense) strand AUACCGUUCACCAUAGAAACUUGGGCA

[0997] SEQ ID NO: 773 - DsiRNA 383 passenger (sense) strand ACUUUCAGCAUGAGAAAAUAACUCC

[0998] SEQ ID NO: 774 - DsiRNA 383 guide (antisense) strand GGAGUUAUUUUCUCAUGCUGAAAGUGA

[0999] SEQ ID NO: 775 - DsiRNA 384 passenger (sense) strand CUUUCAGCAUGAGAAAAUAACUCCT

[1000] SEQ ID NO: 776 - DsiRNA 384 guide (antisense) strand AGGAGUUAUUUUCUCAUGCUGAAAGUG

[1001] SEQ ID NO: 777-PNPLA3 Oligonucleotide 1 Passenger (Sense) Strand UGAGUGACAACGUACCCUUAGCAGCCCGAAAGGCUGC

[1002] SEQ ID NO: 778 - PNPLA3 oligonucleotide 1 guide (antisense) strand UAAGGGUACGUUGUCACUCAGG

[1003] SEQ ID NO: 779 - PNPLA3 oligonucleotide 2 passenger (sense) strand GAGUGACAACGUACCCUUCAGCAGCCGAAAGGCUGC

[1004] SEQ ID NO: 780-PNPLA3 oligonucleotide 2 guide (antisense) strand UGAAGGGUACGUUGUCACUCGG

[1005] SEQ ID NO: 781-PNPLA3 oligonucleotide 3 passenger (sense) strand AGUGACAACGUACCCUUCAAGCAGCCGAAAGGCUGC

[1006] SEQ ID NO: 782 - PNPLA3 oligonucleotide 3 guide (antisense) strand UUGAAGGGUACGUUGUCACUGG

[1007] SEQ ID NO: 783-PNPLA3 oligonucleotide 4 passenger (sense) strand UGACAACGUACCCUUCAUUAGCAGCCCGAAAGGCUGC

[1008] SEQ ID NO: 784-PNPLA3 oligonucleotide 4 guide (antisense) strand UAAUGAAGGGUACGUUGUCAGG

[1009] SEQ ID NO: 785-PNPLA3 oligonucleotide 5 passenger (sense) strand GACAACGUACCCUUCAUUGAGCAGCCGAAAGGCUGC

[1010] SEQ ID NO: 786 - PNPLA3 oligonucleotide 5 guide (antisense) strand UCAAUGAAGGGUACGUUGUCGG

[1011] SEQ ID NO: 787-PNPLA3 Oligonucleotide 6 Passenger (Sense) Strand CAACGUACCCUUCAUUGAUAGCAGCCGAAAGGCUGC

[1012] SEQ ID NO: 788 - PNPLA3 oligonucleotide 6 guide (antisense) strand UAUCAAUGAAGGGUACGUUGGG

[1013] SEQ ID NO: 789 - PNPLA3 oligonucleotide 7 passenger (sense) strand AACGUACCCUUCAUUGAUGAGCAGCCGAAAGGCUGC

[1014] SEQ ID NO: 790 - PNPLA3 oligonucleotide 7 guide (antisense) strand UCAUCAAUGAAGGGUACGUUGG

[1015] SEQ ID NO: 791-PNPLA3 Oligonucleotide 8 Passenger (Sense) Strand ACGUACCCUUCAUUGAUGCAGCAGCCGAAAGGCUGC

[1016] SEQ ID NO: 792 - PNPLA3 oligonucleotide 8 guide (antisense) strand UGCAUCAAUGAAGGGUACGUGG

[1017] SEQ ID NO: 793-PNPLA3 Oligonucleotide 9 Passenger (Sense) Strand CGUACCCUUCAUUGAUGCCAGCAGCCCGAAAGGCUGC

[1018] SEQ ID NO: 794-PNPLA3 oligonucleotide 9 guide (antisense) strand UGGCAUCAAUGAAGGGUACGGG

[1019] SEQ ID NO: 795-PNPLA3 oligonucleotide 10 passenger (sense) strand UACCCUUCAUUGAUGCCAAAGCAGCCGAAAGGCUGC

[1020] SEQ ID NO: 796 - PNPLA3 oligonucleotide 10 guide (antisense) strand UUUGGCAUCAAUGAAGGGUAGG

[1021] SEQ ID NO: 797-PNPLA3 oligonucleotide 11 passenger (sense) strand CACGAACUUUCUUCAUGUGAGCAGCCGAAAGGCUGC

[1022] SEQ ID NO: 798 - PNPLA3 oligonucleotide 11 guide (antisense) strand UCACAUGAAGAAAGUUCGUGGG

[1023] SEQ ID NO: 799-PNPLA3 oligonucleotide 12 passenger (sense) strand ACGAACUUUCUUCAUGUGGAGCAGCCGAAAGGCUGC

[1024] SEQ ID NO: 800-PNPLA3 oligonucleotide 12 guide (antisense) strand UCCACAUGAAGAAAGUUCGUGG

[1025] SEQ ID NO: 801-PNPLA3 oligonucleotide 13 passenger (sense) strand CGAACUUUCUUCAUUGUGGAAGCAGCCGAAAGGCUGC

[1026] SEQ ID NO: 802-PNPLA3 oligonucleotide 13 guide (antisense) strand UUCCACAUGAAGAAAGUUCGGG

[1027] SEQ ID NO: 803-PNPLA3 oligonucleotide 14 passenger (sense) strand ACUUUCUUCAUGUGGACAUAAGCAGCCGAAAGGCUGC

[1028] SEQ ID NO: 804 - PNPLA3 oligonucleotide 14 guide (antisense) strand UAUGUCCACAUGAAGAAAGUGG

[1029] SEQ ID NO: 805-PNPLA3 oligonucleotide 15 passenger (sense) strand UUUCUUCAUGUGGACAUCAAGCAGCCGAAAGGCUGC

[1030] SEQ ID NO: 806 - PNPLA3 oligonucleotide 15 guide (antisense) strand UUGAUGUCCACAUGAAGAAAGG

[1031] SEQ ID NO: 807-PNPLA3 oligonucleotide 16 passenger (sense) strand CUUCAUGUGGACAUCACCAAGCAGCCGAAAGGCUGC

[1032] SEQ ID NO: 808 - PNPLA3 oligonucleotide 16 guide (antisense) strand UUGGUGAUGUCCACAUGAAGGG

[1033] SEQ ID NO: 809 - PNPLA3 oligonucleotide 17 passenger (sense) strand AUGUGGACAUCACCAAGCUAGCAGCCGAAAGGCUGC

[1034] SEQ ID NO: 810-PNPLA3 oligonucleotide 17 guide (antisense) strand UAGCUUGGUGAUGUCCACAUGG

[1035] SEQ ID NO: 811-PNPLA3 oligonucleotide 18 passenger (sense) strand UGUGGACAUCACCAAGCUCAGCAGCCGAAAGGCUGC

[1036] SEQ ID NO: 812-PNPLA3 oligonucleotide 18 guide (antisense) strand UGAGCUUGGUGAUGUCCACAGG

[1037] SEQ ID NO: 813-PNPLA3 oligonucleotide 19 passenger (sense) strand GUGGACAUCACCAAGCUCAAGCAGCCGAAAGGCUGC

[1038] SEQ ID NO: 814-PNPLA3 oligonucleotide 19 guide (antisense) strand UUGAGCUUGGUGAUGUCCACGG

[1039] SEQ ID NO: 815-PNPLA3 oligonucleotide 20 passenger (sense) strand UGGACAUCACCAAGCUCAGAGCAGCCGAAAGGCUGC

[1040] SEQ ID NO: 816 - PNPLA3 oligonucleotide 20 guide (antisense) strand UCUGAGCUUGGUGAUGUCCAGG

[1041] SEQ ID NO: 817-PNPLA3 oligonucleotide 21 passenger (sense) strand AGAUAUGCCUUCGAGGAUAAGCAGCCCGAAAGGCUGC

[1042] SEQ ID NO: 818 - PNPLA3 oligonucleotide 21 guide (antisense) strand UUAUCCUCGAAGGCAUAUCUGG

[1043] SEQ ID NO: 819-PNPLA3 oligonucleotide 22 passenger (sense) strand AUGCCUUCGAGGAUAUUUGAGCAGCCGAAAGGCUGC

[1044] SEQ ID NO: 820-PNPLA3 oligonucleotide 22 guide (antisense) strand UCAAAUAUCCUCGAAGGCAUGG

[1045] SEQ ID NO: 821-PNPLA3 oligonucleotide 23 passenger (sense) strand GCCUUCGAGGAUAUUUGGAAGCAGCCGAAAGGCUGC

[1046] SEQ ID NO: 822 - PNPLA3 oligonucleotide 23 guide (antisense) strand UUCCAAAUAUCCUCGAAGGCGG

[1047] SEQ ID NO: 823-PNPLA3 oligonucleotide 24 passenger (sense) strand UGAAGUCAUCCUCAGAAGGAGCAGCCGAAAGGCUGC

[1048] SEQ ID NO: 824 - PNPLA3 oligonucleotide 24 guide (antisense) strand UCCUUCUGAGGAUGACUUCAGG

[1049] SEQ ID NO: 825-PNPLA3 oligonucleotide 25 passenger (sense) strand GAAGUCAUCCUCAGAAGGGAGCAGCCGAAAGGCUGC

[1050] SEQ ID NO: 826 - PNPLA3 oligonucleotide 25 guide (antisense) strand UCCCUUCUGAGGAUGACUUCGG

[1051] SEQ ID NO: 827 - PNPLA3 oligonucleotide 26 passenger (sense) strand AUCCUCAGAAGGGAUGGAUAGCAGCCGAAAGGCUGC

[1052] SEQ ID NO: 828 - PNPLA3 oligonucleotide 26 guide (antisense) strand UAUCCAUCCCUUCUGAGGAUGG

[1053] SEQ ID NO: 829 - PNPLA3 oligonucleotide 27 passenger (sense) strand AGUGAAGAAAUGAAAGACAAGCAGCCGAAAGGCUGC

[1054] SEQ ID NO: 830-PNPLA3 oligonucleotide 27 guide (antisense) strand UUGUCUUUCAUUUCUUCACUGG

[1055] SEQ ID NO: 831 - PNPLA3 oligonucleotide 28 passenger (sense) strand AAGAAAUGAAAGACAAAGGAGCAGCCGAAAGGCUGC

[1056] SEQ ID NO: 832 - PNPLA3 oligonucleotide 28 guide (antisense) strand UCCUUUGUCUUUCAUUUCUUGG

[1057] SEQ ID NO: 833-PNPLA3 oligonucleotide 29 passenger (sense) strand AGAAAUGAAAGACAAAGGUAGCAGCCGAAAGGCUGC

[1058] SEQ ID NO: 834 - PNPLA3 oligonucleotide 29 guide (antisense) strand UACCUUUGUCUUUCAUUUCUGG

[1059] SEQ ID NO: 835-PNPLA3 oligonucleotide 30 passenger (sense) strand GAAAUGAAAGACAAAGGUGAGCAGCCGAAAGGCUGC

[1060] SEQ ID NO: 836 - PNPLA3 oligonucleotide 30 guide (antisense) strand UCACCUUUGUCUUUCAUUUCGG

[1061] SEQ ID NO: 837 - PNPLA3 oligonucleotide 31 passenger (sense) strand AAAUGAAAGACAAAGGUGGAGCAGCCGAAAGGCUGC

[1062] SEQ ID NO: 838 - PNPLA3 oligonucleotide 31 guide (antisense) strand UCCACCUUUGUCUUUCAUUUGG

[1063] SEQ ID NO: 839 - PNPLA3 oligonucleotide 32 passenger (sense) strand AAUGAAAGACAAAGGUGGAAGCAGCCGAAAGGCUGC

[1064] SEQ ID NO: 840 - PNPLA3 oligonucleotide 32 guide (antisense) strand UUCCACCUUUGUCUUUCAUUGG

[1065] SEQ ID NO: 841 - PNPLA3 oligonucleotide 33 passenger (sense) strand AUGAAAGACAAAGGUGGAUAGCAGCCGAAAGGCUGC

[1066] SEQ ID NO: 842 - PNPLA3 oligonucleotide 33 guide (antisense) strand UAUCCACCUUUGUCUUUCAUGG

[1067] SEQ ID NO: 843 - PNPLA3 oligonucleotide 34 passenger (sense) strand UGAAAGACAAAGGUGGAUAAGCAGCCGAAAGGCUGC

[1068] SEQ ID NO: 844 - PNPLA3 oligonucleotide 34 guide (antisense) strand UUAUCCACCUUUGUCUUUCAGG

[1069] SEQ ID NO: 845 - PNPLA3 oligonucleotide 35 passenger (sense) strand GAAAGACAAAGGUGGAUACAGCAGCCGAAAGGCUGC

[1070] SEQ ID NO: 846 - PNPLA3 oligonucleotide 35 guide (antisense) strand UGUAUCCACCUUUGUCUUUCGG

[1071] SEQ ID NO: 847 - PNPLA3 oligonucleotide 36 passenger (sense) strand AAGACAAGGUGGAUACAUAGCAGCCCGAAAGGCUGC

[1072] SEQ ID NO: 848 - PNPLA3 oligonucleotide 36 guide (antisense) strand UAUGUAUCCACCUUUGUCUUGG

[1073] SEQ ID NO: 849 - PNPLA3 oligonucleotide 37 passenger (sense) strand AGACAAAGGUGGAUACAUGAGCAGCCGAAAGGCUGC

[1074] SEQ ID NO: 850-PNPLA3 oligonucleotide 37 guide (antisense) strand UCAUGUAUCCACCUUUGUCUGG

[1075] SEQ ID NO: 851 - PNPLA3 oligonucleotide 38 passenger (sense) strand GACAAAGGUGGAUACAUGAAGCAGCCCGAAAGGCUGC

[1076] SEQ ID NO: 852 - PNPLA3 oligonucleotide 38 guide (antisense) strand UUCAUGUAUCCACCUUUGUCGG

[1077] SEQ ID NO: 853 - PNPLA3 oligonucleotide 39 passenger guide (sense) strand ACAAAGGUGGAUACAUGAGAGCAGCCGAAAGGCUGC

[1078] SEQ ID NO: 854 - PNPLA3 oligonucleotide 39 guide (antisense) strand UCUCAUGUAUCCACCUUUGUGG

[1079] SEQ ID NO: 855-PNPLA3 oligonucleotide 40 passenger (sense) strand AAGGUGGAUACAUGAGCAAAGCAGCCGAAAGGCUGC

[1080] SEQ ID NO: 856 - PNPLA3 oligonucleotide 40 guide (antisense) strand UUUGCUCAUGUAUCCACCUUGG

[1081] SEQ ID NO: 857 - PNPLA3 oligonucleotide 41 passenger (sense) strand AGGUGGAUACAUGAGCAAGAGCAGCCGAAAGGCUGC

[1082] SEQ ID NO: 858 - PNPLA3 oligonucleotide 41 guide (antisense) strand UCUUGCUCAUGUAUCCACCUGG

[1083] SEQ ID NO: 859 - PNPLA3 oligonucleotide 42 passenger (sense) strand UGGAUACAUGAGCAAGAUUAGCAGCCCGAAAGGCUGC

[1084] SEQ ID NO: 860 - PNPLA3 oligonucleotide 42 guide (antisense) strand UAAUCUUGCUCAUGUAUCCAGG

[1085] SEQ ID NO: 861 - PNPLA3 oligonucleotide 43 passenger (sense) strand GGAUACAUGAGCAAGAUUUAGCAGCCCGAAAGGCUGC

[1086] SEQ ID NO: 862 - PNPLA3 oligonucleotide 43 guide (antisense) strand

[1087] UAAAUCUUGCUCAUGUAUCCGG

[1088] SEQ ID NO: 863 - PNPLA3 oligonucleotide 44 passenger (sense) strand GAUACAUGAGCAAGAUUUGAGCAGCCGAAAGGCUGC

[1089] SEQ ID NO: 864 - PNPLA3 oligonucleotide 44 guide (antisense) strand UCAAAUCUUGCUCAUGUAUCGG

[1090] SEQ ID NO: 865-PNPLA3 oligonucleotide 45 passenger (sense) strand AUACAUGAGCAAGAUUUGCAGCAGCCGAAAGGCUGC

[1091] SEQ ID NO: 866 - PNPLA3 oligonucleotide 45 guide (antisense) strand UGCAAAUCUUGCUCAUGUAUGG

[1092] SEQ ID NO: 867 - PNPLA3 oligonucleotide 46 passenger (sense) strand UACAUGAGCAAGAUUUGCAAGCAGCCGAAAGGCUGC

[1093] SEQ ID NO: 868 - PNPLA3 oligonucleotide 46 guide (antisense) strand UUGCAAAUCUUGCUCAUGUAGG

[1094] SEQ ID NO: 869 - PNPLA3 oligonucleotide 47 passenger (sense) strand ACAUGAGCAAGAUUUGCAAAGCAGCCGAAAGGCUGC

[1095] SEQ ID NO: 870 - PNPLA3 oligonucleotide 47 guide (antisense) strand UUUGCAAAUCUUGCUCAUGUGG

[1096] SEQ ID NO: 871 - PNPLA3 oligonucleotide 48 passenger (sense) strand UGAGCAAGAUUUGCAACUUAGCAGCCCGAAAGGCUGC

[1097] SEQ ID NO: 872 - PNPLA3 oligonucleotide 48 guide (antisense) strand UAAGUUGCAAAUCUUGCUCAGG

[1098] SEQ ID NO: 873 - PNPLA3 oligonucleotide 49 passenger (sense) strand GAGCAAGAUUUGCAACUUGAGCAGCCGAAAGGCUGC

[1099] SEQ ID NO: 874 - PNPLA3 oligonucleotide 49 guide (antisense) strand UCAAGUUGCAAAUCUUGCUCGG

[1100] SEQ ID NO: 875 - PNPLA3 oligonucleotide 50 passenger (sense) strand AGCAAGAUUUGCAACUUGCAGCAGCCGAAAGGCUGC

[1101] SEQ ID NO: 876 - PNPLA3 oligonucleotide 50 guide (antisense) strand UGCAAGUUGCAAAUCUUGCUGG

[1102] SEQ ID NO: 877 - PNPLA3 oligonucleotide 51 passenger (sense) strand GCAAGAUUUGCAACUUGCUAGCAGCCGAAAGGCUGC

[1103] SEQ ID NO: 878 - PNPLA3 oligonucleotide 51 guide (antisense) strand UAGCAAGUUGCAAAUCUUGCGG

[1104] SEQ ID NO: 879 - PNPLA3 oligonucleotide 52 passenger (sense) strand CAAGAUUUGCAACUUGCUAAGCAGCCCGAAAGGCUGC

[1105] SEQ ID NO: 880 - PNPLA3 oligonucleotide 52 guide (antisense) strand UUAGCAAGUUGCAAAUCUUGGG

[1106] SEQ ID NO: 881 - PNPLA3 oligonucleotide 53 passenger (sense) strand AAGAUUUGCAACUUGCUACAGCAGCCGAAAGGCUGC

[1107] SEQ ID NO: 882 - PNPLA3 oligonucleotide 53 guide (antisense) strand UGUAGCAAGUUGCAAAUCUUGG

[1108] SEQ ID NO: 883 - PNPLA3 oligonucleotide 54 passenger (sense) strand AGAUUUGCAACUUGCUACCAGCAGCCGAAAGGCUGC

[1109] SEQ ID NO: 884 - PNPLA3 oligonucleotide 54 guide (antisense) strand UGGUAGCAAGUUGCAAAUCUGG

[1110] SEQ ID NO: 885-PNPLA3 oligonucleotide 55 passenger (sense) strand AUUUGCAACUUGCUACCCAAGCAGCCGAAAGGCUGC

[1111] SEQ ID NO: 886 - PNPLA3 oligonucleotide 55 guide (antisense) strand UUGGGUAGCAAGUUGCAAAUGG

[1112] SEQ ID NO: 887 - PNPLA3 oligonucleotide 56 passenger (sense) strand UUGCAACUUGCUACCCAUUAGCAGCCCGAAAGGCUGC

[1113] SEQ ID NO: 888 - PNPLA3 oligonucleotide 56 guide (antisense) strand UAAUGGGUAGCAAGUUGCAAGG

[1114] SEQ ID NO: 889 - PNPLA3 oligonucleotide 57 passenger (sense) strand UGCAACUUGCUACCCAUUAAGCAGCCGAAAGGCUGC

[1115] SEQ ID NO: 890 - PNPLA3 oligonucleotide 57 guide (antisense) strand UUAAUGGGUAGCAAGUUGCAGG

[1116] SEQ ID NO: 891 - PNPLA3 oligonucleotide 58 passenger (sense) strand GCAACUUGCUACCCAUUAGAGCAGCCCGAAAGGCUGC

[1117] SEQ ID NO: 892 - PNPLA3 oligonucleotide 58 guide (antisense) strand UCUAAUGGGUAGCAAGUUGCGG

[1118] SEQ ID NO: 893 - PNPLA3 oligonucleotide 59 passenger (sense) strand CAACUUGCUACCCAUUAGGAGCAGCCGAAAGGCUGC

[1119] SEQ ID NO: 894 - PNPLA3 oligonucleotide 59 guide (antisense) strand UCCUAAUGGGUAGCAAGUUGGG

[1120] SEQ ID NO: 895 - PNPLA3 oligonucleotide 60 passenger (sense) strand CUUGCUACCCAUUAGGAUAAGCAGCCCGAAAGGCUGC

[1121] SEQ ID NO: 896 - PNPLA3 oligonucleotide 60 guide (antisense) strand UUAUCCUAAUGGGUAGCAAGGG

[1122] SEQ ID NO: 897 - PNPLA3 oligonucleotide 61 passenger (sense) strand UGCUACCCAUUAGGAUAAUAGCAGCCGAAAGGCUGC

[1123] SEQ ID NO: 898 - PNPLA3 oligonucleotide 61 guide (antisense) strand UAUUAUCCUAAUGGGUAGCAGG

[1124] SEQ ID NO: 899 - PNPLA3 oligonucleotide 62 passenger (sense) strand AUUAGGAUAAUGUCUUAUGAGCAGCCGAAAGGCUGC

[1125] SEQ ID NO: 900-PNPLA3 oligonucleotide 62 guide (antisense) strand UCAUAAGACAUUAUCCUAAUGG

[1126] SEQ ID NO: 901-PNPLA3 oligonucleotide 63 passenger (sense) strand UUAGGAUAAUGUCUUAUGUAGCAGCCGAAAGGCUGC

[1127] SEQ ID NO: 902 - PNPLA3 oligonucleotide 63 guide (antisense) strand UACAUAAGACAUUAUCCUAAGG

[1128] SEQ ID NO: 903 - PNPLA3 oligonucleotide 64 passenger (sense) strand UGCGAUUGUCCAGAGACUGAGCAGCCGAAAGGCUGC

[1129] SEQ ID NO: 904 - PNPLA3 oligonucleotide 64 guide (antisense) strand UCAGUCUCUGGACAAUCGCAGG

[1130] SEQ ID NO: 905-PNPLA3 oligonucleotide 65 passenger (sense) strand CGAUUGUCCAGAGACUGGUAGCAGCCGAAAGGCUGC

[1131] SEQ ID NO: 906 - PNPLA3 oligonucleotide 65 guide (antisense) strand UACCAGUCUCUGGACAAUCGGG

[1132] SEQ ID NO: 907 - PNPLA3 Oligonucleotide 66 Passenger (Sense) Strand GUCCAGAGACUGGUGACAUAAGCAGCCGAAAGGCUGC

[1133] SEQ ID NO: 908 - PNPLA3 oligonucleotide 66 guide (antisense) strand UAUGUCACCAGUCUCUGGACGG

[1134] SEQ ID NO: 909 - PNPLA3 oligonucleotide 67 passenger (sense) strand AGAGACUGGUGACAUGGCUAGCAGCCGAAAGGCUGC

[1135] SEQ ID NO: 910 - PNPLA3 oligonucleotide 67 guide (antisense) strand UAGCCAUGUCACCAGUCUCUGG

[1136] SEQ ID NO: 911 - PNPLA3 Oligonucleotide 68 Passenger (Sense) Strand ACUGGUGACAUGGCUUCCAAGCAGCCGAAAGGCUGC

[1137] SEQ ID NO: 912 - PNPLA3 oligonucleotide 68 guide (antisense) strand UUGGAAGCCAUGUCACCAGUGG

[1138] SEQ ID NO: 913 - PNPLA3 Oligonucleotide 69 Passenger (Sense) Strand CUCCACCUUUCCCAGUUUUAGCAGCCGAAAGGCUGC

[1139] SEQ ID NO: 914 - PNPLA3 oligonucleotide 69 guide (antisense) strand UAAAACUGGGAAAGGUGGAGGG

[1140] SEQ ID NO: 915-PNPLA3 oligonucleotide 70 passenger (sense) strand CACCUUUCCCAGUUUUUCAAGCAGCCGAAAGGCUGC

[1141] SEQ ID NO: 916 - PNPLA3 oligonucleotide 70 guide (antisense) strand UUGAAAAACUGGGAAAGGUGGG

[1142] SEQ ID NO: 917 - PNPLA3 oligonucleotide 71 passenger (sense) strand AGUUUUUCACUAGAGAAGAAGCAGCCGAAAGGCUGC

[1143] SEQ ID NO: 918 - PNPLA3 oligonucleotide 71 guide (antisense) strand UUCUUCUCUAGUGAAAAACUGG

[1144] SEQ ID NO: 919 - PNPLA3 oligonucleotide 72 passenger (sense) strand AGCAGAUUCUUUCAGAGGUAGCAGCCGAAAGGCUGC

[1145] SEQ ID NO: 920 - PNPLA3 oligonucleotide 72 guide (antisense) strand UACCUCUGAAAGAAUCUGCUGG

[1146] SEQ ID NO: 921 - PNPLA3 oligonucleotide 73 passenger (sense) strand GCAGAUUCUUUCAGAGGUGAGCAGCCGAAAGGCUGC

[1147] SEQ ID NO: 922 - PNPLA3 oligonucleotide 73 guide (antisense) strand UCACCUCUGAAAGAAUCUGCGG

[1148] SEQ ID NO: 923 - PNPLA3 oligonucleotide 74 passenger (sense) strand AGAUUCUUUCAGAGGUGCUAGCAGCCGAAAGGCUGC

[1149] SEQ ID NO: 924 - PNPLA3 oligonucleotide 74 guide (antisense) strand UAGCACCUCUGAAAGAAUCUGG

[1150] SEQ ID NO: 925-PNPLA3 oligonucleotide 75 passenger (sense) strand AGGUGCUAAAGUUUCCCAUAGCAGCCGAAAGGCUGC

[1151] SEQ ID NO: 926 - PNPLA3 oligonucleotide 75 guide (antisense) strand UAUGGGAAACUUUAGCACCUGG

[1152] SEQ ID NO: 927 - PNPLA3 oligonucleotide 76 passenger (sense) strand AAAGUUUCCCAUCUUUGUGAGCAGCCGAAAGGCUGC

[1153] SEQ ID NO: 928 - PNPLA3 oligonucleotide 76 guide (antisense) strand UCACAAAGAUGGGAAACUUUGG

[1154] SEQ ID NO: 929 - PNPLA3 oligonucleotide 77 passenger (sense) strand AGUUUCCCAUCUUUGUGCAAGCAGCCGAAAGGCUGC

[1155] SEQ ID NO: 930 - PNPLA3 oligonucleotide 77 guide (antisense) strand UUGCACAAAGAUGGGAAACUGG

[1156] SEQ ID NO: 931 - PNPLA3 oligonucleotide 78 passenger (sense) strand AGCCUCUGAGCUGAGUUGGAGCAGCCGAAAGGCUGC

[1157] SEQ ID NO: 932 - PNPLA3 oligonucleotide 78 guide (antisense) strand UCCAACUCAGCUCAGAGGCUGG

[1158] SEQ ID NO: 933 - PNPLA3 oligonucleotide 79 passenger (sense) strand GCCUCUGAGCUGAGUUGGUAGCAGCCGAAAGGCUGC

[1159] SEQ ID NO: 934 - PNPLA3 oligonucleotide 79 guide (antisense) strand UACCAACUCAGCUCAGAGGCGG

[1160] SEQ ID NO: 935 - PNPLA3 oligonucleotide 80 passenger (sense) strand CCUCUGAGCUGAGUUGGUUAGCAGCCCGAAAGGCUGC

[1161] SEQ ID NO: 936 - PNPLA3 oligonucleotide 80 guide (antisense) strand UAACCAACUCAGCUCAGAGGGG

[1162] SEQ ID NO: 937 - PNPLA3 oligonucleotide 81 passenger (sense) strand CUCUGAGCUGAGUUGGUUUAGCAGCCCGAAAGGCUGC

[1163] SEQ ID NO: 938 - PNPLA3 oligonucleotide 81 guide (antisense) strand UAAACCAACUCAGCUCAGAGGG

[1164] SEQ ID NO: 939 - PNPLA3 oligonucleotide 82 passenger (sense) strand UCUGAGCUGAGUUGGUUUUAGCAGCCCGAAAGGCUGC

[1165] SEQ ID NO: 940 - PNPLA3 oligonucleotide 82 guide (antisense) strand UAAAACCAACUCAGCUCAGAGG

[1166] SEQ ID NO: 941 - PNPLA3 oligonucleotide 83 passenger (sense) strand UGAGCUGAGUUGGUUUUAUAGCAGCCGAAAGGCUGC

[1167] SEQ ID NO: 942 - PNPLA3 oligonucleotide 83 guide (antisense) strand UAUAAAACCAACUCAGCUCAGG

[1168] SEQ ID NO: 943 - PNPLA3 oligonucleotide 84 passenger (sense) strand UGAGUUGGUUUUAUGAAAAAGCAGCCGAAAGGCUGC

[1169] SEQ ID NO: 944 - PNPLA3 oligonucleotide 84 guide (antisense) strand UUUUUCAUAAAACCAACUCAGG

[1170] SEQ ID NO: 945 - PNPLA3 oligonucleotide 85 passenger (sense) strand GAGUUGGUUUUAUGAAAAGAGCAGCCGAAAGGCUGC

[1171] SEQ ID NO: 946 - PNPLA3 oligonucleotide 85 guide (antisense) strand UCUUUUCAUAAAACCAACUCGG

[1172] SEQ ID NO: 947 - PNPLA3 oligonucleotide 86 passenger (sense) strand UUGGUUUUAUGAAAAGCUAAGCAGCCCGAAAGGCUGC

[1173] SEQ ID NO: 948 - PNPLA3 oligonucleotide 86 guide (antisense) strand UUAGCUUUUCAUAAAACCAAGG

[1174] SEQ ID NO: 949 - PNPLA3 oligonucleotide 87 passenger (sense) strand UGGUUUUAUGAAAAGCUAGAGCAGCCGAAAGGCUGC

[1175] SEQ ID NO: 950 - PNPLA3 oligonucleotide 87 guide (antisense) strand UCUAGCUUUUCAUAAAACCAGG

[1176] SEQ ID NO: 951 - PNPLA3 oligonucleotide 88 passenger (sense) strand GGUUUUAUGAAAAGCUAGGAGCAGCCGAAAGGCUGC

[1177] SEQ ID NO: 952 - PNPLA3 oligonucleotide 88 guide (antisense) strand UCCUAGCUUUUCAUAAAACCGG

[1178] SEQ ID NO: 953 - PNPLA3 oligonucleotide 89 passenger (sense) strand UUUUAUGAAAAGCUAGGAAAGCAGCCGAAAGGCUGC

[1179] SEQ ID NO: 954 - PNPLA3 oligonucleotide 89 guide (antisense) strand UUUCCUAGCUUUUCAUAAAAGG

[1180] SEQ ID NO: 955-PNPLA3 oligonucleotide 90 passenger (sense) strand UAUGAAAAGCUAGGAAGCAAGCAGCCGAAAGGCUGC

[1181] SEQ ID NO: 956 - PNPLA3 oligonucleotide 90 guide (antisense) strand UUGCUUCCUAGCUUUUCAUAGG

[1182] SEQ ID NO: 957 - PNPLA3 oligonucleotide 91 passenger (sense) strand AUGAAAAGCUAGGAAGCAAAGCAGCCGAAAGGCUGC

[1183] SEQ ID NO: 958 - PNPLA3 oligonucleotide 91 guide (antisense) strand UUUGCUUCCUAGCUUUUCAUGG

[1184] SEQ ID NO: 959 - PNPLA3 oligonucleotide 92 passenger (sense) strand CCAGCACUUAACUCUAAUAAGCAGCCGAAAGGCUGC

[1185] SEQ ID NO: 960 - PNPLA3 oligonucleotide 92 guide (antisense) strand UUAUUAGAGUUAAGUGCUGGGG

[1186] SEQ ID NO: 961 - PNPLA3 oligonucleotide 93 passenger (sense) strand CAGCACUUAACUCUAAUACAGCAGCCGAAAGGCUGC

[1187] SEQ ID NO: 962 - PNPLA3 oligonucleotide 93 guide (antisense) strand UGUAUUAGAGUUAAGUGCUGGG

[1188] SEQ ID NO: 963 - PNPLA3 oligonucleotide 94 passenger (sense) strand UAAUACAUCAGCAUGCGUUAGCAGCCCGAAAGGCUGC

[1189] SEQ ID NO: 964 - PNPLA3 oligonucleotide 94 guide (antisense) strand UAACGCAUGCUGAUGUAUUAGG

[1190] SEQ ID NO: 965 - PNPLA3 oligonucleotide 95 passenger (sense) strand AAUACAUCAGCAUGCGUUAAGCAGCCGAAAGGCUGC

[1191] SEQ ID NO: 966 - PNPLA3 oligonucleotide 95 guide (antisense) strand UUAACGCAUGCUGAUGUAUUGG

[1192] SEQ ID NO: 967 - PNPLA3 oligonucleotide 96 passenger (sense) strand UGCGUUAAUUCAGCUGGUUAGCAGCCCGAAAGGCUGC

[1193] SEQ ID NO: 968 - PNPLA3 oligonucleotide 96 guide (antisense) strand UAACCAGCUGAAUUAACGCAGG

[1194] SEQ ID NO: 969 - PNPLA3 oligonucleotide 97 passenger (sense) strand GCGUUAAUUCAGCUGGUUGAGCAGCCGAAAGGCUGC

[1195] SEQ ID NO: 970 - PNPLA3 oligonucleotide 97 guide (antisense) strand UCAACCAGCUGAAUUAACGCGG

[1196] SEQ ID NO: 971 - PNPLA3 oligonucleotide 98 passenger (sense) strand CGUUAAUUCAGCUGGUUGGAGCAGCCGAAAGGCUGC

[1197] SEQ ID NO: 972 - PNPLA3 oligonucleotide 98 guide (antisense) strand UCCAACCAGCUGAAUUAACGGG

[1198] SEQ ID NO: 973 - PNPLA3 oligonucleotide 99 passenger (sense) strand UUAAUUCAGCUGGUUGGGAAGCAGCCGAAAGGCUGC

[1199] SEQ ID NO: 974 - PNPLA3 oligonucleotide 99 guide (antisense) strand UUCCCAACCAGCUGAAUUAAGG

[1200] SEQ ID NO: 975 - PNPLA3 oligonucleotide 100 passenger (sense) strand UAAUUCAGCUGGUUGGGAAAGCAGCCGAAAGGCUGC

[1201] SEQ ID NO: 976 - PNPLA3 oligonucleotide 100 guide (antisense) strand UUUCCCAACCAGCUGAAUUAGG

[1202] SEQ ID NO: 977 - PNPLA3 oligonucleotide 101 passenger (sense) strand GCAGAGGGUCCCUUACUGAAGCAGCCGAAAGGCUGC

[1203] SEQ ID NO: 978 - PNPLA3 oligonucleotide 101 guide (antisense) strand UUCAGUAAGGGACCCUCUGCGG

[1204] SEQ ID NO: 979 - PNPLA3 oligonucleotide 102 passenger (sense) strand CUAUUAAUGGUCAGACUGUAGCAGCCGAAAGGCUGC

[1205] SEQ ID NO: 980 - PNPLA3 oligonucleotide 102 guide (antisense) strand UACAGUCUGACCAUUAAUAGGG

[1206] SEQ ID NO: 981 - PNPLA3 oligonucleotide 103 passenger (sense) strand UAUUAAUGGUCAGACUGUUAGCAGCCCGAAAGGCUGC

[1207] SEQ ID NO: 982 - PNPLA3 oligonucleotide 103 guide (antisense) strand UAACAGUCUGACCAUUAAUAGG

[1208] SEQ ID NO: 983 - PNPLA3 oligonucleotide 104 passenger (sense) strand AUUAAUGGUCAGACUGUUCAGCAGCCGAAAGGCUGC

[1209] SEQ ID NO: 984 - PNPLA3 oligonucleotide 104 guide (antisense) strand UGAACAGUCUGACCAUUAAUGG

[1210] SEQ ID NO: 985-PNPLA3 oligonucleotide 105 passenger (sense) strand UUAAUGGUCAGACUGUUCCAGCAGCCCGAAAGGCUGC

[1211] SEQ ID NO: 986 - PNPLA3 oligonucleotide 105 guide (antisense) strand UGGAACAGUCUGACCAUUAAGG

[1212] SEQ ID NO: 987 - PNPLA3 oligonucleotide 106 passenger (sense) strand UAAUGGUCAGACUGUUCCAAGCAGCCGAAAGGCUGC

[1213] SEQ ID NO: 988 - PNPLA3 oligonucleotide 106 guide (antisense) strand UUGGAACAGUCUGACCAUUAGG

[1214] SEQ ID NO: 989 - PNPLA3 oligonucleotide 107 passenger (sense) strand AAUGGUCAGACUGUUCCAGAGCAGCCGAAAGGCUGC

[1215] SEQ ID NO: 990 - PNPLA3 oligonucleotide 107 guide (antisense) strand UCUGGAACAGUCUGACCAUUGG

[1216] SEQ ID NO: 991 - PNPLA3 oligonucleotide 108 passenger (sense) strand AGAACACCUUUUUCACCUAAGCAGCCGAAAGGCUGC

[1217] SEQ ID NO: 992 - PNPLA3 oligonucleotide 108 guide (antisense) strand UUAGGUGAAAAAGGUGUUCUGG

[1218] SEQ ID NO: 993 - PNPLA3 oligonucleotide 109 passenger (sense) strand GAACACCUUUUUCACCUAAAGCAGCCGAAAGGCUGC

[1219] SEQ ID NO: 994 - PNPLA3 oligonucleotide 109 guide (antisense) strand UUUAGGUGAAAAAGGUGUUCGG

[1220] SEQ ID NO: 995 - PNPLA3 oligonucleotide 110 passenger (sense) strand AACACCUUUUUCACCUAACAGCAGCCCGAAAGGCUGC

[1221] SEQ ID NO: 996 - PNPLA3 oligonucleotide 110 guide (antisense) strand UGUUAGGUGAAAAAGGUGUUGG

[1222] SEQ ID NO: 997 - PNPLA3 oligonucleotide 111 passenger (sense) strand ACACCUUUUUCACCUAACUAGCAGCCGAAAGGCUGC

[1223] SEQ ID NO: 998 - PNPLA3 oligonucleotide 111 guide (antisense) strand UAGUUAGGUGAAAAAGGUGUGG

[1224] SEQ ID NO: 999 - PNPLA3 oligonucleotide 112 passenger (sense) strand CACCUUUUUCACCUAACUAAGCAGCCGAAAGGCUGC

[1225] SEQ ID NO: 1000-PNPLA3 oligonucleotide 112 guide (antisense) strand UUAGUUAGGUGAAAAAGGUGGG

[1226] SEQ ID NO: 1001-PNPLA3 oligonucleotide 113 passenger (sense) strand ACCUUUUUCACCUAACUAAAGCAGCCCGAAAGGCUGC

[1227] SEQ ID NO: 1002-PNPLA3 oligonucleotide 113 guide (antisense) strand UUUAGUUAGGUGAAAAAGGUGG

[1228] SEQ ID NO: 1003 - PNPLA3 oligonucleotide 114 passenger (sense) strand CUUUUUCACCUAACUAAAAAGCAGCCGAAAGGCUGC

[1229] SEQ ID NO: 1004 - PNPLA3 oligonucleotide 114 guide (antisense) strand UUUUUAGUUAGGUGAAAAAGGG

[1230] SEQ ID NO: 1005-PNPLA3 oligonucleotide 115 passenger (sense) strand UUUUCACCUAACUAAAAUAAGCAGCCGAAAGGCUGC

[1231] SEQ ID NO: 1006 - PNPLA3 oligonucleotide 115 guide (antisense) strand UUAUUUUAGUUAGGUGAAAAGG

[1232] SEQ ID NO: 1007 - PNPLA3 oligonucleotide 116 passenger (sense) strand UUCACCUAACUAAAAUAAUAGCAGCCGAAAGGCUGC

[1233] SEQ ID NO: 1008 - PNPLA3 oligonucleotide 116 guide (antisense) strand UAUUAUUUUAGUUAGGUGAAGG

[1234] SEQ ID NO: 1009 - PNPLA3 oligonucleotide 117 passenger (sense) strand UCACCUAACUAAAAUAAUGAGCAGCCGAAAGGCUGC

[1235] SEQ ID NO: 1010-PNPLA3 oligonucleotide 117 guide (antisense) strand UCAUUAUUUUAGUUAGGUGAGG

[1236] SEQ ID NO: 1011-PNPLA3 oligonucleotide 118 passenger (sense) strand CACCUAACUAAAAUAAUGUAGCAGCCGAAAGGCUGC

[1237] SEQ ID NO: 1012-PNPLA3 oligonucleotide 118 guide (antisense) strand UACAUUAUUUUAGUUAGGUGGG

[1238] SEQ ID NO: 1013-PNPLA3 oligonucleotide 119 passenger (sense) strand ACCUAACUAAAAUAAUGUUAGCAGCCCGAAAGGCUGC

[1239] SEQ ID NO: 1014-PNPLA3 oligonucleotide 119 guide (antisense) strand UAACAUUAUUUUAGUUAGGUGG

[1240] SEQ ID NO: 1015-PNPLA3 oligonucleotide 120 passenger (sense) strand CCUAACUAAAAUAAUGUUUAGCAGCCGAAAGGCUGC

[1241] SEQ ID NO: 1016 - PNPLA3 oligonucleotide 120 guide (antisense) strand UAAACAUUAUUUUAGUUAGGGG

[1242] SEQ ID NO: 1017-PNPLA3 oligonucleotide 121 passenger (sense) strand CUAACUAAAAUAAUGUUUAAGCAGCCGAAAGGCUGC

[1243] SEQ ID NO: 1018 - PNPLA3 oligonucleotide 121 guide (antisense) strand UUAAACAUUAUUUUAGUUAGGG

[1244] SEQ ID NO: 1019-PNPLA3 oligonucleotide 122 passenger (sense) strand UAACUAAAAAAAUGUUUUAAAGCAGCCCGAAAGGCUGC

[1245] SEQ ID NO: 1020 - PNPLA3 oligonucleotide 122 guide (antisense) strand UUUAAACAUUAUUUUAGUUAGG

[1246] SEQ ID NO: 1021-PNPLA3 oligonucleotide 123 passenger (sense) strand AACUAAAAUAAUGUUUAAAAGCAGCCCGAAAGGCUGC

[1247] SEQ ID NO: 1022 - PNPLA3 oligonucleotide 123 guide (antisense) strand UUUUAAACAUUAUUUUAGUUGG

[1248] SEQ ID NO: 1023 - PNPLA3 oligonucleotide 124 passenger (sense) strand ACUAAAAUAAUGUUUAAAGAGCAGCCGAAAGGCUGC

[1249] SEQ ID NO: 1024 - PNPLA3 oligonucleotide 124 guide (antisense) strand UCUUUAAACAUUAUUUUAGUGG

[1250] SEQ ID NO: 1025-PNPLA3 oligonucleotide 125 passenger (sense) strand CUAAAAUAAUGUUUAAAGAAGCAGCCGAAAGGCUGC

[1251] SEQ ID NO: 1026 - PNPLA3 oligonucleotide 125 guide (antisense) strand UUCUUUAAACAUUAUUUUAGGG

[1252] SEQ ID NO: 1027-PNPLA3 oligonucleotide 126 passenger (sense) strand UAAAAUAAUGUUUAAAGAGAGAGCAGCCGAAAGGCUGC

[1253] SEQ ID NO: 1028 - PNPLA3 oligonucleotide 126 guide (antisense) strand UCUCUUUAAACAUUAUUUUAGG

[1254] SEQ ID NO: 1029-PNPLA3 oligonucleotide 127 passenger (sense) strand AAGAGUUUUGUAUAAAAAUAGCAGCCGAAAGGCUGC

[1255] SEQ ID NO: 1030 - PNPLA3 oligonucleotide 127 guide (antisense) strand UAUUUUUAUACAAAACUCUUGG

[1256] SEQ ID NO: 1031-PNPLA3 oligonucleotide 128 passenger (sense) strand GUUUUGUAUAAAAAUGUAAAGCAGCCGAAAGGCUGC

[1257] SEQ ID NO: 1032 - PNPLA3 oligonucleotide 128 guide (antisense) strand UUUACAUUUUUAUACAAAACGG

[1258] SEQ ID NO: 1033-PNPLA3 oligonucleotide 129 passenger (sense) strand UUGUAUAAAAAUGUAAGGAAGCAGCCGAAAGGCUGC

[1259] SEQ ID NO: 1034 - PNPLA3 oligonucleotide 129 guide (antisense) strand UUCCUUACAUUUUUAUACAAGG

[1260] SEQ ID NO: 1035-PNPLA3 oligonucleotide 130 passenger (sense) strand UGUAUAAAAAUGUAAGGAAAGCAGCCGAAAGGCUGC

[1261] SEQ ID NO: 1036 - PNPLA3 oligonucleotide 130 guide (antisense) strand UUUCCUUACAUUUUUAUACAGG

[1262] SEQ ID NO: 1037 - PNPLA3 oligonucleotide 131 passenger (sense) strand GUAUAAAAAAUGUAAGGAAGAGCAGCCGAAAGGCUGC

[1263] SEQ ID NO: 1038 - PNPLA3 oligonucleotide 131 guide (antisense) strand UCUUCCUUACAUUUUUAUACGG

[1264] SEQ ID NO: 1039 - PNPLA3 oligonucleotide 132 passenger (sense) strand AUGUAAGGAAGCGUUGUUAAGCAGCCGAAAGGCUGC

[1265] SEQ ID NO: 1040 - PNPLA3 oligonucleotide 132 guide (antisense) strand UUAACAACGCUUCCUUACAUGG

[1266] SEQ ID NO: 1041-PNPLA3 oligonucleotide 133 passenger (sense) strand UUUUGUAUUAUGUGAAUCAAGCAGCCGAAAGGCUGC

[1267] SEQ ID NO: 1042 - PNPLA3 oligonucleotide 133 guide (antisense) strand UUGAUUCACAUAAUACAAAAGG

[1268] SEQ ID NO: 1043 - PNPLA3 oligonucleotide 134 passenger (sense) strand UUUGUAUUAUGUGAAUCAGAGCAGCCGAAAGGCUGC

[1269] SEQ ID NO: 1044 - PNPLA3 oligonucleotide 134 guide (antisense) strand UCUGAUUCACAUAAUACAAAGG

[1270] SEQ ID NO: 1045-PNPLA3 oligonucleotide 135 passenger (sense) strand UUGUAUUAUGUGAAUCAGUAGCAGCCGAAAGGCUGC

[1271] SEQ ID NO: 1046 - PNPLA3 oligonucleotide 135 guide (antisense) strand UACUGAUUCACAUAAUACAAGG

[1272] SEQ ID NO: 1047 - PNPLA3 oligonucleotide 136 passenger (sense) strand GUAUUAUGUGAAUCAGUGAAGCAGCCGAAAGGCUGC

[1273] SEQ ID NO: 1048 - PNPLA3 oligonucleotide 136 guide (antisense) strand UUCACUGAUUCACAUAAUACGG

[1274] SEQ ID NO: 1049 - PNPLA3 oligonucleotide 137 passenger (sense) strand UAUUAUGUGAAUCAGUGAGAGCAGCCGAAAGGCUGC

[1275] SEQ ID NO: 1050-PNPLA3 oligonucleotide 137 guide (antisense) strand UCUCACUGAUUCACAUAAUAGG

[1276] SEQ ID NO: 1051-PNPLA3 oligonucleotide 138 passenger (sense) strand AUUAUGUGAAUCAGUGAGAAGCAGCCGAAAGGCUGC

[1277] SEQ ID NO: 1052 - PNPLA3 oligonucleotide 138 guide (antisense) strand UUCUCACUGAUUCACAUAAUGG

[1278] SEQ ID NO: 1053 - PNPLA3 oligonucleotide 139 passenger (sense) strand UUAUGUGAAUCAGUGAGAUAGCAGCCGAAAGGCUGC

[1279] SEQ ID NO: 1054 - PNPLA3 oligonucleotide 139 guide (antisense) strand UAUCUCACUGAUUCACAUAAGG

[1280] SEQ ID NO: 1055-PNPLA3 oligonucleotide 140 passenger (sense) strand UAUGUGAAUCAGUGAGAUGAGCAGCCGAAAGGCUGC

[1281] SEQ ID NO: 1056 - PNPLA3 oligonucleotide 140 guide (antisense) strand UCAUCUCACUGAUUCACAUAGG

[1282] SEQ ID NO: 1057 - PNPLA3 oligonucleotide 141 passenger (sense) strand AUGUGAAUCAGUGAGAUGUAGCAGCCGAAAGGCUGC

[1283] SEQ ID NO: 1058 - PNPLA3 oligonucleotide 141 guide (antisense) strand UACAUCUCACUGAUUCACAUGG

[1284] SEQ ID NO: 1059 - PNPLA3 oligonucleotide 142 passenger (sense) strand UGUGAAUCAGUGAGAUGUUAGCAGCCCGAAAGGCUGC

[1285] SEQ ID NO: 1060 - PNPLA3 oligonucleotide 142 guide (antisense) strand UAACAUCUCACUGAUUCACAGG

[1286] SEQ ID NO: 1061-PNPLA3 oligonucleotide 143 passenger (sense) strand GUGAAUCAGUGAGAUGUUAAGCAGCCGAAAGGCUGC

[1287] SEQ ID NO: 1062 - PNPLA3 oligonucleotide 143 guide (antisense) strand UUAACAUCUCACUGAUUCACGG

[1288] SEQ ID NO: 1063 - PNPLA3 oligonucleotide 144 passenger (sense) strand GUGAGAUGUUAGUAGAAUAAGCAGCCGAAAGGCUGC

[1289] SEQ ID NO: 1064 - PNPLA3 oligonucleotide 144 guide (antisense) strand UUAUUCUACUAACAUCUCACGG

[1290] SEQ ID NO: 1065-PNPLA3 oligonucleotide 145 passenger (sense) strand UUUCUAUUUAUGCAUUUGAAGCAGCCCGAAAGGCUGC

[1291] SEQ ID NO: 1066 - PNPLA3 oligonucleotide 145 guide (antisense) strand UUCAAAUGCAUAAAUAGAAAGG

[1292] SEQ ID NO: 1067 - PNPLA3 oligonucleotide 146 passenger (sense) strand CUAUUUAUGCAUUUGAGUAAGCAGCCGAAAGGCUGC

[1293] SEQ ID NO: 1068 - PNPLA3 oligonucleotide 146 guide (antisense) strand UUACUCAAAUGCAUAAAUAGGG

[1294] SEQ ID NO: 1069 - PNPLA3 oligonucleotide 147 passenger (sense) strand UGCUCAAACUGUUAAAUGUAGCAGCCCGAAAGGCUGC

[1295] SEQ ID NO: 1070 - PNPLA3 oligonucleotide 147 guide (antisense) strand UACAUUUAACAGUUUGAGCAGG

[1296] SEQ ID NO: 1071-PNPLA3 oligonucleotide 148 passenger (sense) strand GCUCAAACUGUUAAAUGUUAGCAGCCGAAAGGCUGC

[1297] SEQ ID NO: 1072 - PNPLA3 oligonucleotide 148 guide (antisense) strand UAACAUUUAACAGUUUGAGCGG

[1298] SEQ ID NO: 1073 - PNPLA3 oligonucleotide 149 passenger (sense) strand CUCAAACUGUUAAAUGUUGAGCAGCCGAAAGGCUGC

[1299] SEQ ID NO: 1074 - PNPLA3 oligonucleotide 149 guide (antisense) strand UCAACAUUUAACAGUUUGAGGG

[1300] SEQ ID NO: 1075-PNPLA3 oligonucleotide 150 passenger (sense) strand UCAAACUGUUAAAUGUUGGAGCAGCCGAAAGGCUGC

[1301] SEQ ID NO: 1076 - PNPLA3 oligonucleotide 150 guide (antisense) strand UCCAACAUUUAACAGUUUGAGG

[1302] SEQ ID NO: 1077-PNPLA3 oligonucleotide 151 passenger (sense) strand CAAACUGUUAAAUGUUGGAAGCAGCCGAAAGGCUGC

[1303] SEQ ID NO: 1078 - PNPLA3 oligonucleotide 151 guide (antisense) strand UUCCAACAUUUAACAGUUUGGG

[1304] SEQ ID NO: 1079 - PNPLA3 oligonucleotide 152 passenger (sense) strand AAACUGUUAAAUGUUGGAAAGCAGCCGAAAGGCUGC

[1305] SEQ ID NO: 1080 - PNPLA3 oligonucleotide 152 guide (antisense) strand UUUCCAACAUUUAACAGUUUGG

[1306] SEQ ID NO: 1081-PNPLA3 oligonucleotide 153 passenger (sense) strand AACUGUUAAAUGUUGGAAAAGCAGCCGAAAGGCUGC

[1307] SEQ ID NO: 1082 - PNPLA3 oligonucleotide 153 guide (antisense) strand UUUUCCAACAUUUAACAGUUGG

[1308] SEQ ID NO: 1083 - PNPLA3 oligonucleotide 154 passenger (sense) strand UGUUAAAUGUUGGAAAAGAAGCAGCCGAAAGGCUGC

[1309] SEQ ID NO: 1084 - PNPLA3 oligonucleotide 154 guide (antisense) strand UUCUUUUCCAACAUUUAACAGG

[1310] SEQ ID NO: 1085-PNPLA3 oligonucleotide 155 passenger (sense) strand GUUAAAUGUUGGAAAAGAAAGCAGCCGAAAGGCUGC

[1311] SEQ ID NO: 1086 - PNPLA3 oligonucleotide 155 guide (antisense) strand UUUCUUUUCCAACAUUUAACGG

[1312] SEQ ID NO: 1087 - PNPLA3 oligonucleotide 156 passenger (sense) strand UUAAAUGUUGGAAAAGAAAAGCAGCCCGAAAGGCUGC

[1313] SEQ ID NO: 1088 - PNPLA3 oligonucleotide 156 guide (antisense) strand UUUUCUUUUCCAACAUUUAAGG

[1314] SEQ ID NO: 1089 - PNPLA3 oligonucleotide 157 passenger (sense) strand UAAAUGUUGGAAAAGAAAGAGCAGCCGAAAGGCUGC

[1315] SEQ ID NO: 1090 - PNPLA3 oligonucleotide 157 guide (antisense) strand UCUUUCUUUUCCAACAUUUAGG

[1316] SEQ ID NO: 1091-PNPLA3 oligonucleotide 158 passenger (sense) strand AGAAAAGAGGCUACUUGUGAGCAGCCGAAAGGCUGC

[1317] SEQ ID NO: 1092 - PNPLA3 oligonucleotide 158 guide (antisense) strand UCACAAGUAGCCUCUUUUCUGG

[1318] SEQ ID NO: 1093-PNPLA3 oligonucleotide 159 passenger (sense) strand GAAAAGAGGCUACUUGUGAAGCAGCCCGAAAGGCUGC

[1319] SEQ ID NO: 1094 - PNPLA3 oligonucleotide 159 guide (antisense) strand UUCACAAGUAGCCUCUUUUCGG

[1320] SEQ ID NO: 1095-PNPLA3 oligonucleotide 160 passenger (sense) strand AAAAGAGGCUACUUGUGAAAGCAGCCGAAAGGCUGC

[1321] SEQ ID NO: 1096 - PNPLA3 oligonucleotide 160 guide (antisense) strand UUUCACAAGUAGCCUCUUUUGG

[1322] SEQ ID NO: 1097 - PNPLA3 oligonucleotide 161 passenger (sense) strand AGAGGCUACUUGUGAAAAUAGCAGCCGAAAGGCUGC

[1323] SEQ ID NO: 1098 - PNPLA3 oligonucleotide 161 guide (antisense) strand UAUUUUCACAAGUAGCCUCUGG

[1324] SEQ ID NO: 1099 - PNPLA3 oligonucleotide 162 passenger (sense) strand GAGGCUACUUGUGAAAAUAAGCAGCCGAAAGGCUGC

[1325] SEQ ID NO: 1100-PNPLA3 oligonucleotide 162 guide (antisense) strand UUAUUUUCACAAGUAGCCUCGG

[1326] SEQ ID NO: 1101-PNPLA3 oligonucleotide 163 passenger (sense) strand AAAGUUACAAGUUUCUUUUAGCAGCCCGAAAGGCUGC

[1327] SEQ ID NO: 1102 - PNPLA3 oligonucleotide 163 guide (antisense) strand UAAAAGAAACUUGUAACUUUGG

[1328] SEQ ID NO: 1103-PNPLA3 oligonucleotide 164 passenger (sense) strand CAACAGUAUUUUCUAAUAAAGCAGCCGAAAGGCUGC

[1329] SEQ ID NO: 1104 - PNPLA3 oligonucleotide 164 guide (antisense) strand UUUAUUAGAAAAUACUGUUGGG

[1330] SEQ ID NO: 1105-PNPLA3 oligonucleotide 165 passenger (sense) strand AACAGUAUUUUCUAAUAAACAGCAGCCGAAAGGCUGC

[1331] SEQ ID NO: 1106 - PNPLA3 oligonucleotide 165 guide (antisense) strand UGUUAUUAGAAAAUACUGUUGG

[1332] SEQ ID NO: 1107-PNPLA3 oligonucleotide 166 passenger (sense) strand ACAGUAUUUUCUAAUAACCAGCAGCCGAAAGGCUGC

[1333] SEQ ID NO: 1108 - PNPLA3 oligonucleotide 166 guide (antisense) strand UGGUUAUUAGAAAAUACUGUGG

[1334] SEQ ID NO: 1109 - PNPLA3 oligonucleotide 167 passenger (sense) strand CAGUAUUUUCUAAUAAACCAAGCAGCCCGAAAGGCUGC

[1335] SEQ ID NO: 1110-PNPLA3 oligonucleotide 167 guide (antisense) strand UUGGUUAUUAGAAAAUACUGGG

[1336] SEQ ID NO: 1111-PNPLA3 oligonucleotide 168 passenger (sense) strand UUGUGAUUGUUAUCAGGAAAGCAGCCGAAAGGCUGC

[1337] SEQ ID NO: 1112-PNPLA3 oligonucleotide 168 guide (antisense) strand UUUCCUGAUAACAAUCACAAGG

[1338] SEQ ID NO: 1113-PNPLA3 oligonucleotide 169 passenger (sense) strand UGUGAUUGUUAUCAGGAAAAGCAGCCGAAAGGCUGC

[1339] SEQ ID NO: 1114-PNPLA3 oligonucleotide 169 guide (antisense) strand UUUUCCUGAUAACAAUCACAGG

[1340] SEQ ID NO: 1115-PNPLA3 oligonucleotide 170 passenger (sense) strand GUGAUUGUUAUCAGGAAAAAGCAGCCGAAAGGCUGC

[1341] SEQ ID NO: 1116-PNPLA3 oligonucleotide 170 guide (antisense) strand UUUUUCCUGAUAACAAUCACGG

[1342] SEQ ID NO: 1117-PNPLA3 oligonucleotide 171 passenger (sense) strand UGAUUGUUAUCAGGAAAAAAGCAGCCCGAAAGGCUGC

[1343] SEQ ID NO: 1118-PNPLA3 oligonucleotide 171 guide (antisense) strand UUUUUUCCUGAUAACAAUCAGG

[1344] SEQ ID NO: 1119-PNPLA3 oligonucleotide 172 passenger (sense) strand GAUUGUUAUCAGGAAAAAAAGCAGCCCGAAAGGCUGC

[1345] SEQ ID NO: 1120-PNPLA3 oligonucleotide 172 guide (antisense) strand UUUUUUUCCUGAUAACAAUCGG

[1346] SEQ ID NO: 1121-PNPLA3 oligonucleotide 173 passenger (sense) strand AUUGUUAUCAGGAAAAAAUAGCAGCCCGAAAGGCUGC

[1347] SEQ ID NO: 1122-PNPLA3 oligonucleotide 173 guide (antisense) strand UAUUUUUUCCUGAUAACAAUGG

[1348] SEQ ID NO: 1123-PNPLA3 oligonucleotide 174 passenger (sense) strand UUGUUAUCAGGAAAAAAUAAGCAGCCGAAAGGCUGC

[1349] SEQ ID NO: 1124-PNPLA3 oligonucleotide 174 guide (antisense) strand UUAUUUUUUCCUGAUAACAAGG

[1350] SEQ ID NO: 1125-PNPLA3 oligonucleotide 175 passenger (sense) strand UGUUAUCAGGAAAAAAUAUAGCAGCCGAAAGGCUGC

[1351] SEQ ID NO: 1126 - PNPLA3 oligonucleotide 175 guide (antisense) strand UAUAUUUUUUCCUGAUAACAGG

[1352] SEQ ID NO: 1127-PNPLA3 oligonucleotide 176 passenger (sense) strand GUUAUCAGGAAAAAAUAUAAGCAGCCGAAAGGCUGC

[1353] SEQ ID NO: 1128 - PNPLA3 oligonucleotide 176 guide (antisense) strand UUAUAUUUUUUCCUGAUAACGG

[1354] SEQ ID NO: 1129-PNPLA3 oligonucleotide 177 passenger (sense) strand UUAUCAGGAAAAAAUAUAUAGCAGCCGAAAGGCUGC

[1355] SEQ ID NO: 1130-PNPLA3 oligonucleotide 177 guide (antisense) strand UAUAUAUUUUUUCCUGAUAAGG

[1356] SEQ ID NO: 1131-PNPLA3 oligonucleotide 178 passenger (sense) strand AGGAAAAAAUAUUUAAAUAGCAGCCCGAAAGGCUGC

[1357] SEQ ID NO: 1132 - PNPLA3 oligonucleotide 178 guide (antisense) strand UAUUUAAUAUAUUUUUUCCUGG

[1358] SEQ ID NO: 1133-PNPLA3 oligonucleotide 179 passenger (sense) strand GGAAAAAAUAUAUUAAAUGAGCAGCCGAAAGGCUGC

[1359] SEQ ID NO: 1134 - PNPLA3 oligonucleotide 179 guide (antisense) strand UCAUUUAAUAUAUUUUUUCCGG

[1360] SEQ ID NO: 1135-PNPLA3 oligonucleotide 180 passenger (sense) strand GAAAAAAUAUAUUAAAUGGAGCAGCCGAAAGGCUGC

[1361] SEQ ID NO: 1136 - PNPLA3 oligonucleotide 180 guide (antisense) strand UCCAUUUAAUAUAUUUUUUCGG

[1362] SEQ ID NO: 1137-PNPLA3 oligonucleotide 181 passenger (sense) strand AUUUUCUUUCUGCUUUUAAAGCAGCCGAAAGGCUGC

[1363] SEQ ID NO: 1138 - PNPLA3 oligonucleotide 181 guide (antisense) strand UUUAAAAGCAGAAAGAAAAUGG

[1364] SEQ ID NO: 1139 - PNPLA3 oligonucleotide 182 passenger (sense) strand UCUUUCUGCUUUUAAAAAUAGCAGCCGAAAGGCUGC

[1365] SEQ ID NO: 1140-PNPLA3 oligonucleotide 182 guide (antisense) strand UAUUUUUAAAAGCAGAAAGAGG

[1366] SEQ ID NO: 1141-PNPLA3 oligonucleotide 183 passenger (sense) strand UAAGGAAAUCAGGAAGUGUAGCAGCCCGAAAGGCUGC

[1367] SEQ ID NO: 1142 - PNPLA3 oligonucleotide 183 guide (antisense) strand UACACUUCCUGAUUUCCUUAGG

[1368] SEQ ID NO: 1143-PNPLA3 oligonucleotide 184 passenger (sense) strand AAGGAAAUCAGGAAGUGUAAGCAGCCGAAAGGCUGC

[1369] SEQ ID NO: 1144 - PNPLA3 oligonucleotide 184 guide (antisense) strand UUACACUUCCUGAUUUCCUUGG

[1370] SEQ ID NO: 1145-PNPLA3 oligonucleotide 185 passenger (sense) strand GGAAAUCAGGAAGUGUAAUAGCAGCCGAAAGGCUGC

[1371] SEQ ID NO: 1146 - PNPLA3 oligonucleotide 185 guide (antisense) strand UAUUACACUUCCUGAUUUCCGG

[1372] SEQ ID NO: 1147-PNPLA3 oligonucleotide 186 passenger (sense) strand CCACACCCAGCUAGUUUUUAGCAGCCCGAAAGGCUGC

[1373] SEQ ID NO: 1148 - PNPLA3 oligonucleotide 186 guide (antisense) strand UAAAAAACUAGCUGGGUGUGGGG

[1374] SEQ ID NO: 1149-PNPLA3 oligonucleotide 187 passenger (sense) strand CACACCCAGCUAGUUUUUUAGCAGCCCGAAAGGCUGC

[1375] SEQ ID NO: 1150-PNPLA3 oligonucleotide 187 guide (antisense) strand UAAAAAACUAGCUGGGUGUGGG

[1376] SEQ ID NO: 1151-PNPLA3 oligonucleotide 188 passenger (sense) strand CUAGGAUUACAGGUGUGAGAGCAGCCGAAAGGCUGC

[1377] SEQ ID NO: 1152 - PNPLA3 oligonucleotide 188 guide (antisense) strand UCUCACACCUGUAAUCCUAGGG

[1378] SEQ ID NO: 1153-PNPLA3 oligonucleotide 189 passenger (sense) strand AGAGUAUGAGCCUGAUUUUAGCAGCCCGAAAGGCUGC

[1379] SEQ ID NO: 1154 - PNPLA3 oligonucleotide 189 guide (antisense) strand UAAAAUCAGGCUCAUACUCUGG

[1380] SEQ ID NO: 1155-PNPLA3 oligonucleotide 190 passenger (sense) strand GAGUAUGAGCCUGAUUUUGAGCAGCCGAAAGGCUGC

[1381] SEQ ID NO: 1156 - PNPLA3 oligonucleotide 190 guide (antisense) strand UCAAAAUCAGGCUCAUACUCGG

[1382] SEQ ID NO: 1157-PNPLA3 oligonucleotide 191 passenger (sense) strand CCCAUCUCUACUAAAAAAUAGCAGCCCGAAAGGCUGC

[1383] SEQ ID NO: 1158 - PNPLA3 oligonucleotide 191 guide (antisense) strand UAUUUUUUAGUAGAGAUGGGGG

[1384] SEQ ID NO: 1159 - PNPLA3 oligonucleotide 192 passenger (sense) strand ACUUUCAGCAUGAGAAAAUAGCAGCCGAAAGGCUGC

[1385] SEQ ID NO: 1160-PNPLA3 oligonucleotide 192 guide (antisense) strand UAUUUUCUCAUGCUGAAAGUGG

[1386] SEQ ID NO: 1161-PNPLA3 oligonucleotide 193 passenger (sense) strand CUGAGCUGAGUUGGUUUUAGCAGCCGAAAGGCUGC

[1387] SEQ ID NO: 1162 - PNPLA3 oligonucleotide 193 guide (antisense) strand UUAAAACCAACUCAGCUCAGGG

[1388] SEQ ID NO: 1163-PNPLA3 oligonucleotide 194 passenger (sense) strand GCUGAGUUGGUUUUAUGAAAGCAGCCGAAAGGCUGC

[1389] SEQ ID NO: 1164-PNPLA3 oligonucleotide 194 guide (sense) strand UUUCAUAAAACCAACUCAGCGG

[1390] SEQ ID NO: 1165-PNPLA3 control passenger (sense) strand CUGUUGAAUUUUGUAUUAUA

[1391] SEQ ID NO: 1166 - PNPLA3 control guide (antisense) strand UAUAAUACAAAAUUCAACAGGG

[1392] SEQ ID NO: 1167 - Target sequence 1 CAACGTACCCTTCATTGAT

[1393] SEQ ID NO: 1168 - Target sequence 2 TGAAAGACAAAGGTGGATA

[1394] SEQ ID NO: 1169 - Target sequence 3 TACATGAGCAAGATTTGCA

[1395] SEQ ID NO: 1170 - Target sequence 4 TGAGCAAGATTTGCAACTT

[1396] SEQ ID NO: 1171 - Target sequence 5 CTCTGAGCTGAGTTGGTTT

[1397] SEQ ID NO: 1172 - Target sequence 6 CTTTTTCACCTAACTAAAA

[1398] SEQ ID NO: 1173 - Target sequence 7 TTCACCTAACTAAAATAAT

[1399] SEQ ID NO: 1174 - Target sequence 8 CTAACTAAAATAATGTTTA

[1400] SEQ ID NO: 1175 - Target sequence 9 CTGAGCTGAGTTGGTTTTA

[1401] SEQ ID NO: 1176 - Target sequence 10 GCTGAGTTGGTTTTATGAA SEQ ID NO: 1177 - Artificial sequence GCAGCCGAAAGGCUGC [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4] [Table 13-1] [Table 13-2]

Table 13-3

Table 13-4

Table 14-1

Table 14-2

Table 14-3

Table 14-4

Claims

1. An RNAi oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double-stranded region; The sense strand is [mCs][mU][mA][mA][mC][mU][mA][fA][fA][fA][fU][mA][mA][mU][mG][mU][mU][mU][mA][mA][mG][mC][mA][mG][mC][mC][mG][ademA-GalN Ac][ademA-GalN Ac][ademA-GalNAc][mG][mG][mC][mU][mG][mC] (SEQ ID NO: 1250) and wherein the nucleotides at positions 1, 2, 3, 4, 5, 6, 7, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 31, 32, 33, 34, 35, and 36 are modified with 2'-O-methyl, the nucleotides at positions 8, 9, 10, and 11 are modified with 2'-fluoro, the internucleotide linkage between the nucleotides at positions 1 and 2 is a phosphorothioate bond, and the nucleotides at positions 28, 29, and 30 are modified with adem-GalNAc; The antisense strand is [MePhosphonate-4O-mUs][fUs][fAs][fA][fA][mC][fA][mU][mU][fA][mU][mU][mU][fU][mA][mG][mU][mU][mA][mGs][mGs][mG] (SEQ ID NO: 1251) and an RNAi oligonucleotide, wherein the nucleotides at positions 1, 6, 8, 9, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, and 22 are modified with 2'-O-methyl; the nucleotides at positions 2, 3, 4, 5, 7, 10, and 14 are modified with 2'-fluoro; the internucleotide linkages between the nucleotides at positions 1 and 2, 2 and 3, 3 and 4, 20 and 21, and 21 and 22 are phosphorothioate linkages; and the nucleotide at position 1 is a 4'-phosphate analog that includes 5'-methoxyphosphonate-4'-oxy.

2. A pharmaceutical composition comprising an RNAi oligonucleotide, the RNAi oligonucleotide comprising a sense strand and an antisense strand, the sense strand and the antisense strand forming a double-stranded region; The sense strand is [mCs][mU][mA][mA][mC][mU][mA][fA][fA][fA][fU][mA][mA][mU][mG][mU][mU][mU][mA][mA][mG][mC][mA][mG][mC][mC][mG][ademA-GalN Ac][ademA-GalN Ac][ademA-GalNAc][mG][mG][mC][mU][mG][mC] (SEQ ID NO: 1250) and wherein the nucleotides at positions 1, 2, 3, 4, 5, 6, 7, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 31, 32, 33, 34, 35, and 36 are modified with 2'-O-methyl, the nucleotides at positions 8, 9, 10, and 11 are modified with 2'-fluoro, the internucleotide linkage between the nucleotides at positions 1 and 2 is a phosphorothioate bond, and the nucleotides at positions 28, 29, and 30 are modified with adem-GalNAc; The antisense strand is [MePhosphonate-4O-mUs][fUs][fAs][fA][fA][mC][fA][mU][mU][fA][mU][mU][mU][fU][mA][mG][mU][mU][mA][mGs][mGs][mG] (SEQ ID NO: 1251) and wherein the nucleotides at positions 1, 6, 8, 9, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, and 22 are modified with 2'-O-methyl, the nucleotides at positions 2, 3, 4, 5, 7, 10, and 14 are modified with 2'-fluoro, the internucleotide linkages between the nucleotides at positions 1 and 2, 2 and 3, 3 and 4, 20 and 21, and 21 and 22 are phosphorothioate linkages, and the nucleotide at position 1 is a 4'-phosphate analog containing 5'-methoxyphosphonate-4'-oxy.

3. 3. The pharmaceutical composition of claim 2, further comprising a carrier suitable for intravenous administration.

4. The pharmaceutical composition of claim 3 , wherein the carrier comprises water.

5. The pharmaceutical composition of claim 3, wherein the carrier comprises phosphate buffered saline.

6. The RNAi oligonucleotide of claim 1 or the pharmaceutical composition of any one of claims 2 to 5 for use in reducing PNPLA3 expression in a cell, a population of cells, or a subject.

7. The RNAi oligonucleotide or pharmaceutical composition of claim 6, wherein decreasing PNPLA3 expression comprises decreasing the amount or level of PNPLA3 mRNA, the amount or level of PNPLA3 protein, or both.

8. The RNAi oligonucleotide or pharmaceutical composition of claim 6, wherein the subject has a disease, disorder, or condition associated with PNPLA3 expression.

9. The RNAi oligonucleotide or pharmaceutical composition of claim 8, wherein the disease, disorder, or condition associated with PNPLA3 expression is a cardiometabolic disease, alcoholic hepatitis (AH), alcoholic liver disease (ALD), cirrhosis, hepatocellular carcinoma (HCC), nonalcoholic fatty liver disease (NAFLD), or nonalcoholic steatohepatitis (NASH).

10. 10. The RNAi oligonucleotide of claim 1 or the pharmaceutical composition of any one of claims 2 to 5 for use in treating a subject having a cardiometabolic disease, alcoholic hepatitis (AH), alcoholic liver disease (ALD), liver cirrhosis, hepatocellular carcinoma (HCC), nonalcoholic fatty liver disease (NAFLD), or nonalcoholic steatohepatitis (NASH).

11. The RNAi oligonucleotide or pharmaceutical composition of claim 6 , administered in combination with a second composition or therapeutic agent.

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