RNAI agents targeting GPAM and related methods

Abstract

Provided herein are, inter alia, agents (e.g., RNAi agents, dsRNA agents) comprising a sense strand and an antisense strand targeting GPAM (e.g., hGPAM); and methods of manufacturing and pharmaceutical compositions comprising the same. Further provided herein are methods of utilizing the agents (e.g., RNAi agents, dsRNA agents) including, e.g., methods of inhibiting or decreasing GPAM expression (e.g., mRNA expression), methods of treating GPAM associated diseases, and methods of treating liver diseases (e.g., MASH).

Description

Attorney Docket No. 62801.94WO01RNAI AGENTS TARGETING GPAM AND RELATED METHODS RELATED APPLICATIONS

[0001] This application claims priority to U. S. Serial No.: 63 / 762,389. filed February 24, 2025, the entire contents of each of which is incorporated herein by reference.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on February 11, 2026, is named 62801_94W001_SL.xml and is 411,645 bytes in size.1. FIELD

[0003] This disclosure relates to RNAi agents (e.g., double stranded RNA (dsRNA) agents comprising a sense strand and an antisense strand) targeting glycerol-3-phosphate acyltransferase 1. mitochondrial (GPAM). The disclosure further relates to pharmaceutical compositions comprising the same; and methods of utilizing the same, including, e.g., methods of treating GPAM associated diseases (e.g., liver diseases).2. BACKGROUND

[0004] GPAM is an enzyme expressed in the mitochondria that functions in, inter alia, glycerolipid synthesis, including the synthesis of e.g., triglycerides, phosphatidic acids, and lysophosphatidic acids. GPAM esterifies acyl-group from acyl-ACP to the sn-1 position of glycerol-3-phosphate, an essential step in the glycerolipid biosynthesis pathway. GPAM is a member of the larger glycerol-3-phosphate acyltransferase (GPAT) family of proteins. All GPATs mediate glycerolipid synthesis, but are differentiated based on e.g., subcellular localization, substrate preferences and sulfhydryl-group modifying reagents like N-ethylmaleimide (NEM).3. SUMMARY

[0005] Provided herein are, inter alia, agents (e.g., RNAi agents, dsRNA agents) comprising a sense strand and an antisense strand targeting GPAM (e.g., hGPAM); and methods of manufacturing and pharmaceutical compositions comprising the same. Further provided herein areAttorney Docket No. 62801.94WO01methods of utilizing the agents (e.g., RNAi agents, dsRNA agents) including, e.g., methods of inhibiting or decreasing GPAM expression (e.g., mRNA expression), methods of treating GRAM associated diseases, and methods of treating liver diseases e.g., nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD)).

[0006] Accordingly, provided herein are, inter alia, agents (e.g., RNAi agents, dsRNA agents) comprising a sense strand and an antisense strand targeting GPAM (e.g., hGPAM); and methods of manufacturing and pharmaceutical compositions comprising the same. Further provided herein are methods of utilizing the agents (e.g., RNAi agents, dsRNA agents) including, e.g., methods of inhibiting or decreasing GPAM expression (e.g., mRNA expression), methods of treating GPAM associated diseases, and methods of treating liver diseases (e.g., nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD)).

[0007] Accordingly, in one aspect provided herein are double stranded ribonucleic acid (dsRNA) agents for inhibiting expression of glycerol-3-phosphate acyltransferase 1 (GPAM) (e.g., human GPAM (hGPAM)), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3. 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or set forth in any one of SEQ ID NOS: 153-301.

[0008] In some embodiments, the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or the corresponding sense strand set forth in any one of SEQ ID NOS: 4-152.

[0009] In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or set forth in any one of SEQ ID NOS: 153-301; and the nucleotide sequence of the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or the corresponding sense strand set forth in one of SEQ ID NOS: 4-152.

[0010] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2 or set forth in any one of SEQ ID NOS: 153-301; and the nucleotide sequence of the sense strand comprises the nucleotide sequence of the corresponding sense strand set forth in Table 2 or the correspondingAttorney Docket No. 62801.94WO01sense strand set forth in one of SEQ ID NOS: 4-152.

[0011] In one aspect, provided herein are dsRNA agents for inhibiting expression of GPAM {e.g., hGPAM), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, and wherein the nucleotide sequence of the antisense strand differs by no more than 5 {e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149 set forth in Table 2; and the nucleotide sequence of the sense strand differs by no more than 5 {e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the sense strand of the corresponding dsRNA agent set forth in Table 2.

[0012] In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149 set forth in Table 2; and the nucleotide sequence of the sense strand differs by no more than 3 e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding dsRNA agent set forth in Table 2.

[0013] In one aspect, provided herein are dsRNA agents for inhibiting expression of GPAM {e.g., hGPAM), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, and wherein the sense strand comprises at least 15 {e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 5 {e.g., 0, 1, 2, 3, 4 or 5 {e.g., 3 {e.g., 0, 1, 2, or 3))) nucleotides from nucleotides 350-388, 392-420, 430-482, 481-509, 508-536, 530-560, 606-634, 640-668, 668-704, 735-766, 768-796, 850-879, 871-923, 937-980, 1037-1067, 1077-1127, 1144-1172, 1187-1217, 1249-1277, 1269-1301, 1360-1398, 1430-1457, 1469-1501. 1613-1666, 1691-1816, 1894-2001, 1905-1945. 1946-1990, 2005-2038, 2095-2123, 2163-2191, 2291-2335, 2489-2517, 2620-2647, 2669-2702, 2894-2922, 2918-2946, 3083-3113, 3237-3265, 3318-3356, 3586-3624, 3676-3704, 3725-3769, 3836-3864, 3889-3930, 4325-4355, 4422-4451.4511-4546, 5003-5035, 5501-5542. 5565-5593, 5662-5710. 5805-5835, or 6015-6043 of SEQ ID NO: 1; wherein the nucleotide sequence of the antisense strand comprises at least 15 {e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 5 {e.g., 0, 1, 2, 3, 4, or 5 {e.g., 2 or 3)) nucleotides from the nucleotide sequence of the corresponding complementary nucleotide sequence of SEQ ID NO: 2.

[0014] In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 5 {e.g., 0, 1, 2, 3, 4, or 5 {e.g., 3 {e.g., 0, 1, 2, or 3))) nucleotides from the nucleotideAttorney Docket No. 62801.94WO01sequence of any one of the antisense strands set forth in Table 2 or set forth in any one of SEQ ID NOS: 153-301.

[0015] In some embodiments, the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or set forth in any one of SEQ ID NOS: 4-152.

[0016] In one aspect, provided herein are dsRNA agent for inhibiting expression of GPAM (e.g., hGPAM), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the nucleotide sequence of the antisense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or set forth in any one of SEQ ID NOS: 153-301.

[0017] In some embodiments, the nucleotide sequence of the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or the corresponding sense strand set forth in one of SEQ ID NOS: SEQ ID NOS: 4-152.

[0018] In some embodiments, the nucleotide sequence of the antisense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or set forth in any one of SEQ ID NOS: 153-301; and wherein the nucleotide sequence of the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or the corresponding sense strand set forth in one of SEQ ID NOS: 4-152.

[0019] In some embodiments, the nucleotide sequence of the antisense strand comprises at least 21 (e.g., 21, 22, or 23) contiguous nucleotides of the nucleotide sequence of any one of the antisense strands set forth in Table 2 or set forth in any one of SEQ ID NOS: 153-301; and wherein the nucleotide sequence of the sense strand comprises at least 18 (e.g., 18, 19, 20, 21) contiguous nucleotides of the nucleotide sequence of the corresponding sense strand set forth in Table 2 or the corresponding sense strand set forth in one of SEQ ID NOS: 4-152.

[0020] In one aspect, provided herein are dsRNA agent for inhibiting expression of GPAMAttorney Docket No. 62801.94WO01(e.g., hGPAM), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the nucleotide sequence of the antisense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strand of any one of dsRNA agents 1-149.

[0021] In some embodiments, the nucleotide sequence of the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the corresponding sense strand of the dsRNA agent.

[0022] In some embodiments, the nucleotide sequence of the antisense strand comprises at least 15 (e.g., 16. 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strand of any one of dsRNA agents 1-149; and wherein the nucleotide sequence of the sense strand comprises at least 15 (e.g., 16, 17. 18. 19, 20, 21) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand of the dsRNA agent.

[0023] In some embodiments, the nucleotide sequence of the antisense strand comprises at least 21 (e.g., 21, 22, or 23) contiguous nucleotides of the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149; and wherein the nucleotide sequence of the sense strand comprises at least 18 (e.g., 18, 19, 20, 21) contiguous nucleotides of the nucleotide sequence of the corresponding sense strand of the dsRNA agent.

[0024] In one aspect, provided herein are dsRNA agents for inhibiting expression of GPAM (e.g., hGPAM), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or set forth in any one of SEQ ID NOS: 153-301.

[0025] In some embodiments, the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from any sense strand set forth in Table 2 or set forth in any one of SEQ ID NOS: 4-152.

[0026] In some embodiments, the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20,Attorney Docket No. 62801.94WO0121 ) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding sense strand set forth in Table 2 or the corresponding sense strand set forth in one of SEQ ID NOS: 4-152.

[0027] In some embodiments, the sense strand comprises at least one modified nucleotide and / or the antisense strand comprises at least one modified nucleotide. In some embodiments, at least 25%, 30%. 35%, 40%, 45%, 50%. 55%, 60%, 65%. 70%, 75%, 80%. 85%. 90%, 95%, or 100% of the nucleotides of the sense strand and / or antisense strand are modified. In some embodiments, substantially all (or all) of the nucleotides in the sense strand and / or antisense strand are modified.

[0028] In some embodiments, at least one of the modified nucleotides comprises a modified sugar (e.g., ribose moiety). In some embodiments, at least one of the modified nucleotides comprises a modified nucleobase.

[0029] In some embodiments, the sense strand comprises at least one modified internucleoside linkage and / or the antisense strand comprises at least one modified internucleoside linkage.

[0030] In some embodiments, each of the antisense strand and the sense strand are not more than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 nucleotides in length. In some embodiments, the antisense strand comprises from about 15-30, 16-30, 17-30, 18-30, 19-30, 20-30, 21-30, 22-30, 23-30, 24-30, 25-30, 26-30, 27-30, 28-30, 29-30, 19-20, 19-21, 19-22, 19-23, 19-24, or 19-25 nucleotides; and / or the sense strand comprises from about 15-30, 16-30, 17-30, 18-30, 19-30, 20-30, 21-30, 22-30, 23-30, 24-30, 25-30, 26-30, 27-30, 28-30, 29-30, 19-20, 19-21, 19-22, 19-23, 19-24, or 19-25 nucleotides. In some embodiments, antisense strand comprises from about 19-23 nucleotides; and / or the sense strand comprises from about 19-23 nucleotides. In some embodiments, the antisense strand comprises or consists of about 23 nucleotides; and / or the sense strand comprises or consists of about 21 nucleotides.

[0031] In some embodiments, the sense strand and / or the antisense strand comprises a 3' and / or 5' overhang of 1, 2, or 3 nucleotides. In some embodiments, the antisense strand comprises a 3' overhang of 1, 2, or 3 nucleotides (e.g., 2 nucleotides).

[0032] In some embodiments, the double stranded region is from about 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-20, 19-21, 23-30, 23-29, 23-28, 23-27, 23-26, 23-25, 23-24, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23. or 21-22 nucleotide pairs in length. In some embodiments, the double stranded region is from about 19-23 or 19-21 nucleotide pairsAttorney Docket No. 62801.94WO01in length. Tn some embodiments, the double stranded region is about 21 nucleotide pairs in length.

[0033] In some embodiments, the sense strand and the antisense strand are part of a single nucleic acid molecule (e.g., wherein a hairpin loop is between the sense strand and the antisense strand of the single nucleic acid molecule. In some embodiments, the sense strand and the antisense strand are separate nucleic acid molecules (z.e., connected only through the double stranded region).

[0034] In one aspect, provided herein are dsRNA agents for inhibiting expression of GPAM (e.g., hGPAM), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, and wherein the antisense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strands of any one of dsRNA agents 1-149 set forth in Table 2; and wherein the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding dsRNA agent set forth in Table 2.

[0035] In some embodiments, the sense strand comprises at least one modified nucleotide and / or the antisense strand comprises at least one modified nucleotide. In some embodiments, at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the nucleotides of the sense strand and / or antisense strand are modified. In some embodiments, substantially all (or all) of the nucleotides in the sense strand and / or antisense strand are modified.

[0036] In some embodiments, at least one of the modified nucleotides comprises a modified sugar (e.g., ribose moiety). In some embodiments, at least one of the modified nucleotides comprises a modified nucleobase.

[0037] In some embodiments, the sense strand comprises at least one modified internucleoside linkage and / or the antisense strand comprises at least one modified internucleoside linkage.

[0038] In some embodiments, each of the antisense strand and the sense strand are not more than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 nucleotides in length. In some embodiments, the antisense strand comprises from about 15-30, 16-30, 17-30, 18-30, 19-30, 20-30, 21-30, 22-30, 23-30, 24-30, 25-30, 26-30, 27-30, 28-30, 29-30, 19-20, 19-21, 19-22, 19-23, 19-24, or 19-25 nucleotides; and / or the sense strand comprises from about 15-30, 16-30, 17-30,Attorney Docket No. 62801.94WO0118-30, 19-30, 20-30, 21-30, 22-30, 23-30, 24-30, 25-30, 26-30, 27-30, 28-30, 29-30, 19-20, 19-21, 19-22, 19-23, 19-24, or 19-25 nucleotides. In some embodiments, antisense strand comprises from about 19-23 nucleotides; and / or the sense strand comprises from about 19-23 nucleotides. In some embodiments, the antisense strand comprises or consists of about 23 nucleotides; and / or the sense strand comprises or consists of about 21 nucleotides.

[0039] In some embodiments, the sense strand and / or the antisense strand comprises a 3' and / or 5' overhang of 1, 2, or 3 nucleotides. In some embodiments, the antisense strand comprises a 3' overhang of 1, 2, or 3 nucleotides (e.g., 2 nucleotides).

[0040] In some embodiments, the double stranded region is from about 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-20, 19-21, 23-30, 23-29, 23-28, 23-27, 23-26, 23-25, 23-24, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23. or 21-22 nucleotide pairs in length. In some embodiments, the double stranded region is from about 19-23 or 19-21 nucleotide pairs in length. In some embodiments, the double stranded region is about 21 nucleotide pairs in length.

[0041] In some embodiments, the sense strand and the antisense strand are part of a single nucleic acid molecule (e.g., wherein a hairpin loop is between the sense strand and the antisense strand of the single nucleic acid molecule. In some embodiments, the sense strand and the antisense strand are separate nucleic acid molecules (i.e., connected only through the double stranded region).

[0042] In one aspect, provided herein are dsRNA agents for inhibiting expression of GPAM (e.g., hGPAM), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, and wherein the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 3 (e.g., 0. 1, 2. or 3) nucleotides from nucleotides 68-106, 81-103, 138-190, 169-206, 232-254, 230-300, 280-312, 298-327. 444-498, 510-538. 521-558, 560-617, 692-778, 961-1037, 1035-1060, 1105-1133, 1171-1213. 1216-1287, 1294-1346, 1366-1400. 1724-1753, 1757-1812, 1833-1864. 1900-1927, 1915-1966, 2082-2110, 2143-2198, or 2197-2225 of SEQ ID NO: 1; wherein the antisense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2.

[0043] In some embodiments, the antisense strand comprises at least 15 (e.g., 16, 17. 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3)Attorney Docket No. 62801.94WO01nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or set forth in any one of SEQ ID NOS: 153-301.

[0044] In some embodiments, the sense strand comprises at least 15 (e.g., 16, 17. 18. 19, 20, 21) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or set forth in any one of SEQ ID NOS: 4-152.

[0045] In some embodiments, the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or the corresponding sense strand set forth in one of SEQ ID NOS: 4-152.

[0046] In some embodiments, the sense strand comprises at least one modified nucleotide and / or the antisense strand comprises at least one modified nucleotide. In some embodiments, at least 25%, 30%, 35%. 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the nucleotides of the sense strand and / or antisense strand are modified. In some embodiments, substantially all (or all) of the nucleotides in the sense strand and / or antisense strand are modified.

[0047] In some embodiments, at least one of the modified nucleotides comprises a modified sugar (e.g., ribose moiety). In some embodiments, at least one of the modified nucleotides comprises a modified nucleobase.

[0048] In some embodiments, the sense strand comprises at least one modified internucleoside linkage and / or the antisense strand comprises at least one modified internucleoside linkage.

[0049] In some embodiments, each of the antisense strand and the sense strand are not more than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 nucleotides in length. In some embodiments, the antisense strand comprises from about 15-30, 16-30, 17-30, 18-30, 19-30 20-30, 21-30, 22-30, 23-30, 24-30, 25-30, 26-30, 27-30, 28-30, 29-30, 19-20, 19-21, 19-22, 19-23, 19-24, or 19-25 nucleotides; and / or the sense strand comprises from about 15-30, 16-30, 17-30, 18-30, 19-30, 20-30, 21-30, 22-30, 23-30, 24-30, 25-30, 26-30, 27-30, 28-30, 29-30, 19-20, 19-21, 19-22, 19-23, 19-24, or 19-25 nucleotides. In some embodiments, antisense strand comprises from about 19-23 nucleotides; and / or the sense strand comprises from about 19-23 nucleotides. In some embodiments, the antisense strand comprises or consists of about 23 nucleotides: and / or the sense strand comprises or consists of about 21 nucleotides.Attorney Docket No. 62801.94WO01

[0050] In some embodiments, the sense strand and / or the antisense strand comprises a 3' and / or 5' overhang of 1, 2, or 3 nucleotides. In some embodiments, the antisense strand comprises a 3' overhang of 1. 2, or 3 nucleotides (e.g., 2 nucleotides).

[0051] In some embodiments, the double stranded region is from about 19-30, 19-29, 19-28, 19-27, 19-26. 19-25, 19-24, 19-23, 19-22, 19-20, 19-21, 23-30, 23-29, 23-28, 23-27, 23-26, 23-25, 23-24, 21-30, 21-29. 21-28. 21-27, 21-26, 21-25, 21-24, 21-23. or 21-22 nucleotide pairs in length. In some embodiments, the double stranded region is from about 19-23 or 19-21 nucleotide pairs in length. In some embodiments, the double stranded region is about 21 nucleotide pairs in length.

[0052] In some embodiments, the sense strand and the antisense strand are part of a single nucleic acid molecule (e.g., wherein a hairpin loop is between the sense strand and the antisense strand of the single nucleic acid molecule. In some embodiments, the sense strand and the antisense strand are separate nucleic acid molecules (i.e., connected only through the double stranded region).

[0053] In one aspect, provided herein are conjugates comprising any dsRNA agent described herein and a heterologous moiety.

[0054] In some embodiments, the heterologous moiety is a peptide, protein, carbohydrate, lipid, polymer, or small molecule. In some embodiments, the heterologous moiety is carbohydrate. In some embodiments, the heterologous moiety comprises one or more GalNac. In some embodiments, the GalNac is triantennary GalNac.

[0055] In some embodiments, the heterologous moiety is a targeting moiety. In some embodiments, the targeting moiety specifically binds to a moiety expressed by hepatocytes e.g., on the surface of the hepatocytes). In some embodiments, the targeting moiety comprises GalNac. In some embodiments, the GalNac is triantennary GalNac. In some embodiments, the targeting moiety directs the agent to hepatocytes through specific binding to the asialoglycoprotein receptor (e.g., expressed on the surface of hepatocytes).

[0056] In some embodiments, the heterologous moiety is attached to the dsRNA agent via a linker. In some embodiments, the linker is cleavable.

[0057] In some embodiments, the heterologous moiety attached to the 3 '-end of the sense and / or antisense strand and / or the 5 '-end of the sense and / or antisense strand, and / or at an internal site of the sense and / or antisense strand.

[0058] In one aspect, provided herein are vectors encoding any antisense strand describedAttorney Docket No. 62801.94WO01herein (e.g., any antisense strand of a dsRNA agent described herein (e.g., described above)), any sense strand described herein (e.g., any sense strand of a dsRNA agent described herein (e.g., described above)), or both any antisense described herein (e.g., any antisense strand of a dsRNA agent described herein (e.g., described above)) and any sense strand described herein (e.g., any sense strand of a dsRNA agent described herein (e.g., described above)). In some embodiments, the vector is a viral vector. In some embodiments, the vector is a non-viral vector (e.g., a plasmid).

[0059] In one aspect, provided herein are carriers comprising a dsRNA agent described herein (e.g., described above) or a vector described herein (e.g., described above). In some embodiments, the carrier comprises a nanoparticle, a polymer, a lipid-based delivery system, a dendrimer, a cationic delivery system, or a hydrogel. In some embodiments, the lipid-based delivery system is a lipid nanoparticle (LNP), liposome, lipoplex, nanoliposome, an exosome. or a micelle.

[0060] In one aspect, provided herein are cells (or populations of cells) comprising a dsRNA described herein (e.g., described above), a conjugate described herein (e.g., described above), a vector described herein (e.g., described above), or a earner described herein (e.g., described above).

[0061] In one aspect, provided herein are pharmaceutical compositions comprising a dsRNA described herein (e.g., described above), a conjugate described herein (e.g., described above), a vector described herein (e.g., described above), a carrier described herein (e.g., described above), or a cell (or population of cells) described herein (e.g., described above), and a pharmaceutically acceptable excipient.

[0062] In one aspect, provided herein are kits comprising a dsRNA described herein (e.g., described above), a conjugate described herein (e.g., described above), a vector described herein (e.g., described above), a carrier described herein (e.g., described above), a cell (or population of cells) described herein (e.g., described above), or a pharmaceutical composition described herein (e.g., described above).

[0063] In one aspect, provided herein are methods of delivering a dsRNA, conjugate, vector, carrier, or pharmaceutical composition to a cell, the method comprising introducing into a cell a dsRNA described herein (e.g., described above), a conjugate described herein (e.g., described above), a vector described herein (e.g., described above), a carrier described herein (e.g., described above), or a pharmaceutical composition described herein (e.g., described above), to thereby deliver the dsRNA, conjugate, vector, carrier, or pharmaceutical composition into the cell.Attorney Docket No. 62801.94WO01

[0064] In some embodiments, the cell is in vitro, ex vivo, or in vivo. In some embodiments, the cell is a subject (e.g., a human subject).

[0065] In one aspect, provided herein are methods of delivering a dsRNA, conjugate, vector, carrier, or pharmaceutical composition to a subject, the method comprising administering to the subject a dsRNA described herein (e.g., described above), a conjugate described herein e.g., described above), a vector described herein e.g., described above), a carrier described herein e.g., described above), or a pharmaceutical composition described herein (e.g., described above), to thereby deliver the dsRNA, conjugate, vector, carrier, or pharmaceutical composition to the subject. In some embodiments, the subject is a human.

[0066] In some embodiments, the dsRNA described herein e.g., described above), the conjugate described herein (e.g., described above), the vector described herein e.g., described above), the carrier described herein e.g., described above), or the pharmaceutical composition described herein e.g., described above), is administered to the subject at a dose of from about 1-10 mg / kg, 2-10 mg / kg, 3-10 mg / kg, 4-10 mg / kg, 5-10 mg / kg, 6-10 mg / kg, 7-10 mg / kg, 8-10 mg / kg 9-10 mg / kg, 1-5 mg / kg, 1-4 mg / kg, 1-3 mg / kg, 1-2 mg / kg, 1-2.5 mg / kg, 2-5 mg / kg, 2-4 mg / kg, 2-3 mg / kg, or 2-2.5 mg / kg. In some embodiments, the dsRNA described herein e.g., described above), the conjugate described herein e.g., described above), the vector described herein e.g., described above), the carrier described herein (e.g., described above), or the pharmaceutical composition described herein e.g., described above), is administered to the subject at a dose of about 1 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, or 10 mg / kg. In some embodiments, the dsRNA described herein e.g., described above), the conjugate described herein e.g., described above), the vector described herein (e.g., described above), the carrier described herein e.g., described above), or the pharmaceutical composition described herein e.g., described above), is administered to the subject at least once per month, once per month, at least twice per month, twice per month, at least once a week, or once per week.

[0067] In one aspect, provided herein are methods of reducing or inhibiting expression of GPAM e.g., hGPAM) in a cell, the method comprising delivering into the cell a dsRNA described herein e.g., described above), a conjugate described herein e.g., described above), a vector described herein e.g., described above), a carrier described herein (e.g., described above), or a pharmaceutical composition described herein (e.g., described above), to thereby reduce or inhibit expression of GPAM (e.g., hGPAM) in the cell.Attorney Docket No. 62801.94WO01

[0068] In one aspect, provided herein are methods of reducing or inhibiting expression of GPAM (e.g., hGPAM) in a cell in a subject, the method comprising administering to the subject a dsRNA described herein (e.g., described above), a conjugate described herein (e.g., described above), a vector described herein (e.g., described above), a carrier described herein (e.g., described above), or a pharmaceutical composition described herein (e.g., described above), to thereby reduce or inhibit expression of GPAM e.g., hGPAM) in the cell in the subject. In some embodiments, the subject is a human.

[0069] In some embodiments, the dsRNA described herein (e.g., described above), the conjugate described herein (e.g., described above), the vector described herein (e.g., described above), the carrier described herein (e.g., described above), or the pharmaceutical composition described herein (e.g., described above), is administered to the subject at a dose of from about 1-10 mg / kg, 2-10 mg / kg, 3-10 mg / kg, 4-10 mg / kg, 5-10 mg / kg, 6-10 mg / kg, 7-10 mg / kg, 8-10 mg / kg 9-10 mg / kg, 1-5 mg / kg, 1-4 mg / kg, 1-3 mg / kg, 1-2 mg / kg, 1-2.5 mg / kg. 2-5 mg / kg, 2-4 mg / kg, 2-3 mg / kg, or 2-2.5 mg / kg. In some embodiments, the dsRNA described herein (e.g., described above), the conjugate described herein (e.g., described above), the vector described herein (e.g., described above), the carrier described herein (e.g., described above), or the pharmaceutical composition described herein (e.g., described above), is administered to the subject at a dose of about 1 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, or 10 mg / kg. In some embodiments, the dsRNA described herein (e.g., described above), the conjugate described herein (e.g., described above), the vector described herein (e.g., described above), the carrier described herein (e.g., described above), or the pharmaceutical composition described herein (e.g., described above), is administered to the subject at least once per month, once per month, at least twice per month, twice per month, at least once a week, or once per week.

[0070] In one aspect, provided herein are methods of treating, ameliorating, or preventing a GPAM (e.g., hGPAM) associated disease in a subject, the method comprising administering to the subject a dsRNA described herein (e.g., described above), a conjugate described herein (e.g., described above), a vector described herein (e.g., described above), a carrier described herein (e.g., described above), or a pharmaceutical composition described herein (e.g., described above), to thereby treat, ameliorate, or prevent the GPAM (e.g., hGPAM) associated disease in the subject.

[0071] In some embodiments, the treating, ameliorating, or preventing of the GPAM (e.g., hGPAM) associated disease is mediated (at least in part) through the by reducing or inhibitingAttorney Docket No. 62801.94WO01expression of GPAM (e.g., hGPAM) in the subject (e.g., a population of cells within the subject).

[0072] In some embodiments, the GPAM (e.g., hGPAM) associated disease is fatty liver disease, steatotic liver disease, liver inflammation, NASH, NAFLD, MASLD, MASH, MAFLD, MetALD, SLD, or cryptogenic SLD.

[0073] In some embodiments, the GPAM (e.g., hGPAM) associated disease is liver fibrosis, cirrhosis, liver failure, jaundice. AFLD, obesity-induced metabolic syndrome, insulin insensitivity, or type-2 diabetes.

[0074] In some embodiments, the GPAM (e.g., hGPAM) associated disease is fatty liver, liver inflammation, nonalcoholic steatohepatitis (NASH) or nonalcoholic fatty liver disease (NAFLD).

[0075] In some embodiments, the GPAM (e.g., hGPAM) associated disease is obesity-induced metabolic syndrome, insulin insensitivity, obesity, type-2 diabetes, alcoholic fatty liver disease (AFLD), or cirrhosis.

[0076] In some embodiments, the GPAM (e.g., hGPAM) associated disease is fatty liver, liver inflammation, NASH, NAFLD, obesity-induced metabolic syndrome, insulin insensitivity, obesity, type-2 diabetes, AFLD, cirrhosis, MASLD, MASH, MetALD, SLD, or cryptogenic SLD.

[0077] In some embodiments, the subject is a human.

[0078] In some embodiments, the dsRNA described herein (e.g., described above), the conjugate described herein (e.g., described above), the vector described herein (e.g., described above), the earner described herein (e.g., described above), or the pharmaceutical composition described herein (e.g., described above), is administered to the subject at a dose of from about 1-10 mg / kg, 2-10 mg / kg, 3-10 mg / kg, 4-10 mg / kg, 5-10 mg / kg, 6-10 mg / kg, 7-10 mg / kg, 8-10 mg / kg 9-10 mg / kg, 1-5 mg / kg, 1-4 mg / kg, 1-3 mg / kg, 1-2 mg / kg, 1-2.5 mg / kg, 2-5 mg / kg, 2-4 mg / kg, 2-3 mg / kg, or 2-2.5 mg / kg. In some embodiments, the dsRNA described herein (e.g., described above), the conjugate described herein (e.g., described above), the vector described herein (e.g., described above), the earner described herein (e.g., described above), or the pharmaceutical composition described herein (e.g., described above), is administered to the subject at a dose of about 1 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, or 10 mg / kg. In some embodiments, the dsRNA described herein (e.g., described above), the conjugate described herein (e.g., described above), the vector described herein (e.g., described above), the carrier described herein (e.g., described above), or the pharmaceutical composition described herein (e.g., described above), is administered to the subject at least once per month,Attorney Docket No. 62801.94WO01once per month, at least twice per month, twice per month, at least once a week, or once per week.

[0079] In one aspect, provide herein are methods of treating, ameliorating, or preventing a liver disease in a subject, the method comprising administering to the subject a dsRNA described herein (e.g., described above), a conjugate described herein (e.g., described above), a vector described herein (e.g., described above), a carrier described herein e.g., described above), or a pharmaceutical composition described herein (e.g., described above), to thereby treat, ameliorate, or prevent the liver disease in the subject.

[0080] In some embodiments, the treating, ameliorating, or preventing of the liver disease is mediated (at least in part) through the by reducing or inhibiting expression of GPAM (e.g., hGPAM) in the subject (e.g., a population of cells within the subject).

[0081] In some embodiments, the liver disease is fatty liver disease, steatotic liver disease, liver inflammation, NASH, NAFLD, MASLD, MASH, MAFLD, MetALD, SLD, or cryptogenic SLD.

[0082] In some embodiments, the liver disease is liver fibrosis, cirrhosis, liver failure, jaundice, AFLD, obesity-induced metabolic syndrome, insulin insensitivity, or type-2 diabetes.

[0083] In some embodiments, the liver disease is fatty liver, liver inflammation, nonalcoholic steatohepatitis (NASH) or nonalcoholic fatty liver disease (NAFLD).

[0084] In some embodiments, the liver disease is fatty liver, liver inflammation, NASH, NAFLD, obesity-induced metabolic syndrome, insulin insensitivity, obesity, type-2 diabetes, AFLD, cirrhosis, MASLD, MASH, MetALD, SLD, or cryptogenic SLD.

[0085] In some embodiments, the subject is a human.

[0086] In some embodiments, the dsRNA described herein (e.g., described above), the conjugate described herein (e.g., described above), the vector described herein (e.g., described above), the carrier described herein (e.g., described above), or the pharmaceutical composition described herein (e.g., described above), is administered to the subject at a dose of from about 1-10 mg / kg, 2-10 mg / kg, 3-10 mg / kg, 4-10 mg / kg, 5-10 mg / kg, 6-10 mg / kg, 7-10 mg / kg, 8-10 mg / kg 9-10 mg / kg, 1-5 mg / kg, 1-4 mg / kg, 1-3 mg / kg, 1-2 mg / kg, 1-2.5 mg / kg, 2-5 mg / kg, 2-4 mg / kg, 2-3 mg / kg, or 2-2.5 mg / kg. In some embodiments, the dsRNA described herein (e.g., described above), the conjugate described herein (e.g., described above), the vector described herein (e.g., described above), the earner described herein (e.g., described above), or the pharmaceutical composition described herein (e.g., described above), is administered to the subject at a dose ofAttorney Docket No. 62801.94WO01about 1 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, or 10 mg / kg. In some embodiments, the dsRNA described herein (e.g., described above), the conjugate described herein (e.g., described above), the vector described herein (e.g., described above), the carrier described herein (e.g., described above), or the pharmaceutical composition described herein (e.g., described above), is administered to the subject at least once per month, once per month, at least twice per month, twice per month, at least once a week, or once per week.

[0087] In one aspect, provided herein are methods of diagnosing a GPAM (e.g., hGPAM) associated disease in a subject, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; and (b) detecting, or having detected, the presence or absence of one or more somatic GPAM mutation in the DNA, RNA, or protein, wherein the presence of the one or more somatic mutation indicates that the subject has a GPAM (e.g., hGPAM) associated disease.

[0088] In some embodiments, the GPAM (e.g., hGPAM) associated disease is fatty liver disease, steatotic liver disease, liver inflammation, NASH, NAFLD, MASLD, MASH, MAFLD, MetALD, SLD, or cryptogenic SLD.

[0089] In some embodiments, the GPAM (e.g., hGPAM) associated disease is liver fibrosis, cirrhosis, liver failure jaundice, AFLD, obesity-induced metabolic syndrome, insulin insensitivity, or type-2 diabetes.

[0090] In some embodiments, the GPAM (e.g., hGPAM) associated disease is a liver disease. In some embodiments, the GPAM (e.g., hGPAM) associated disease is fatty liver, liver inflammation, NASH, NAFLD, obesity-induced metabolic syndrome, insulin insensitivity, obesity, type-2 diabetes. AFLD, cirrhosis, MASLD, MASH, MetALD, SLD, or cryptogenic SLD.

[0091] In some embodiments, the sample is a blood, tissue, or cell sample. In some embodiments, the sample is biopsy. In some embodiments, the sample is a liver biopsy. In some embodiments, the subject is a human.

[0092] In some embodiments, at least one of the one or more somatic mutation is a loss of function mutation. In some embodiments, at least one of the one or more somatic mutation is a gain of function mutation.

[0093] In one aspect, provided herein are methods of diagnosing a liver disease in a subject, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; and (b) detecting, orAttorney Docket No. 62801.94WO01having detected, the presence or absence of one or more somatic GPAM mutation in the DNA, RNA, or protein, wherein the presence of the one or more somatic mutation indicates that the subject has a liver disease.

[0094] In some embodiments, the liver disease is fatty liver disease, steatotic liver disease, liver inflammation, NASH, NAFLD, MASLD, MASH, MAFLD, MetALD, SLD, or cryptogenic SLD.

[0095] In some embodiments, the liver disease is liver fibrosis, cirrhosis, liver failure, jaundice, AFLD, obesity-induced metabolic syndrome, insulin insensitivity, or type-2 diabetes.

[0096] In some embodiments, the liver disease fatty liver, liver inflammation, NASH, NAFLD, obesity-induced metabolic syndrome, insulin insensitivity, obesity, type-2 diabetes, AFLD, cirrhosis. MASLD, MASH, MetALD, SLD, or cryptogenic SLD.

[0097] In some embodiments, (a) comprises isolating and purifying DNA, or having DNA isolated and purified, from a sample obtained from the subject; and (b) comprises detecting, or having detected, the presence or absence of the one or more somatic GPAM mutation in the DNA.

[0098] In some embodiments, the method further comprises administering to the subject an inhibitory nucleic acid molecule that inhibits expression of GPAM if a GPAM somatic mutation is detected in the DNA, RNA, or protein. In some embodiments, the inhibitory nucleic acid molecule comprises a dsRNA agent described herein, a conjugate described herein, a vector described herein, a earner described herein, or a pharmaceutical composition described herein.

[0099] In some embodiments, the sample is a blood, tissue, or cell sample. In some embodiments, the sample is biopsy. In some embodiments, the sample is a liver biopsy. In some embodiments, the subject is a human.

[0100] In some embodiments, at least one of the one or more somatic mutation is a loss of function mutation. In some embodiments, at least one of the one or more somatic mutation is a gain of function mutation.

[0101] In one aspect, provided herein are methods of selecting a subject for administration of an inhibitory nucleic acid molecule that inhibits expression of GPAM, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; and (b) detecting, or having detected, the presence or absence of one or more somatic GPAM mutation in the DNA, RNA, or protein, wherein the subject is selected for administration of the inhibitory nucleic acid molecule if the oneAttorney Docket No. 62801.94WO01or more somatic mutation is present.

[0102] In some embodiments, (a) comprises isolating and purifying DNA, or having DNA isolated and purified, from a sample obtained from the subject; and (b) comprises detecting, or having detected, the presence or absence of the one or more somatic GPAM mutation in the DNA.

[0103] In some embodiments, the method further comprises administering to the subject the inhibitory nucleic acid molecule if the subject is selected. In some embodiments, the inhibitory nucleic acid molecule comprises a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, or a pharmaceutical composition described herein.

[0104] In some embodiments, the sample is a blood, tissue, or cell sample. In some embodiments, the sample is biopsy. In some embodiments, the sample is a liver biopsy. In some embodiments, the subject is a human.

[0105] In some embodiments, at least one of the one or more somatic mutation is a loss of function mutation. In some embodiments, at least one of the one or more somatic mutation is a gain of function mutation.

[0106] In one aspect, provided herein are methods of treating, ameliorating, or preventing a GPAM (e.g., hGPAM) associated disease in a subject, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; (b) detecting, or having detected, the presence or absence of one or more somatic GPAM mutation in the DNA, RNA, or protein, and (c) administering to the subject an inhibitory nucleic acid that inhibits expression of GPAM if the one or more GPAM somatic mutation is detected in the DNA, RNA, or protein.

[0107] In some embodiments, the treating, ameliorating, or preventing of the GPAM (e.g., hGPAM) associated disease is mediated (at least in part) through the by reducing or inhibiting expression of GPAM (e.g., hGPAM) in the subject (e.g., a population of cells within the subject).

[0108] In some embodiments, the GPAM (e.g., hGPAM) associated disease is fatty liver disease, steatotic liver disease, liver inflammation, NASH, NAFLD, MASLD, MASH, MAFLD, MetALD, SLD, or cryptogenic SLD.

[0109] In some embodiments, the GPAM (e.g., hGPAM) associated disease is liver fibrosis, cirrhosis, liver failure jaundice. AFLD, obesity-induced metabolic syndrome, insulin insensitivity, or type-2 diabetes.Attorney Docket No. 62801.94WO01

[0110] In some embodiments, the GPAM (e.g., hGPAM) associated disease is a liver disease. In some embodiments, the liver disease is fatty liver, liver inflammation, NASH, NAFLD, obesity-induced metabolic syndrome, insulin insensitivity, obesity, type-2 diabetes. AFLD, cirrhosis, MASLD, MASH, MetALD, SLD, or cryptogenic SLD.

[0111] In some embodiments, the sample is a blood, tissue, or cell sample. In some embodiments, the sample is biopsy. In some embodiments, the sample is a liver biopsy. In some embodiments, the subject is a human.

[0112] In some embodiments, at least one of the one or more somatic mutation is a loss of function mutation. In some embodiments, at least one of the one or more somatic mutation is a gain of function mutation.

[0113] In one aspect, provided herein are methods of treating, ameliorating, or preventing a liver disease in a subject, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; (b) detecting, or having detected, the presence or absence of one or more somatic GPAM mutation in the DNA, RNA, or protein, and (c) administering to the subject an inhibitory nucleic acid that inhibits expression of GPAM if the one or more GPAM somatic mutation is detected in the DNA, RNA, or protein.

[0114] In some embodiments, the inhibitory nucleic acid molecule comprises a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, or a pharmaceutical composition described herein.

[0115] In some embodiments, the treating, ameliorating, or preventing of the liver disease is mediated (at least in part) through the by reducing or inhibiting expression of GPAM (e.g., hGPAM) in the subject (e.g., a population of cells within the subject).

[0116] In some embodiments, the liver disease is fatty liver disease, steatotic liver disease, liver inflammation, NASH, NAFLD, MASLD, MASH, MAFLD, MetALD, SLD, or cryptogenic SLD.

[0117] In some embodiments, the liver disease is liver fibrosis, cirrhosis, liver failure, jaundice, AFLD, obesity-induced metabolic syndrome, insulin insensitivity, or type-2 diabetes.

[0118] In some embodiments, the liver disease is fatty liver, liver inflammation, NASH, NAFLD, obesity-induced metabolic syndrome, insulin insensitivity, obesity, type-2 diabetes, AFLD, cirrhosis, MASLD, MASH, MetALD, SLD, or cryptogenic SLD.Attorney Docket No. 62801.94WO01

[0119] In some embodiments, (a) comprises isolating and purifying DNA, or having DNA isolated and purified, from a sample obtained from the subject; and (b) comprises detecting, or having detected, the presence or absence of the one or more somatic GPAM mutation in the DNA.

[0120] In some embodiments, the sample is a blood, tissue, or cell sample. In some embodiments, the sample is biopsy. In some embodiments, the sample is a liver biopsy. In some embodiments, the subject is a human.

[0121] In some embodiments, at least one of the one or more somatic mutation is a loss of function mutation. In some embodiments, at least one of the one or more somatic mutation is a gain of function mutation.

[0122] In one aspect, provided herein are in vitro methods of screening a sample from a subject for one or more somatic GPAM mutation, the method comprising (a) isolating and purifying DNA, RNA, or protein from a sample obtained from the subject; and (b) detecting the presence or absence of one or more somatic GPAM mutation in the DNA, RNA, or protein.

[0123] In some embodiments, the sample is a blood, tissue, or cell sample. In some embodiments, the sample is biopsy. In some embodiments, the sample is a liver biopsy. In some embodiments, the subject is a human.

[0124] In some embodiments, at least one of the one or more somatic mutation is a loss of function mutation. In some embodiments, at least one of the one or more somatic mutation is a gain of function mutation.

[0125] In one aspect, provided herein is a dsRNA agent described herein, conjugate described herein, vector described herein, carrier described herein, cell (or population of cells) described herein, or pharmaceutical composition described herein for use in a method of treating, ameliorating, or preventing a GPAM associated disease {e.g., a GPAM associated disease described herein) in a subject.

[0126] In one aspect, provided herein is a dsRNA agent described herein, conjugate described herein, vector described herein, carrier described herein, cell (or population of cells) described herein, or pharmaceutical composition described herein for use in a method of treating, ameliorating, or preventing a liver disease {e.g., a liver disease described herein) in a subject.

[0127] In one aspect, provided herein is a use of dsRNA agent described herein, conjugate described herein, vector described herein, earner described herein, cell (or population of cells) described herein, or pharmaceutical composition described herein for treating, ameliorating, orAttorney Docket No. 62801.94WO01preventing a GPAM associated disease (e.g., a GPAM associated disease described herein) in a subject.

[0128] In one aspect, provided herein is a use of a dsRNA agent described herein, conjugate described herein, vector described herein, carrier described herein, cell (or population of cells) described herein, or pharmaceutical composition described herein for treating, ameliorating, or preventing a liver disease (e.g., a liver disease described herein) in a subject.

[0129] In one aspect, provided herein is a use of a dsRNA agent described herein, conjugate described herein, vector described herein, carrier described herein, cell (or population of cells) described herein, or pharmaceutical composition described herein for the manufacture of a medicament for the treatment, amelioration, or prevention of a GPAM associated disease (e.g., a GPAM associated disease described herein) in a subject.

[0130] In one aspect, provided herein is a use of a dsRNA agent described herein, conjugate described herein, vector described herein, carrier described herein, cell (or population of cells) described herein, or pharmaceutical composition described herein for the manufacture of a medicament for the treatment, amelioration, or prevention of a liver disease (e.g., a liver disease described herein) in a subject.4. DETAILED DESCRIPTION

[0131] The inventors have further discovered, inter alia, RNAi agents that inhibit expression of GPAM (e.g., hGPAM). As such, the RNAi agents described herein are useful for the treatment of GPAM mediated diseases such as liver diseases (e.g., fatty liver disease, NASH, nonalcoholic fatty liver disease (NAFLD)). As such, the current disclosure provides RNAi agents (e.g., dsRNAi agents comprising a sense strand and an antisense strand) capable of inhibiting GPAM expression (e.g., in a cell, in a cell in a subject); and their use in, inter alia, pharmaceutical compositions, and methods of treating diseases (e.g., liver diseases).TABLE OF CONTENTS4.1 Definitions4.2 RNAi Agents4.2.1 Antisense Strand4.2.1.1 Targeting Region4.2.1.2 Overall LengthAttorney Docket No. 62801.94WO01Antisense Strandsde Linkagescleoside LinkagesAttorney Docket No. 62801.94WO014.4.4 Exemplary Conjugates4.5 Activity of RNAi Agents & Conjugates Thereof4.6 Methods of Making RNAi Agents & Conjugates Thereof4.7 Vectors4.8 Carriers4.8.1 Lipid Based Carriers / Lipid Nanoformulations4.8.1.1 Cationic Lipids (Positively Charged) and Ionizable Lipids4.8.1.2 Non-Cationic Lipids (e.g., Phospholipids)4.8.1.3 Structural Lipids4.8.1.4 Polymers and Polyethylene Glycol (PEG) - Lipids4.8.1.5 Percentages of Lipid Nanoformulation Components4.9 Cells4.10 Pharmaceutical Compositions4.11 Methods of Use4.11.1 Methods of Delivery4.11.2 Methods of Reducing or Inhibiting GPAM Expression4.11.3 Methods of Treating, Ameliorating, or Preventing a GPAM Associated Disease4.11.4 Methods of Treating, Ameliorating, or Preventing a Liver Disease4.11.5 Methods of Diagnosing and / or Prognosticating a Liver Disease4.11.6 Methods of Screening, Identifying, and Selecting a Subject for Treatment with a GPAM Inhibitory Agent4.11.7 In Vitro Methods of Screening Samples for Somatic GPAM Mutations 4.12 Kits4.1 Definitions

[0132] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0133] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailedAttorney Docket No. 62801.94WO01description are exemplary and explanatory only and are not restrictive of any subject matter claimed.

[0134] In this application, the use of the singular includes the plural unless specifically stated otherwise. For example, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Furthermore, use of the term “including” as well as other forms, such as “include.” “includes,” and “included,” is not limiting.

[0135] It is understood that wherever aspects are described herein with the language “comprising,” otherwise analogous aspects described in terms of “consisting of’ and “consisting essentially of’ are also provided.

[0136] The term “and / or” where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and / or” as used in a phrase such as “A and / or B” herein is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0137] As described herein, any concentration range, percentage range, ratio range or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.

[0138] The terms “about” or “comprising essentially of’ refer to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. When particular values or compositions are provided in the application and claims, unless otherwise stated, the meaning of “about” or “comprising essentially of’ should be assumed to be within an acceptable error range for that particular value or composition.

[0139] As used herein, the term “administering” refers to the physical introduction of an agent, e.g., a therapeutic agent (or a precursor of the therapeutic agent that is metabolized or altered within the body of the subject to produce the therapeutic agent in vivo) to a subject, using any of the various methods and delivery systems known to those skilled in the art. Administering can also beAttorney Docket No. 62801.94WO01performed, for example, once, a plurality of times, and / or over one or more extended periods.

[0140] As used herein, the term “agent” is used generically to describe any macro or micro molecule. Exemplary moieties include, but are not limited polypeptides, proteins, peptides, polynucleotides (e.g., DNA, RNA), small molecules, carbohydrates, lipids, synthetic polymers (e.g., polymers of PEG).

[0141] As used herein, the term “antisense strand” refers to an RNA molecule (e.g., part of an RNAi agent (e.g., described herein), part of a dsRNA agent (e.g., described herein)) that comprises a region of complementarity comprising a nucleotide sequence that is at least partially (e.g., substantially, fully) complementary to a target nucleic acid sequence (e.g., a target mRNA (e.g., a GPAM mRNA), a portion of a target mRNA (e.g., a GPAM mRNA)).

[0142] As used herein, the term “bicyclic sugar” refers to a modified sugar (e.g., ribose) moiety comprising two rings, wherein the second ring is formed via a bridge connecting two of the atoms in the first ring thereby forming a bicyclic structure. In some embodiments, the first ring of the bicyclic sugar moiety is a furanosyl moiety. In some embodiments, the furanosyl sugar moiety is a ribosyl moiety.

[0143] As used herein, the term “bicyclic nucleoside” (“BNA”) is a nucleoside comprising a bicyclic sugar.

[0144] As used herein, the term “blunt end” refers to a dsRNA molecule that does not contain any unpaired nucleotides at the end (e.g., 3' terminus, 5' terminus) of the dsRNA molecule (i.e., no nucleotide overhang(s)). The dsRNA molecule can have, for example, a blunt end at the 3 '-end, 5 '-end, or both the 3' and 5 '-end of the molecule.

[0145] As used herein, the term “complementary” in reference to a first nucleotide sequence (e.g., a sense strand or a target mRNA) in relation to a second nucleotide sequence (e.g., an antisense strand), refers to the ability of a nucleic acid molecule comprising the first nucleotide sequence to hybridize to a nucleic acid molecule comprising the second nucleotide sequence and form a double stranded region (through base pair hydrogen bonds) under suitable in vivo or vitro conditions (e.g., under certain standard conditions, under mammalian (e.g., human) physiological conditions). A person of ordinary skill in the art would be able to select the set of conditions most appropriate for a hybridization test. Complementary sequences include, e.g., Watson-Crick base pairs. For example, complementary nucleobase pairs include adenine (A) and thymine (T); adenine (A) and uracil (U); and cytosine (C) and guanine (G). Complementary nucleobase pairs includeAttorney Docket No. 62801.94WO01natural and modified nucleotides, and nucleotide mimics, at least to the extent that the above hybridization requirements are fulfilled. As such, determinations of complementarity (as described herein) are independent of nucleotide chemical modifications (e.g., as described herein). For example, (C) and 5-methyl cytosine (mC) are both complementary to (G).

[0146] As used herein, the term “conjugation” refers to chemical conjugation of an agent (e.g., a nucleic acid molecule) with a moiety (e.g., carbohydrate, small molecule, polypeptide, polynucleotide, lipid, synthetic polymer (e.g., polymers of polyethylene glycol (PEG)), etc.). The moiety can be directly connected to the agent (e.g., nucleic acid molecule) or indirectly connected through a linker, e.g., as described herein. Chemical conjugation methods are well known in the art, as are commercially available conjugation reagents and kits, with detailed instructions for their use readily available from the commercial suppliers.

[0147] As used herein, the term “differing by no more than X nucleotides” in reference to a nucleotide sequence means that the nucleotide sequence comprises no more than X (wherein X is a specified number (e.g., 3, 2, 1, 0)) nucleotide variations (as defined herein) relative to a reference sequence. For example, the phrase “wherein the nucleotide sequence of the antisense strand differs by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO: X” means that the nucleotide sequence comprises no more than 3 nucleotide variations relative to the nucleotide sequence set forth in the cited SEQ ID NO: X.

[0148] As used herein, the term “disease” refers to any abnormal condition that impairs physiological function. The term is used broadly to encompass any disorder, illness, abnormality, pathology, sickness, condition, or syndrome in which physiological function is impaired, irrespective of the nature of the etiology. The term disease includes infection (e.g., a viral, bacterial, fungal, protozoal infection).

[0149] As used herein, the term “double stranded RNA agent” or “dsRNA agent” refers to a complex of two RNA molecules comprising a double stranded region comprising two anti-parallel and at least partially (e.g., substantially, fully) complementary nucleic acid sequences that form the double stranded region. For example, in some embodiments, the dsRNA agent comprises a sense strand and an antisense strand.

[0150] The terms “DNA” and “polydeoxyribonucleotide” are used interchangeably herein and refer to macromolecules that include multiple deoxyribonucleotides that are polymerized via phosphodiester bonds. Deoxyribonucleotides are nucleotides in which the sugar is deoxyribose.Attorney Docket No. 62801.94WO01

[0151] As used herein, the term “fully complementary” means that in a hybridized pair of a first nucleic acid molecule and a second nucleic acid molecule, 100% (all), of the bases in a contiguous sequence of the first nucleic acid molecule will hybridize with the same number of bases in a contiguous sequence of the second nucleic acid molecule. The contiguous sequence may comprise all or a part of the first and / or second nucleic acid molecule.

[0152] As used herein, the term “GPAM” or “glycerol-3-phosphate acyltransferase 1, mitochondrial” refers to the enzyme expressed in the mitochondria that functions in, inter alia, glycerolipid synthesis through the esterification of acyl-group from acyl-ACP to the sn-1 position of glycerol-3-phosphate. The mRNA sequence of a reference hGPAM gene is set forth in SEQ ID NO: 1 (NCBI Ref.: NM_001244949.2). The amino acid sequence of a reference hGPAM protein is set forth in SEQ ID NO: 3 (NCBI Ref.: NP_001231878.1). The term GPAM includes naturally occurring variants of GPAM. GPAM gene and mRNA sequences of e.g., human, mouse, rat, nonhuman primate (e.g., rhesus macaque, Macaca fascicularis (cynomolgus monkey)), are readily available through publicly available databases, including, e.g., GenBank, UniProt, OMIM, and the Macaca genome project web site.

[0153] As used herein, the term “heterologous,” when used to describe a first element in reference to a second element means that the first element and second element do not exist in nature disposed as described. For example, a nucleic acid molecule comprising a “heterologous moiety” means a nucleic acid molecule that is joined to a moiety (e.g., carbohydrate, small molecule, polypeptide, polynucleotide, lipid, synthetic polymer (e.g., polymers of PEG), etc.) that is not joined to the nucleic acid molecule in nature.

[0154] As used herein, the term “isolated” with reference to a polypeptide, protein, or polynucleotide refers to a polypeptide, protein, or polynucleotide that is substantially free of other cellular components with which it is associated in the natural state.

[0155] As used herein, the term “nucleotide variation,” “variant nucleotide.” or use of the term “variation” and the like in reference to a nucleotide or nucleic acid sequence refers to a nucleic acid molecule that comprises at least one substitution, addition, deletion, or inversion of one or more nucleotide compared to a reference nucleic acid molecule. As used herein, the term “variant” or “variation” with reference to a peptide or protein refers to a peptide or protein that comprises at least one substitution, addition, deletion, or inversion of an amino acid residue compared to a reference peptide or protein.Attorney Docket No. 62801.94WO01

[0156] As used herein, the term “modified agent” refers to any agent (or any component thereof (e.g., any nucleic acid molecule thereof)) (e.g., described herein, e.g., an antisense strand, a sense strand, a dsRNA agent, RNAi agent, etc.) that comprises one or more modified nucleotide (as defined herein).

[0157] As used herein, the term “modified nucleotide,” “nucleotide modification,” or use of the term “modification” and the like in reference to a nucleotide or nucleic acid sequence refers to a nucleotide comprising a chemical modification, e.g., a modified sugar moiety, a modified nucleobase, and / or a modified internucleoside linkage, or any combination thereof. Exemplary modifications are provided herein, see, e.g., §§ 4.3, 4.3.1. In certain embodiments of the instant disclosure, inclusion of a deoxynucleotide - which is acknowledged as a naturally occurring form of nucleotide - if present within an RNAi agent or component thereof (e.g., described herein, e.g., a sense strand, an antisense strand, a dsRNA agent) is considered to constitute a modified nucleotide.

[0158] As used herein, the term “moiety” is used generically to describe any macro or micro molecule that can be operably connected to a protein described herein. Exemplary moieties include, but are not limited small molecules, polypeptides, polynucleotides (e.g., DNA, RNA), carbohydrates, lipids, synthetic polymers (e.g., polymers of PEG).

[0159] As used herein, the term “nucleotide overhang” refers to at least one unpaired nucleotide that extends from the double stranded region of a nucleic acid molecule (e.g., a dsRNA molecule (e.g., a dsRNA molecule described herein)). For example, when a 3'-end of one strand of a dsRNA extends beyond the 5'-end of the other strand, or vice versa, there is a nucleotide overhang.

[0160] As used herein, the term, “non-complementary nucleotide mismatch” refers to a nucleotide within a region of complementarity (as described herein) that is not complementary to the corresponding nucleotide in the target nucleic acid molecule.

[0161] As used herein, the term “operably connected” refers to the linkage of two moieties in a functional relationship. For example, a polypeptide is operably connected to another polypeptide when they are linked (either directly or indirectly via a peptide linker) in frame such that both polypeptides are functional (e.g., a fusion protein described herein). Or for example, a transcription regulatory polynucleotide e.g., a promoter, enhancer, or other expression control element is operably linked to a polynucleotide that encodes a protein if it affects the transcription of theAttorney Docket No. 62801.94WO01polynucleotide that encodes the protein. The term “operably connected” can also refer to the conjugation of a moiety to e.g., a polynucleotide or polypeptide {e.g., the conjugation of a PEG polymer to a protein).

[0162] As used herein, “partially complementary” means that in a hybridized pair of a first nucleic acid molecule and a second nucleic acid molecule, at least 70%, but not all, of the bases in a contiguous sequence of the first nucleic acid molecule will hybridize with the same number of bases in a contiguous sequence of the second nucleic acid molecule. The contiguous sequence may comprise all or a part of a first or second nucleic acid molecule.

[0163] The determination of “percent identity” between two sequences {e.g., protein (amino acid sequences) or polynucleotide (nucleic acid sequences)) can be accomplished using a mathematical algorithm. Determinations of identity (as described herein) are independent of nucleotide chemical modifications e.g., as described herein). For example, (mC) is identical to (C) for the purposes of determining identity. A specific, non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin S & Altschul SF (1990) PNAS 87: 2264-2268, modified as in Karlin S & Altschul SF (1993) PNAS 90: 5873-5877, each of which is herein incorporated by reference in its entirety. Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul SFet al., (1990) J Mol Biol 215: 403, which is herein incorporated by reference in its entirety. BLAST nucleotide searches can be performed with the NBLAST nucleotide program parameters set, e.g., for score=100, wordlength=12 to obtain nucleotide sequences homologous to a nucleic acid molecule described herein. BLAST protein searches can be performed with the XBLAST program parameters set, e.g., to score 50, wordlength=3 to obtain amino acid sequences homologous to a protein molecule described herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul SF et al., (1997) Nuc Acids Res 25: 3389-3402, which is herein incorporated by reference in its entirety. Alternatively, PSI BLAST can be used to perform an iterated search which detects distant relationships between molecules (Id.). When utilizing BLAST, Gapped BLAST, and PSI Blast programs, the default parameters of the respective programs {e.g., of XBLAST and NBLAST) can be used {see, e.g., National Center for Biotechnology Information (NCBI) on the worldwide web, ncbi.nlm.nih.gov). Another specific, non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, 1988, CABIOS 4:11-17, which is herein incorporated by reference in its entirety. Such anAttorney Docket No. 62801.94WO01algorithm is incorporated in the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM 120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used. The percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. In calculating percent identity, typically only exact matches are counted.

[0164] As used herein, the term “pharmaceutical composition” means a composition that is suitable for administration to an animal, e.g., a human subject, and comprises a therapeutic agent and a pharmaceutically acceptable carrier or diluent. A “pharmaceutically acceptable carrier or diluent” means a substance intended for use in contact with the tissues of human beings and / or non-human animals, and without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable therapeutic benefit / risk ratio.

[0165] The terms “nucleic acid molecule” and “polynucleotide” are used interchangeably herein and refer to a polymer of DNA or RNA. The nucleic acid molecule can be single- stranded or double- stranded; contain natural, non-natural, or altered nucleotides; and contain a natural, nonnatural, or altered internucleoside linkage, such as a phosphoroamidate linkage or a phosphorothioate linkage, instead of the phosphodiester found between the nucleotides of an unmodified nucleic acid molecule. Nucleic acid molecules include, but are not limited to, all nucleic acid molecules which are obtained by any means available in the art, including, without limitation, recombinant means, e.g., the cloning of nucleic acid molecules from a recombinant library or a cell genome, using ordinary cloning technology and polymerase chain reaction, and the like, and by synthetic means. The skilled artisan will appreciate that, except where otherwise noted, nucleic acid sequences set forth in the instant application will recite thymidine (T) in a representative DNA sequence but where the sequence represents RNA (e.g., mRNA), the thymidines (Ts) would be substituted for uracils (Us). Thus, any of the RNA polynucleotides encoded by a DNA identified by a particular sequence identification number may also comprise the corresponding RNA (e.g., mRNA) sequence encoded by the DNA, where each thymidine (T) of the DNA sequence is substituted with uracil (U).

[0166] As used herein, the term “plurality” means 2 or more (e.g., 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 9 or more, or 10 or more).

[0167] As used herein, the terms “protein” and “polypeptide” refers to a polymer of at least 2Attorney Docket No. 62801.94WO01(e.g., at least 5) amino acids linked by a peptide bond. The term “polypeptide” does not denote a specific length of the polymer chain of amino acids. It is common in the art to refer to shorter polymers of amino acids (e.g., approximately 2-50 amino acids) as peptides; and to refer to longer polymers of amino acids (e.g., approximately over 50 amino acids) as polypeptides. However, the terms “peptide” and “polypeptide” and “protein” are used interchangeably herein. In some embodiments, the protein is folded into its three-dimensional structure. Where proteins are contemplated herein, it should be understood that proteins folded into their three-dimensional structure are also provided herein.

[0168] As used herein, the term “region of complementarity” refers to a portion of a first nucleic acid molecule comprising a nucleotide sequence that is at least partially complementary to the nucleotide sequence of at least a portion of a second nucleic acid molecule.

[0169] The terms “RNA” and “polyribonucleotide” are used interchangeably herein and refer to macromolecules that include multiple ribonucleotides that are polymerized via phosphodiester bonds. Ribonucleotides are nucleotides in which the sugar is ribose. RNA may contain modified nucleotides; and contain natural, non-natural, or altered internucleoside linkages, such as a phosphoroamidate linkage or a phosphorothioate linkage, instead of the phosphodiester found between the nucleotides of an unmodified nucleic acid molecule.

[0170] As used herein, the term “RNAi agent” refers to an agent that contains one or more RNA molecules which can mediate the targeted cleavage of an RNA molecule (e.g., an mRNA molecule) via an RNA-induced silencing complex (RISC) pathway. The RNAi agent, is thereby capable of e.g., modulating, e.g., inhibiting, the expression of a target gene (e.g., GPAM) in a cell, e.g., a cell within a subject, such as a mammalian subject. In some embodiments, the RNAi agent is a dsRNA agent comprising a sense strand and an antisense strand that form a double stranded region, wherein optionally the sense strand and the antisense strand each independently comprise or consist of from about 19-23 nucleotides.

[0171] As used herein, the term “sense strand” refers to an RNA molecule (e.g., part of an RNAi agent (e.g., described herein), part of a dsRNA agent (e.g., described herein)) that comprises a region that is at least partially (e.g., substantially, fully) complementary to a region of the antisense strand (as defined herein). The sense strand is often referred to as such with reference to the orientation of the sequence of the sense strand being the same with respect to a target RNA (e.g., mRNA sequence).Attorney Docket No. 62801.94WO01

[0172] As used herein, the term “subject” includes any animal, such as a human or other animal. In some embodiments, the subject is a vertebrate animal (e.g., mammal, bird, fish, reptile, or amphibian). In some embodiments, the subject is a human. In some embodiments, the method subject is a non-human mammal. In some embodiments, the subject is a non-human mammal is such as anon-human primate (e.g., monkeys, apes), ungulate (e.g., cattle, buffalo, sheep, goat, pig, camel, llama, alpaca, deer, horses, donkeys), carnivore (e.g., dog, cat), rodent (e.g., rat, mouse), or lagomorph (e.g., rabbit). In some embodiments, the subject is a bird, such as a member of the avian taxa Galliformes (e.g., chickens, turkeys, pheasants, quail), Anseriformes (e.g., ducks, geese), Paleaognathae (e.g., ostriches, emus), Columbiformes (e.g., pigeons, doves), or Psittaciformes (e.g., parrots).

[0173] As used herein, “substantially complementary” means that in a hybridized pair of a first nucleic acid molecule and a second nucleic acid molecule, at least 85%, but not all, of the bases in a contiguous sequence of the first nucleic acid molecule will hybridize with the same number of bases in a contiguous sequence of the second nucleic acid molecule. The contiguous sequence may comprise all or a part of a first or second nucleic acid molecule.

[0174] In some embodiments, the term “substantially all” means at least 95%, 96%, 97%, 98% or 99%, e.g., of the subject of said sentence. The term “substantially all” preferably excludes 100%. For example, in some embodiments, the term “substantially all of the nucleotides in the sense strand and / or antisense strand are modified” means that at least 95%, 96%, 97%, 98% or 99% of said nucleotides are modified. For example, in some embodiments, the term “substantially all of the nucleotides of the agent are modified” means that at least 95%, 96%, 97%, 98% or 99% of said nucleotides are modified. For example, in some embodiments, the term “substantially all of the nucleotides of the agent are unmodified” means that at least 95%, 96%, 97%, 98% or 99% of said nucleotides are unmodified. For example, in some embodiments the term “wherein the dsRNA agent is in the sodium salt form, sodium ions are present in the composition comprising the dsRNA agent as counterions for substantially all of the phosphodiester or phosphorothioate groups present in the dsRNA agent” means that wherein the dsRNA agent is in the sodium salt form, sodium ions are present in the composition comprising the dsRNA agent as counterions for at least 95%, 96%, 97%, 98% or 99% of the phosphodiester or phosphorothioate groups present in the dsRNA agent.

[0175] As used herein, the term “target nucleic acid sequence” refers to a contiguous portion of the nucleotide sequence of a nucleic acid sequence (e.g., an mRNA molecule formed during theAttorney Docket No. 62801.94WO01transcription of a target gene (e.g., GPAM)). In some embodiments, the target nucleic acid sequence is an mRNA molecule formed during the transcription of a target gene (e.g., GPAM)). In some embodiments, the target nucleic acid molecule comprises an mRNA that is a product of RNA processing of a primary transcription product. The target portion of the sequence (e.g., mRNA) will be at least long enough to serve as a substrate for RNAi-directed cleavage at or near that portion of the nucleotide sequence of an mRNA molecule formed during the transcription of a GPAM gene. In one embodiment, the target sequence is within the protein coding region of GPAM.

[0176] As used herein, the term “therapeutically effective amount” of a therapeutic agent refers to any amount of the therapeutic agent that, when used alone or in combination with another therapeutic agent, improves a disease condition, e.g., protects a subject against the onset of a disease (or infection); improves a symptom of disease or infection, e.g., decreases severity of disease or infection symptoms, decreases frequency or duration of disease or infection symptoms, increases disease or infection symptom-free periods; prevents or reduces impairment or disability due to the disease or infection; or promotes disease (or infection) regression. The ability of a therapeutic agent to improve a disease condition can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.

[0177] As used herein, the terms “treat,” treating,” “treatment,” and the like refer to reducing or ameliorating a disease and / or symptom(s) associated therewith or obtaining a desired pharmacologic and / or physiologic effect. It will be appreciated that, although not precluded, treating a disease does not require that the disease, or symptom(s) associated therewith be completely eliminated. In some embodiments, the effect is therapeutic, i.e., without limitation, the effect partially or completely reduces, diminishes, abrogates, abates, alleviates, decreases the intensity of, or cures a disease and / or adverse symptom attributable to the disease. In some embodiments, the effect is preventative, i.e., the effect protects or prevents an occurrence or reoccurrence of a disease. To this end, the presently disclosed methods comprise administering a therapeutically effective amount of a composition as described herein.4.2 RNAi Agents

[0178] Provided herein are, inter alia, agents (e.g., RNAi agents, dsRNA agents), useful in,Attorney Docket No. 62801.94WO01inter alia, inhibiting expression of glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM) (e.g., human GPAM (hGPAM)) (e.g., within a cell, e.g., within a cell in a subject, e.g., a mammalian subject, e.g., a human subject) (e.g., through the degradation of GPAM (e.g., hGPAM) mRNA).

[0179] GPAM is an enzyme expressed in the mitochondria that functions in, inter alia, glycerolipid synthesis through the esterification of acyl-group from acyl-ACP to the sn-1 position of glycerol-3-phosphate. The mRNA sequence of a reference hGPAM gene is set forth in SEQ ID NO: 1 (NCBI Ref.: NM_001244949.2). The reverse complement sequence of the hGPAM mRNA is set forth in SEQ ID NO: 2. The amino acid sequence of a reference hGPAM protein is set forth in SEQ ID NO: 3 (NCBI Ref.: NP_001231878.1). See Table 1, herein.Table 1. The mRNA and Amino Acid Sequence of a Reference hGPAM Protein.SEQ IDDescription Amino Acid SequenceNO GCGCCACUGCAGCUGGCAUUGGCCGGGACUGGAAGUGCGGGCUUCUGC AGCAGCCGAAGCUGGAGCUGCUAGGGCAGCAGCGGCUCCCCUGUUGUA UGGACAUUCUGCACCCGAAACUGAUAGCUGAGUCCUGAAGUUUUAUGU UAUGAAACAGAAGAACUUUCAUCCCAGCACAUGAUUUGGGAAUUACAC UUUGUGACAUGGAUGAAUCUGCACUGACCCUUGGUACAAUAGAUGUUU CUUAUCUGCCACAUUCAUCAGAAUACAGUGUUGGUCGAUGUAAGCACA CAAGUGAGGAAUGGGGUGAGUGUGGCUUUAGACCCACCAUCUUCAGAU CUGCAACUUUAAAAUGGAAAGAAAGCCUAAUGAGUCGGAAAAGGCCAU UUGUUGGAAGAUGUUGUUACUCCUGCACUCCCCAGAGCUGGGACAAAU UUUUCAACCCCAGUAUCCCGUCUUUGGGUUUGCGGAAUGUUAUUUAUA UCAAUGAAACUCACACAAGACACCGCGGAUGGCUUGCAAGACGCCUUU CUUACGUUCUUUUUAUUCAAGAGCGAGAUGUGCAUAAGGGCAUGUUUG CCACCAAUGUGACUGAAAAUGUGCUGAACAGCAGUAGAGUACAAGAGGhGPAM mRNA CAAUUGCAGAAGUGGCUGCUGAAUUAAACCCUGAUGGUUCUGCCCAGC AGCAAUCAAAAGCCGUUAACAAAGUGAAAAAGAAAGCUAAAAGGAUUC NCBI Ref.: UUCAAGAAAUGGUUGCCACUGUCUCACCGGCAAUGAUCAGACUGACUG 1 NM_001244949 GGUGGGUGCUGCUAAAACUGUUCAACAGCUUCUUUUGGAACAUUCAAA.2 UUCACAAAGGUCAACUUGAGAUGGUUAAAGCUGCAACUGAGACGAAUU UGCCGCUUCUGUUUCUACCAGUUCAUAGAUCCCAUAUUGACUAUCUGC UGCUCACUUUCAUUCUCUUCUGCCAUAACAUCAAAGCACCAUACAUUG CUUCAGGCAAUAAUCUCAACAUCCCAAUCUUCAGUACCUUGAUCCAUA AGCUUGGGGGCUUCUUCAUACGACGAAGGCUCGAUGAAACACCAGAUG GACGGAAAGAUGUUCUCUAUAGAGCUUUGCUCCAUGGGCAUAUAGUUG AAUUACUUCGACAGCAGCAAUUCUUGGAGAUCUUCCUGGAAGGCACAC GUUCUAGGAGUGGAAAAACCUCUUGUGCUCGGGCAGGACUUUUGUCAG UUGUGGUAGAUACUCUGUCUACCAAUGUCAUCCCAGACAUCUUGAUAA UACCUGUUGGAAUCUCCUAUGAUCGCAUUAUCGAAGGUCACUACAAUG GUGAACAACUGGGCAAACCUAAGAAGAAUGAGAGCCUGUGGAGUGUAG CAAGAGGUGUUAUUAGAAUGUUACGAAAAAACUAUGGUUGUGUCCGAG UGGAUUUUGCACAGCCAUUUUCCUUAAAGGAAUAUUUAGAAAGCCAAAGUCAGAAACCGGUGUCUGCUCUACUUUCCCUGGAGCAAGCGUUGUUACAttorney Docket No. 62801.94WO01CAGCUAUACUUCCUUCAAGACCCAGUGAUGCUGCUGAUGAAGGUAGAG ACACGUCCAUUAAUGAGUCCAGAAAUGCAACAGAUGAAUCCCUACGAA GGAGGUUGAUUGCAAAUCUGGCUGAGCAUAUUCUAUUCACUGCUAGCA AGUCCUGUGCCAUUAUGUCCACACACAUUGUGGCUUGCCUGCUCCUCU ACAGACACAGGCAGGGAAUUGAUCUCUCCACAUUGGUCGAAGACUUCU UUGUGAUGAAAGAGGAAGUCCUGGCUCGUGAUUUUGACCUGGGGUUCU CAGGAAAUUCAGAAGAUGUAGUAAUGCAUGCCAUACAGCUGCUGGGAA AUUGUGUCACAAUCACCCACACUAGCAGGAACGAUGAGUUUUUUAUCA CCCCCAGCACAACUGUCCCAUCAGUCUUCGAACUCAACUUCUACAGCA AUGGGGUACUUCAUGUCUUUAUCAUGGAGGCCAUCAUAGCUUGCAGCC UUUAUGCAGUUCUGAACAAGAGGGGACUGGGGGGUCCCACUAGCACCC CACCUAACCUGAUCAGCCAGGAGCAGCUGGUGCGGAAGGCGGCCAGCC UGUGCUACCUUCUCUCCAAUGAAGGCACCAUCUCACUGCCUUGCCAGA CAUUUUACCAAGUCUGCCAUGAAACAGUAGGAAAGUUUAUCCAGUAUG GCAUUCUUACAGUGGCAGAGCACGAUGACCAGGAAGAUAUCAGUCCUA GUCUUGCUGAGCAGCAGUGGGACAAGAAGCUUCCAGAACCUUUGUCUU GGAGAAGUGAUGAAGAAGAUGAAGACAGUGACUUUGGGGAGGAACAGC GAGAUUGCUACCUGAAGGUGAGCCAAUCCAAGGAGCACCAGCAGUUUA UCACCUUCUUACAGAGACUCCUUGGGCCUUUGCUGGAGGCCUACAGCU CUGCUGCCAUCUUUGUUCACAACUUCAGUGGUCCUGUUCCAGAACCUG AGUAUCUGCAAAAGUUGCACAAAUACCUAAUAACCAGAACAGAAAGAA AUGUUGCAGUAUAUGCUGAGAGUGCCACAUAUUGUCUUGUGAAGAAUG CUGUGAAAAUGUUUAAGGAUAUUGGGGUUUUCAAGGAGACCAAACAAA AGAGAGUGUCUGUUUUAGAACUGAGCAGCACUUUUCUACCUCAAUGCA ACCGACAAAAACUUCUAGAAUAUAUUCUGAGUUUUGUGGUGCUGUAGG UAACGUGUGGCACUGCUGGCAAAUGAAGGUCAUGAGAUGAGUUCCUUG UAGGUACCAGCUUCUGGCUCAAGAGUUGAAGGUGCCAUCGCAGGGUCA GGCCUGCCCUGUCCCGAAGUGAUCUCCUGGAAGACAAGUGCCUUCUCC CUCCAUGGAUCUGUGAUCUUCCCAGCUCUGCAUCAACACAGCAGCCUG CAGAUAACACUUGGGGGGACCUCAGCCUCUAUUCGCAACUCAUAAUCC GUAGACUACAAGAUGAAAUCUCAAUAAAUUAUUUUUGAGUUUAUUAAA GAUUGACAUUUUAAGUACAACUUUUAAGGACUAAUUACUGUGAUGGAC ACAGAAAUGUAGCUGUGUUCUGGAACUGAAUCUUACAUGGUAUACUUA GUGCUGCUGGGUAAUUUGUUGGUAUAUUAUCUGGUUAGUGGUUAAUGC UUCCUUUAAAAAUAAUUGAGUCAUCCAUUCACUCUUUUUCAGUUUUAU CUGUCAAUAGUAGCUACAUUUUUAAUGGGAGCACCUUUUAUCCCAAAG UGCUUUAUAAAUUGAGUGGACUGAUAUAUAUCACACCCAGGUAUCACU GUGCUGUCCUUUGCUGUCAGAUUUAGAAAUGUUUUUAAGAGCUAUGUG AAAACAGACAAUAUUAGUUUAGGUCGGGAACUGAGAUAUUGUAAUCAA AUAGUUAACAUCAGGAAGUUAAUUUGGCUGGCAAAAUUCUAGGGAAAC UUGGCCAGAAAACUGGUGUUGAAGGCUUUUGCUCAUAUAAACAAGUGC CAUUGAGUUUCAAAUGACCAGCAAAUAUAUUUAGAACCCUUCCUGUUU UAUGUCUGUACCUCGUCCACCCCUCAGGUAAUACCUGCCUCUCACAGG UACAGCUGUUUCUUGGAAAUCCUCCAACCAAAUAGCAGUUUUCCUAAC UUGAUUAGCUUGAGCUGACAGACUGUUAGAAUACAGUUCUCUGGCCAC AGCUGAUGAGGGCUUUCUGUACUGCACACAGAUUGUGUACUGCACCCC AGUCCAGGUGACUGGUACCCACUCGAGUUGUGCCGUGCACAACCUGUC CAGUAUAUGCAUGUGGUGGCCCUACUGACUGGUAAUGGUUAGAGGCAU UUAUGGAUUUUUAGCUUUGAGGAAAAACCAUGACUUUUAACAAAUUUU UAUGGGUUAUAUGCCUAAACCCUUAUGCCACAUAGUGGUAAAUAAUUAUGAAAAAUGGUCUGUUCAUAAUUGGUAGGUGCCUUUUGUGAGCAGGGAAttorney Docket No. 62801.94WO01GCAUAAUUAUUGGUUUAUUAUGGUAAUUAUGGUGAUUUUUUAAAUAUC AUGUAAUGUUAAAACGUUUUCUAACAGUUUACUGUUGCUUAUCUCCAA GAUAUUAUGGAAUUAAGAAUUUUUCCAGAUGAGUGUUACAUAGAUUCU UUGAAUUUAGUAUAAAAGUACUGAGAAUUAAGUUUGUACUUCCAUAAG CUUGGAUUUUAAACACUGAUAGUAUCUCAUGAGUAAUGUGUGUUUUGG GAGAGGGAGGGAUGCUGAUUGAUAUUUCACAUUGUAUGAAAUACCAUG UUUGAAACUCAUAGCAAUAAUGCUAUGCUGUUGUGAUCCCUCUCAAGU UCUGCAUUUAAAAUAUAUUUUUUCUUUAUAGGAAUUGAUGUAUACCAU GAAGUCAUUGUCAGUUGUAGUAGCUCUGAUGUUGAAUGAGAUAUCAUG UUUUAGCAUUCCAUUUUACUGACUAGGGUAGAAGAACACUUUUCUUGG CUACAUUUGGAGGAUACCCAGGGAGUCUUGGGUGUUCCUUAUCUGGGG AAGCAAACAUUUCACUAGUCUCUUUUUUUCAUCCUUUAAAUUGUAAAU UAAGGAUUACUCAAGCUCACCAUUAUUCAAGAUUGGGACUCGCUUCCC AGUCGACACUCUGCCCUGCCUGUCAUUGCUGCAAAGAGCUGCUGCUUU GCCAACCUAAGCAAAGAAAAUACGGCUUCUCUUGCAUUAUUUUCCCUU UUGGUUGGUUUGUUUUCUAGAAGUACGUUCAGAUGCUUUGGGGAAUGC AAUGUAUGAUUUGCUAGCUCUCUCACCACUUAACUCACUGUGAGGAUA AAUAUGCAUGCUUUUUGUAAUUAACUGGUGCUUUGAAAAUCUUUUUUA AGGGAGAAAAAUCUCAACCAAAGUUAUGCUCAUCCAGACAAGCUGACC UUUGAGUUAAUUUCAGCACAACUCAUUCUUCAGUGCCUCAUGACUGAA AACAAAAAACAAAAAAACGAAAGCAUCUUCACAAUGAAGCUUCCAGAU AGCACCGUUUUGCUAAAAGAUACAUUCUCAUUGUUUUCCAACAGUGAU GGCUUCCACAUAAGGUUAAACAAACUAGGUGCUUGUAAAUAAUUUAUU ACAGUUUACUCUAUCGCAUUUCUGUAACAUGAAAUGCAUGCCCUUCUU CAGGGGAAGACUGUGGUCAAGUUAAAAAAAAAAAACAAUAUUAAACAA CAUGAAACUGCAGUCUGUUUUUGAAAAUGAGAAUGUCCUAAGUGAUUC AGAAGAGAGGAGGGAAGUUGUGCACUCUGAAAAUGCAUGAAAAACAAA GGCAAAAACUAGUGGGAAAUGUGUAGAACUGUUAACUGAGAUGGCUUC GAGUCUUCCUUCUGGAAUCUGUUAAAUUUCACAAAGUCAUGAGGGUAA AUGGAGAAAAUAUUUCUGGGAUUACAAUGAAUGUAAGCCCAAAUUGUG GAAUUGCCAGUAACCUGGAUGGGGAAAAGCAUUUCCCAUAGCACUCCA UGUAAUAUGAGUGCUCUGUGAGAUGUUCAUCAGUGUUUUAUAGAAAUG GUGUUGCUGGGAAACCAAGUUUGCACCUGGAAACUUACAAUGCACUUU AGCGCAGUAAGGGCUUGGCAUCCGGUAGUGAAAAACUGUCUAACCCAG CAUUGCCCAAACUAUUUUGACACCAGGACCUUUUUCUCCUUUGGGAUA CUUAUGAACCUCUCACUAAUGUCCUGUGGAGAACAUUUUGGGAAACAC UAUGUUAGAUAGUUCUUUAAGGAGACAAAACGGUAAUGAACAGAUAGC ACUGGGGCAGAAUAUGCAUGCAUUUUGUAACGUCCAGUGUGGCGUUGA AUAGAUGUGUAUUUCCUCCCCUGCAGAAAAUAAGCACAGAAAAUUAUA AUGUAGGUGAUCGGAGCUCUUUCCUUUGAUAGAGAGAACAGCCCCAAU GAUCCUGGCUUUUUCACUGAACGUAUCAGAAUACAUGGAUGAAUUGGG GUAAAUAAGGUUUUAAUUCAGAUCUAGAAGAAAGUAUUGUACGUUUGA AUGCAGAUUUUUAUCCACAGAUAGUUGUAGUGUUUAGACAUGACAGGA CCUAUCGUUGAGGUUUCUAAGACUUACUAUGGGCUGUAAACCUGUUUU UUAAAACUAUUUUAGAAACCUGAGACUUGCCGUCUGGCAUUUUAGUUU AAUACAAACUAAUGAUUGCAUUUGAAAGAGAUUCUUGACCUUAUUUCU AAACGUCUAGAGCUCUGAAAUGUCUUGAUGGAAGGUAUUAAACUAUUU GCCUGUUGUACAAAGAAAUGUUAAGACUCGUGAAAAGAAUUACUAUAA GGUACUGUGAAAUAACUGCGAUUUUGUGAGCAAAACAUACUUGGAAAU GCUGAUUGAUUUUUAUGCUUGUUAGUGUAUUGCAAGAAACACAGAAAAUGUAGUUUUGUUUUAAUAAACCAAAAAUUGAACAUAAttorney Docket No. 62801.94WO01UAUGUUCAAUUUUUGGUUUAUUAAAACAAAACUACAUUUUCUGUGUUU CUUGCAAUACACUAACAAGCAUAAAAAUCAAUCAGCAUUUCCAAGUAU GUUUUGCUCACAAAAUCGCAGUUAUUUCACAGUACCUUAUAGUAAUUC UUUUCACGAGUCUUAACAUUUCUUUGUACAACAGGCAAAUAGUUUAAU ACCUUCCAUCAAGACAUUUCAGAGCUCUAGACGUUUAGAAAUAAGGUC AAGAAUCUCUUUCAAAUGCAAUCAUUAGUUUGUAUUAAACUAAAAUGC CAGACGGCAAGUCUCAGGUUUCUAAAAUAGUUUUAAAAAACAGGUUUA CAGCCCAUAGUAAGUCUUAGAAACCUCAACGAUAGGUCCUGUCAUGUC UAAACACUACAACUAUCUGUGGAUAAAAAUCUGCAUUCAAACGUACAA UACUUUCUUCUAGAUCUGAAUUAAAACCUUAUUUACCCCAAUUCAUCC AUGUAUUCUGAUACGUUCAGUGAAAAAGCCAGGAUCAUUGGGGCUGUU CUCUCUAUCAAAGGAAAGAGCUCCGAUCACCUACAUUAUAAUUUUCUG UGCUUAUUUUCUGCAGGGGAGGAAAUACACAUCUAUUCAACGCCACAC UGGACGUUACAAAAUGCAUGCAUAUUCUGCCCCAGUGCUAUCUGUUCA UUACCGUUUUGUCUCCUUAAAGAACUAUCUAACAUAGUGUUUCCCAAA AUGUUCUCCACAGGACAUUAGUGAGAGGUUCAUAAGUAUCCCAAAGGA GAAAAAGGUCCUGGUGUCAAAAUAGUUUGGGCAAUGCUGGGUUAGACA GUUUUUCACUACCGGAUGCCAAGCCCUUACUGCGCUAAAGUGCAUUGU AAGUUUCCAGGUGCAAACUUGGUUUCCCAGCAACACCAUUUCUAUAAA ACACUGAUGAACAUCUCACAGAGCACUCAUAUUACAUGGAGUGCUAUG GGAAAUGCUUUUCCCCAUCCAGGUUACUGGCAAUUCCACAAUUUGGGC UUACAUUCAUUGUAAUCCCAGAAAUAUUUUCUCCAUUUACCCUCAUGA CUUUGUGAAAUUUAACAGAUUCCAGAAGGAAGACUCGAAGCCAUCUCA GUUAACAGUUCUACACAUUUCCCACUAGUUUUUGCCUUUGUUUUUCAUReverse GCAUUUUCAGAGUGCACAACUUCCCUCCUCUCUUCUGAAUCACUUAGG Complement of ACAUUCUCAUUUUCAAAAACAGACUGCAGUUUCAUGUUGUUUAAUAUU 2 hGPAM mRNA GUUUUUUUUUUUUAACUUGACCACAGUCUUCCCCUGAAGAAGGGCAUG CAUUUCAUGUUACAGAAAUGCGAUAGAGUAAACUGUAAUAAAUUAUUU ACAAGCACCUAGUUUGUUUAACCUUAUGUGGAAGCCAUCACUGUUGGA AAACAAUGAGAAUGUAUCUUUUAGCAAAACGGUGCUAUCUGGAAGCUU CAUUGUGAAGAUGCUUUCGUUUUUUUGUUUUUUGUUUUCAGUCAUGAG GCACUGAAGAAUGAGUUGUGCUGAAAUUAACUCAAAGGUCAGCUUGUC UGGAUGAGCAUAACUUUGGUUGAGAUUUUUCUCCCUUAAAAAAGAUUU UCAAAGCACCAGUUAAUUACAAAAAGCAUGCAUAUUUAUCCUCACAGU GAGUUAAGUGGUGAGAGAGCUAGCAAAUCAUACAUUGCAUUCCCCAAA GCAUCUGAACGUACUUCUAGAAAACAAACCAACCAAAAGGGAAAAUAA UGCAAGAGAAGCCGUAUUUUCUUUGCUUAGGUUGGCAAAGCAGCAGCU CUUUGCAGCAAUGACAGGCAGGGCAGAGUGUCGACUGGGAAGCGAGUC CCAAUCUUGAAUAAUGGUGAGCUUGAGUAAUCCUUAAUUUACAAUUUA AAGGAUGAAAAAAAGAGACUAGUGAAAUGUUUGCUUCCCCAGAUAAGG AACACCCAAGACUCCCUGGGUAUCCUCCAAAUGUAGCCAAGAAAAGUG UUCUUCUACCCUAGUCAGUAAAAUGGAAUGCUAAAACAUGAUAUCUCA UUCAACAUCAGAGCUACUACAACUGACAAUGACUUCAUGGUAUACAUC AAUUCCUAUAAAGAAAAAAUAUAUUUUAAAUGCAGAACUUGAGAGGGA UCACAACAGCAUAGCAUUAUUGCUAUGAGUUUCAAACAUGGUAUUUCA UACAAUGUGAAAUAUCAAUCAGCAUCCCUCCCUCUCCCAAAACACACA UUACUCAUGAGAUACUAUCAGUGUUUAAAAUCCAAGCUUAUGGAAGUA CAAACUUAAUUCUCAGUACUUUUAUACUAAAUUCAAAGAAUCUAUGUA ACACUCAUCUGGAAAAAUUCUUAAUUCCAUAAUAUCUUGGAGAUAAGC AACAGUAAACUGUUAGAAAACGUUUUAACAUUACAUGAUAUUUAAAAAAUCACCAUAAUUACCAUAAUAAACCAAUAAUUAUGCUCCCUGCUCACAAttorney Docket No. 62801.94WO01AAAGGCACCUACCAAUUAUGAACAGACCAUUUUUCAUAAUUAUUUACC ACUAUGUGGCAUAAGGGUUUAGGCAUAUAACCCAUAAAAAUUUGUUAA AAGUCAUGGUUUUUCCUCAAAGCUAAAAAUCCAUAAAUGCCUCUAACC AUUACCAGUCAGUAGGGCCACCACAUGCAUAUACUGGACAGGUUGUGC ACGGCACAACUCGAGUGGGUACCAGUCACCUGGACUGGGGUGCAGUAC ACAAUCUGUGUGCAGUACAGAAAGCCCUCAUCAGCUGUGGCCAGAGAA CUGUAUUCUAACAGUCUGUCAGCUCAAGCUAAUCAAGUUAGGAAAACU GCUAUUUGGUUGGAGGAUUUCCAAGAAACAGCUGUACCUGUGAGAGGC AGGUAUUACCUGAGGGGUGGACGAGGUACAGACAUAAAACAGGAAGGG UUCUAAAUAUAUUUGCUGGUCAUUUGAAACUCAAUGGCACUUGUUUAU AUGAGCAAAAGCCUUCAACACCAGUUUUCUGGCCAAGUUUCCCUAGAA UUUUGCCAGCCAAAUUAACUUCCUGAUGUUAACUAUUUGAUUACAAUA UCUCAGUUCCCGACCUAAACUAAUAUUGUCUGUUUUCACAUAGCUCUU AAAAACAUUUCUAAAUCUGACAGCAAAGGACAGCACAGUGAUACCUGG GUGUGAUAUAUAUCAGUCCACUCAAUUUAUAAAGCACUUUGGGAUAAA AGGUGCUCCCAUUAAAAAUGUAGCUACUAUUGACAGAUAAAACUGAAA AAGAGUGAAUGGAUGACUCAAUUAUUUUUAAAGGAAGCAUUAACCACU AACCAGAUAAUAUACCAACAAAUUACCCAGCAGCACUAAGUAUACCAU GUAAGAUUCAGUUCCAGAACACAGCUACAUUUCUGUGUCCAUCACAGU AAUUAGUCCUUAAAAGUUGUACUUAAAAUGUCAAUCUUUAAUAAACUC AAAAAUAAUUUAUUGAGAUUUCAUCUUGUAGUCUACGGAUUAUGAGUU GCGAAUAGAGGCUGAGGUCCCCCCAAGUGUUAUCUGCAGGCUGCUGUG UUGAUGCAGAGCUGGGAAGAUCACAGAUCCAUGGAGGGAGAAGGCACU UGUCUUCCAGGAGAUCACUUCGGGACAGGGCAGGCCUGACCCUGCGAU GGCACCUUCAACUCUUGAGCCAGAAGCUGGUACCUACAAGGAACUCAU CUCAUGACCUUCAUUUGCCAGCAGUGCCACACGUUACCUACAGCACCA CAAAACUCAGAAUAUAUUCUAGAAGUUUUUGUCGGUUGCAUUGAGGUA GAAAAGUGCUGCUCAGUUCUAAAACAGACACUCUCUUUUGUUUGGUCU CCUUGAAAACCCCAAUAUCCUUAAACAUUUUCACAGCAUUCUUCACAA GACAAUAUGUGGCACUCUCAGCAUAUACUGCAACAUUUCUUUCUGUUC UGGUUAUUAGGUAUUUGUGCAACUUUUGCAGAUACUCAGGUUCUGGAA CAGGACCACUGAAGUUGUGAACAAAGAUGGCAGCAGAGCUGUAGGCCU CCAGCAAAGGCCCAAGGAGUCUCUGUAAGAAGGUGAUAAACUGCUGGU GCUCCUUGGAUUGGCUCACCUUCAGGUAGCAAUCUCGCUGUUCCUCCC CAAAGUCACUGUCUUCAUCUUCUUCAUCACUUCUCCAAGACAAAGGUU CUGGAAGCUUCUUGUCCCACUGCUGCUCAGCAAGACUAGGACUGAUAU CUUCCUGGUCAUCGUGCUCUGCCACUGUAAGAAUGCCAUACUGGAUAA ACUUUCCUACUGUUUCAUGGCAGACUUGGUAAAAUGUCUGGCAAGGCA GUGAGAUGGUGCCUUCAUUGGAGAGAAGGUAGCACAGGCUGGCCGCCU UCCGCACCAGCUGCUCCUGGCUGAUCAGGUUAGGUGGGGUGCUAGUGG GACCCCCCAGUCCCCUCUUGUUCAGAACUGCAUAAAGGCUGCAAGCUA UGAUGGCCUCCAUGAUAAAGACAUGAAGUACCCCAUUGCUGUAGAAGU UGAGUUCGAAGACUGAUGGGACAGUUGUGCUGGGGGUGAUAAAAAACU CAUCGUUCCUGCUAGUGUGGGUGAUUGUGACACAAUUUCCCAGCAGCU GUAUGGCAUGCAUUACUACAUCUUCUGAAUUUCCUGAGAACCCCAGGU CAAAAUCACGAGCCAGGACUUCCUCUUUCAUCACAAAGAAGUCUUCGA CCAAUGUGGAGAGAUCAAUUCCCUGCCUGUGUCUGUAGAGGAGCAGGC AAGCCACAAUGUGUGUGGACAUAAUGGCACAGGACUUGCUAGCAGUGA AUAGAAUAUGCUCAGCCAGAUUUGCAAUCAACCUCCUUCGUAGGGAUU CAUCUGUUGCAUUUCUGGACUCAUUAAUGGACGUGUCUCUACCUUCAUCAGCAGCAUCACUGGGUCUUGAAGGAAGUAUAGCUGGUAACAACGCUUAttorney Docket No. 62801.94WO01GCUCCAGGGAAAGUAGAGCAGACACCGGUUUCUGACUUUGGCUUUCUA AAUAUUCCUUUAAGGAAAAUGGCUGUGCAAAAUCCACUCGGACACAAC CAUAGUUUUUUCGUAACAUUCUAAUAACACCUCUUGCUACACUCCACA GGCUCUCAUUCUUCUUAGGUUUGCCCAGUUGUUCACCAUUGUAGUGAC CUUCGAUAAUGCGAUCAUAGGAGAUUCCAACAGGUAUUAUCAAGAUGU CUGGGAUGACAUUGGUAGACAGAGUAUCUACCACAACUGACAAAAGUC CUGCCCGAGCACAAGAGGUUUUUCCACUCCUAGAACGUGUGCCUUCCA GGAAGAUCUCCAAGAAUUGCUGCUGUCGAAGUAAUUCAACUAUAUGCC CAUGGAGCAAAGCUCUAUAGAGAACAUCUUUCCGUCCAUCUGGUGUUU CAUCGAGCCUUCGUCGUAUGAAGAAGCCCCCAAGCUUAUGGAUCAAGG UACUGAAGAUUGGGAUGUUGAGAUUAUUGCCUGAAGCAAUGUAUGGUG CUUUGAUGUUAUGGCAGAAGAGAAUGAAAGUGAGCAGCAGAUAGUCAA UAUGGGAUCUAUGAACUGGUAGAAACAGAAGCGGCAAAUUCGUCUCAG UUGCAGCUUUAACCAUCUCAAGUUGACCUUUGUGAAUUUGAAUGUUCC AAAAGAAGCUGUUGAACAGUUUUAGCAGCACCCACCCAGUCAGUCUGA UCAUUGCCGGUGAGACAGUGGCAACCAUUUCUUGAAGAAUCCUUUUAG CUUUCUUUUUCACUUUGUUAACGGCUUUUGAUUGCUGCUGGGCAGAAC CAUCAGGGUUUAAUUCAGCAGCCACUUCUGCAAUUGCCUCUUGUACUC UACUGCUGUUCAGCACAUUUUCAGUCACAUUGGUGGCAAACAUGCCCU UAUGCACAUCUCGCUCUUGAAUAAAAAGAACGUAAGAAAGGCGUCUUG CAAGCCAUCCGCGGUGUCUUGUGUGAGUUUCAUUGAUAUAAAUAACAU UCCGCAAACCCAAAGACGGGAUACUGGGGUUGAAAAAUUUGUCCCAGC UCUGGGGAGUGCAGGAGUAACAACAUCUUCCAACAAAUGGCCUUUUCC GACUCAUUAGGCUUUCUUUCCAUUUUAAAGUUGCAGAUCUGAAGAUGG UGGGUCUAAAGCCACACUCACCCCAUUCCUCACUUGUGUGCUUACAUC GACCAACACUGUAUUCUGAUGAAUGUGGCAGAUAAGAAACAUCUAUUG UACCAAGGGUCAGUGCAGAUUCAUCCAUGUCACAAAGUGUAAUUCCCA AAUCAUGUGCUGGGAUGAAAGUUCUUCUGUUUCAUAACAUAAAACUUC AGGACUCAGCUAUCAGUUUCGGGUGCAGAAUGUCCAUACAACAGGGGA GCCGCUGCUGCCCUAGCAGCUCCAGCUUCGGCUGCUGCAGAAGCCCGC ACUUCCAGUCCCGGCCAAUGCCAGCUGCAGUGGCGC MDESALTLGTIDVSYLPHSSEYSVGRCKHTSEEWGECGFRPTIFRSAT LKWKESLMSRKRPFVGRCCYSCTPQSWDKFFNPSIPSLGLRNVIYINE THTRHRGWLARRLSYVLFIQERDVHKGMFATNVTENVLNSSRVQEAIA EVAAELNPDGSAQQQSKAVNKVKKKAKRILQEMVATVSPAMIRLTGWV LLKLFNSFFWNIQIHKGQLEMVKAATETNLPLLFLPVHRSHIDYLLLT FILFCHNIKAPYIASGNNLNIPIFSTLIHKLGGFFIRRRLDETPDGRKhGPAM Protein DVLYRALLHGHIVELLRQQQFLEIFLEGTRSRSGKTSCARAGLLSVW DTLSTNVIPDILIIPVGISYDRIIEGHYNGEQLGKPKKNESLWSVARG VIRMLRKNYGCVRVDFAQPFSLKEYLESQSQKPVSALLSLEQALLPAI NCBI Ref.: LPSRPSDAADEGRDTSINESRNATDESLRRRLIANLAEHILFTASKSC 3 NP_001231878. AIMSTHIVACLLLYRHRQGIDLSTLVEDFFVMKEEVLARDFDLGFSGN1 SEDVVMHAIQLLGNCVTITHTSRNDEFFITPSTTVPSVFELNFYSNGV LHVFIMEAIIACSLYAVLNKRGLGGPTSTPPNLISQEQLVRKAASLCY LLSNEGTISLPCQTFYQVCHETVGKFIQYGILTVAEHDDQEDISPSLA EQQWDKKLPEPLSWRSDEEDEDSDFGEEQRDCYLKVSQSKEHQQFITF LQRLLGPLLEAYSSAAIFVHNFSGPVPEPEYLQKLHKYLITRTERNVA V Y AE S AT Y C L VKNAVKMF KD I GVF KE TKQKRVS VLE LS S T F LP Q CNRQKLLEYILSFVVL

[0180] In some embodiments, the agent (e.g., RNAi agent, dsRNA agent) comprises one orAttorney Docket No. 62801.94WO01more RNA molecule. In some embodiments, the agent (e.g., RNAi agent, dsRNA agent) comprises an antisense strand. In some embodiments, the agent (e.g., RNAi agent, dsRNA agent) comprises a sense strand. In some embodiments, the agent comprises one or more single stranded RNA (ssRNA) molecules. In some embodiments, the agent (e.g., RNAi agent, dsRNA agent) comprises a dsRNA agent.

[0181] In some embodiments, the agent (e.g., RNAi agent) comprises a dsRNA agent comprising a sense strand and an antisense strand. In some embodiments, the agent (e.g., RNAi agent) comprises a dsRNA agent comprising a sense strand and an antisense strand that form a double stranded region. In some embodiments, the agent (e.g., RNAi agent) comprises a dsRNA agent comprising a sense strand and an antisense strand that hybridize to form a double stranded region. In some embodiments, the sense strand and the antisense strand are part of a single nucleic acid molecule (e.g., a single nucleic acid molecule comprising a hairpin loop). In some embodiments, the sense strand and the antisense strand are separate nucleic acid molecules.4.2.1 Antisense Strand4.2.1.1 Targeting Region

[0182] As described above, antisense strands (e.g., described herein) comprise a region of complementarity that comprises a nucleotide sequence that is at least partially (e.g., substantially, fully) complementary to the nucleotide sequence of a target nucleic acid molecule (e.g., a target mRNA (e.g., a GPAM mRNA), a portion of a target mRNA (e.g., a GPAM mRNA)). In some embodiments, the nucleotide sequence of the region of complementarity is at least substantially complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a GPAM mRNA), a portion of a target mRNA (e.g., a GPAM mRNA)). In some embodiments, the nucleotide sequence of the region of complementarity is fully complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a GPAM mRNA), a portion of a target mRNA (e.g., a GPAM mRNA)).

[0183] In some embodiments, the nucleotide sequence of the region of complementarity is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%. 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA e.g., a GPAM mRNA), a portion of a target mRNA (e.g., a GPAM mRNA)). For example, the nucleotide sequence of the region of complementarity may be at least 70% complementary to theAttorney Docket No. 62801.94WO01nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a GPAM mRNA), a portion of a target mRNA (e.g., a GPAM mRNA)). The nucleotide sequence of the region of complementarity may be at least 75% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a GPAM mRNA), a portion of a target mRNA (e.g., a GPAM mRNA)). The nucleotide sequence of the region of complementarity may be at least 80% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a GPAM mRNA), a portion of a target mRNA (e.g., a GPAM mRNA)). The nucleotide sequence of the region of complementarity may be at least 85% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a GPAM mRNA), a portion of a target mRNA (e.g., a GPAM mRNA)). The nucleotide sequence of the region of complementarity may be at least 90% complementary to the nucleotide sequence of the target nucleic acid molecule e.g., a target mRNA (e.g., a GPAM mRNA), a portion of a target mRNA (e.g., a GPAM mRNA)). The nucleotide sequence of the region of complementarity may be at least 95% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a GPAM mRNA), a portion of a target mRNA (e.g., a GPAM mRNA)). In some embodiments, the nucleotide sequence of the region of complementarity is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a GPAM mRNA), a portion of a target mRNA (e.g., a GPAM mRNA)). In some embodiments, the nucleotide sequence of the region of complementarity is at least 95%, 96%, 97%, 98%, 99%, or 100% (e.g., in some embodiments, preferably at least 95%, more preferably at least 98%) complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a GPAM mRNA), a portion of a target mRNA (e.g., a GPAM mRNA)). In some embodiments, the nucleotide sequence of the region of complementarity is 100% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a GPAM mRNA), a portion of a target mRNA (e.g., a GPAM mRNA)).

[0184] In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of one or more non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a GPAM mRNA), a portion of a target mRNA (e.g., a GPAM mRNA)). In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 5Attorney Docket No. 62801.94WO01(e.g., 4, 3, 2, 1, or 0) non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 3 (e.g., 2, 1, or 0) non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 2 (e.g., 1 or 0) non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 1 (e.g., 0) non-complementary nucleotide mismatch relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the nucleotide sequence of the region of complementarity comprises 0 non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the region of complementarity comprises one or more (e.g., 2, 3, or more) non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule, wherein the one or more non-complementary nucleotide mismatches are within the last 5 (e.g., 4, 3, 2, or 1) nucleotides from either the 5'- and / or 3'-end of the region of complementarity. In some embodiments, the region of complementarity comprises at least one but not more than 3 non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule, wherein the one or more non-complementary nucleotide mismatches are within the last 5 (e.g., 4, 3, 2, or 1) nucleotides from either the 5'- and / or 3'-end of the region of complementarity. In some embodiments, the region of complementarity comprises one or more (e.g., 2, 3, or more) non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule, wherein the one or more non-complementary nucleotide mismatches are within the last 3 (e.g., 2 or 1) nucleotides from either the 5'- and / or 3'-end of the region of complementarity. In some embodiments, the region of complementarity comprises at least one but not more than 3 non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule, wherein the one or more non-complementary nucleotide mismatches are within the last 3 (e.g., 2 or 1) nucleotides from either the 5'- and / or 3'-end of the region of complementarity. Methods known in the art and described herein can be utilized to evaluate the effect of any non-complementary mismatches between an antisense strand and a target nucleic acid molecule on functional properties (e.g., inhibition of expression of theAttorney Docket No. 62801.94WO01target nucleic acid molecule (e.g., a target mRNA (e.g., a GPAM mRNA), a portion of a target mRNA (e.g., a GPAM mRNA))).

[0185] In some embodiments, the region of complementarity comprises or consists of from about 15-30 nucleotides, e.g., 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15- 20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29. 19-28. 19-27, 19-26, 19-25, 19-24, 19-23. 19-22. 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotides. In some embodiments, the region of complementarity comprises from about 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-25, 19-24, 19-23, 19-22, 19- 21, 19-20, 20-25, 20-24, 20-23, 20-22, 20-21, 21-25, 21-24, 21-23, 21-22, 22-25, 22-24, 22-23, 23-25, 23-24 or 24-25 nucleotides. In some embodiments, the region of complementarity comprises from about 19-21 e.g., 19-20) nucleotides. In some embodiments, the region of complementarity comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26. 27, 28, 29, or 30 nucleotides. In some embodiments, the region of complementarity comprises or consists of about 19, 20, 21, 22, or 23 nucleotides. In some embodiments, the region of complementarity comprises or consists of about 19 nucleotides. In some embodiments, the region of complementarity comprises or consists of about 20 nucleotides. In some embodiments, the region of complementarity comprises or consists of about 21 nucleotides. In some embodiments, the region of complementarity comprises or consists of about 22 nucleotides. In some embodiments, the region of complementarity comprises or consists of about 23 nucleotides. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.

[0186] In some embodiments, the target nucleic acid molecule is part (e.g., a contiguous portion) of a larger nucleic acid molecule. For example, in some embodiments, the target nucleic acid molecule is a portion (e.g., a contiguous portion) of a target mRNA (e.g., a GPAM mRNA). In some embodiments, the target nucleic acid molecule is a contiguous nucleotide sequence of a target mRNA (e.g., a GPAM mRNA) of sufficient length to allow it to be a substrate for cleavage directed by an RNAi agent (e.g., an RNAi agent described herein, e.g., a dsRNA agent (e.g., described herein)) (i.e., cleavage through a RISC pathway).

[0187] In some embodiments, the target nucleic acid molecule is a target mRNA (e.g., a GPAM mRNA). In some embodiments, the target nucleic acid molecule is at least a portion (e.g.,Attorney Docket No. 62801.94WO01a portion) of a target mRNA (e.g., a GPAM mRNA). In some embodiments, the target nucleic acid molecule is at least a portion {e.g., a portion) of an mRNA {e.g., a GPAM mRNA) formed in the expression of a target gene {e.g., a mammalian, primate, human, non-human primate, mouse, and / or rat gene) e.g., a GPAM gene). In some embodiments, the target nucleic acid molecule is at least a portion {e.g., a portion) of a GPAM {e.g., hGPAM) mRNA. In some embodiments, the target nucleic acid molecule is at least a portion {e.g., a portion) of an mRNA formed in the expression of a GPAM {e.g., hGPAM) gene. In some embodiments, the target nucleic acid molecule comprises at least a portion {e.g., a portion) of the nucleotide sequence set forth in SEQ ID NO: 1 (or a variant or fragment thereof). In some embodiments, the target nucleic acid molecule comprises at least a portion {e.g., a portion) of an mRNA encoding a target protein. In some embodiments, the target nucleic acid molecule comprises at least a portion {e.g., a portion) of an mRNA encoding a GPAM {e.g., hGPAM) protein. In some embodiments, the target nucleic acid molecule comprises at least a portion {e.g., a portion) of an mRNA sequence encoding a protein comprising the amino acid sequence set forth in SEQ ID NO: 3 (or a variant or fragment thereof).

[0188] In some embodiments, the target nucleic acid molecule comprises or consists of from about 19-30 nucleotides, e.g., 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, 21-22, 22-30, 22-29, 22-28, 22-27, 22-26, 22-25, 22-24, 22-23, 23-30, 23-29, 23-28, 23-27, 23-26, 23-27, 23-26, 23-25, or 23-24 nucleotides. In some embodiments, the target nucleic acid molecule comprises or consists of from about 19-25 nucleotides. In some embodiments, the target nucleic acid molecule comprises or consists of from about 19-23 nucleotides. In some embodiments, the target nucleic acid molecule comprises or consists of from about 21-25 nucleotides. In some embodiments, the target nucleic acid molecule comprises or consists of from about 21-23 nucleotides. In some embodiments, the target nucleic acid molecule comprises or consists of about 18, 19. 20. 21, 22, 23, 24, 25, 26, 27, 28. 29. or 30 nucleotides. In some embodiments, the target nucleic acid molecule comprises or consists of about 19 nucleotides. In some embodiments, the target nucleic acid molecule comprises or consists of about 20 nucleotides. In some embodiments, the target nucleic acid molecule comprises or consists of about 21 nucleotides. In some embodiments, the target nucleic acid molecule comprises or consists of about 23 nucleotides. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.Attorney Docket No. 62801.94WO014.2. L2 Overall Length

[0189] In some embodiments, the antisense strand comprises or consists of from about 15-30 nucleotides (e.g., 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24. 20-23, 20-22, 20-21, 21-30, 21-29, 21-28. 21-27. 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotides). In some embodiments, the antisense strand comprises or consists of from about 18-25 nucleotides (e.g., 18-24, 18-23, 18-22, 18-21, 18-20, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-25, 20-24, 20-23, 20-22, 20-21, 21-25, 21-24, 21-23, 21-22, 22-25, 22-24, 22-23, 23-25, 23-24 or 24-25 nucleotides). In some embodiments, the antisense strand comprises or consists of from about 19-25 nucleotide (e.g., 19-20, 19-21, 19-22, 19-23, 19-24, 19-25, 20-21, 20-22, 20-23, 20-24, 20-25, 21-22, 21-23, 21-24, 21-25, 22-23, 22-24, 22-25, 23-24, 23-25, 24-25 nucleotides). In some embodiments, the antisense strand comprises or consists of from about 15-30, 16-30, 17-30, 18-30, 19-30, 20-30, 21-30, 22-30, 23-30, 24-30, 25-30, 26-30, 27-30, 28-30, 29-30, 19-20, 19-21, 19-22, 19-23, 19-24, or 19-25 nucleotides.

[0190] In some embodiments, the antisense strand comprises or consists of not more than about 15, 16, 17, 18. 19, 20, 21, 22, 23, 24, 25. 26, 27, 28. 29, or 30 nucleotides. In some embodiments, the antisense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the antisense strand comprises or consists of about 21 nucleotides. In some embodiments, the antisense strand comprises or consists of about 23 nucleotides. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.4.2.1.3 Exemplary Antisense Strands

[0191] In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 1 (e.g., 0 orAttorney Docket No. 62801.94WO011) nucleotide from the nucleotide sequence of any one of the antisense strands set forth in Table 2.

[0192] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2 differing by no more than 5 (e.g., 0, 1. 2, 3, 4, or 5) nucleotides from the antisense strand set forth in Table 2. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in Table 2. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2 differing by no more than 2 (e.g., 0, 1, or 2) nucleotides from the antisense strand set forth in Table 2. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2 differing by no more than 1 (e.g., 0 or 1) nucleotide from the antisense strand set forth in Table 2.

[0193] In some embodiments, the nucleotide sequence of the antisense strand is at least 85%, 86%, 87%, 88%, 89%. 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the antisense strand is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the antisense strand is at least 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the antisense strand is at least 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the antisense strand is at least 97% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the antisense strand is at least 98% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the antisense strand is at least 99% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the antisense strand is 100% identical to the nucleotide sequence of any one of the antisense strands set forth in TableAttorney Docket No. 62801.94WO012.

[0194] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the antisense strand consists of the nucleotide sequence of any one of the antisense strands set forth in Table 2.

[0195] Table 2 further identifies the target nucleic acid molecule within the cited reference GPAM mRNA transcript (SEQ ID NO: 1) targeted by each of the antisense strands. As such, the disclosure further provides antisense strands wherein the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5 (e.g., no more than 3 (e.g., 0, 1, 2, or 3))) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially complementary to the region contiguous (e.g., either at the 3'-end, the 5'-end, or both the 3' and 5'-end) of the GPAM mRNA transcript targeted by the select antisense strand.

[0196] In some embodiments, the antisense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the antisense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27. 28. 29, 30 (e.g., 19. 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25. 26. 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3. 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the antisense strand comprises at least 23 (e.g., 24, 25. 26, 27, 28, 29, 30) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2.

[0197] In some embodiments, the antisense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, theAttorney Docket No. 62801.94WO01antisense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the antisense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2.

[0198] In some embodiments, the antisense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19. 15-18, 15-17, 15-16, 16-22, 16-21, 16-20. 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the antisense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the antisense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2.

[0199] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in Table 2. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2.

[0200] Table 2 further identifies the target nucleic acid molecule within the cited reference GPAM mRNA transcript (SEQ ID NO: 1) targeted by each of the antisense strands. As such, the disclosure further provides antisense strands comprising at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 and further comprising additional nucleotideAttorney Docket No. 62801.94WO01sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially complementary to the region contiguous (e.g., either at the 3 '-end, the 5 '-end, or both the 3' and 5 ’-end) of the GPAM mRNA transcript targeted by the select antisense strand.

[0201] In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301.

[0202] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301 differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301 differing by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301 differing by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301.

[0203] In some embodiments, the nucleotide sequence of the antisense strand is at least 85%, 86%, 87%, 88%, 89%. 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the nucleotide sequence of the antisense strand is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the nucleotide sequence of the antisense strand is at least 95%,Attorney Docket No. 62801.94WO0196%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the nucleotide sequence of the antisense strand is at least 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the nucleotide sequence of the antisense strand is at least 97% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the nucleotide sequence of the antisense strand is at least 98% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the nucleotide sequence of the antisense strand is at least 99% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the nucleotide sequence of the antisense strand is 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301.

[0204] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the nucleotide sequence of the antisense strand consists of the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301.

[0205] Table 2 further identifies the target nucleic acid molecule within the cited reference GPAM mRNA transcript (SEQ ID NO: 1) targeted by each of the antisense strands. As such, the disclosure further provides antisense strands wherein the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0. 1, 2, 3, 4, or 5 (e.g., no more than 3 (e.g., 0, 1, 2, or 3))) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301 and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3. or 1-2 nucleotides) at least partially complementary to the region contiguous (e.g., either at the 3 '-end, the 5 '-end, or both the 3' and 5 '-end) of the GPAM mRNA transcript targeted by the select antisense strand.

[0206] In some embodiments, the antisense strand comprises at least 15 (e.g., 15. 16. 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the antisense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in SEQ ID NOS: 153-301. InAttorney Docket No. 62801.94WO01some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the antisense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301.

[0207] In some embodiments, the antisense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-21, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the antisense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the antisense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301.

[0208] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301.

[0209] As described above, Table 2 further identifies the target nucleic acid molecule within the cited reference GPAM mRNA transcript (SEQ ID NO: 1) targeted by each of the antisense strands. The disclosure further provides antisense strands comprising at least 15 (e.g., 15. 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301 and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially complementary to the region contiguous (e.g., either at the 3 '-end, the 5 '-end, or both the 3' and 5 '-end) of the GPAM mRNA transcript targeted by the select antisenseAttorney Docket No. 62801.94WO01strand.

[0210] In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0. 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149. In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149. In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149. In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149.

[0211] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149 differing by no more than 5 (e.g., 0, 1. 2, 3. 4, or 5) nucleotides from the antisense strand of any one of dsRNA agents 1-149. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand of any one of dsRNA agents 1-149. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149 differing by no more than 2 (e.g., 0, 1, or 2) nucleotides from the antisense strand of any one of dsRNA agents 1-149. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149 differing by no more than 1 (e.g., 0 or 1) nucleotide from the antisense strand of any one of dsRNA agents 1-149.

[0212] In some embodiments, the nucleotide sequence of the antisense strand is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149. In some embodiments, the nucleotide sequence of the antisense strand is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149. In some embodiments, the nucleotide sequence of the antisense strand is at least 95%, 96%, 97%, 98%, 99% or 100% identical to theAttorney Docket No. 62801.94WO01nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149. In some embodiments, the nucleotide sequence of the antisense strand is at least 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149. In some embodiments, the nucleotide sequence of the antisense strand is at least 97% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149. In some embodiments, the nucleotide sequence of the antisense strand is at least 98% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149. In some embodiments, the nucleotide sequence of the antisense strand is at least 99% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149. In some embodiments, the nucleotide sequence of the antisense strand is 100% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149.

[0213] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149. In some embodiments, the nucleotide sequence of the antisense strand consists of the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149.

[0214] Table 2 further identifies the target nucleic acid molecule within the cited reference GPAM mRNA transcript (SEQ ID NO: 1) targeted by each of the antisense strands. As such, the disclosure further provides antisense strands wherein the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5 (e.g., no more than 3 (e.g., 0, 1, 2, or 3))) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149 and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially complementary to the region contiguous (e.g., either at the 3'-end, the 5'-end, or both the 3' and 5'-end) of the GPAM mRNA transcript targeted by the select antisense strand.

[0215] In some embodiments, the antisense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149 set forth in Table 2. In some embodiments, the antisense strand comprises at least 19 (e.g., 20, 21, 22, 23. 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no moreAttorney Docket No. 62801.94WO01than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149 set forth in Table 2. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149 set forth in Table 2. In some embodiments, the antisense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149 set forth in Table 2.

[0216] In some embodiments, the antisense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19. 15-18, 15-17, 15-16, 16-22, 16-21, 16-20. 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149 set forth in Table 2. In some embodiments, the antisense strand comprises from about 19-23 (e.g., 19-22. 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149 set forth in Table 2. In some embodiments, the antisense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149 set forth in Table 2.

[0217] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149 set forth in Table 2 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in Table 2. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149 set forth in Table 2.

[0218] As described above, Table 2 further identifies the target nucleic acid molecule within the cited reference GPAM mRNA transcript (SEQ ID NO: 1) targeted by each of the antisense strands. The disclosure further provides antisense strands comprising at least 15 (e.g., 15, 16, 17,Attorney Docket No. 62801.94WO0118, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149 set forth in Table 2 and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially complementary to the region contiguous (e.g., either at the 3'-end, the 5'-end, or both the 3' and 5'-end) of the GPAM mRNA transcript targeted by the select antisense strand.

[0219] It is to be understood, that although the antisense strands set forth in Table 2 are not described as being modified (e.g., comprising chemically modified nucleotides), conjugated, etc., the disclosure includes any antisense strand set forth in Table 2 that is unmodified, unconjugated, modified (e.g., as described herein), or conjugated (e.g., as described herein).4.2.2 Sense Strand4.2.2.1 Antisense Strand Complementarity

[0220] As described above, sense strands (e.g., described herein) comprise a region of complementarity that comprises a nucleotide sequence that is at least partially (e.g., substantially, fully) complementary to the nucleotide sequence of at least a portion of an antisense strand. As such, pairs of sense and antisense strands can hybridize to form a double stranded region (e.g., under conditions in which the pairs will be used).

[0221] In some embodiments, the nucleotide sequence of the region of complementarity is at least substantially complementary to the nucleotide sequence of at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity is fully complementary to the nucleotide sequence of at least a portion of an antisense strand.

[0222] In some embodiments, the nucleotide sequence of the region of complementarity is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to the nucleotide sequence of at least a portion of an antisense strand. For example, the nucleotide sequence of the region of complementarity may be at least 70% complementary to the nucleotide sequence of at least a portion of an antisense strand. The nucleotide sequence of the region of complementarity may be at least 75% complementary to the nucleotide sequence of at least a portion of an antisense strand. The nucleotide sequence of the region of complementarity may be at least 80% complementary to the nucleotide sequence of at least a portion of an antisenseAttorney Docket No. 62801.94WO01strand. The nucleotide sequence of the region of complementarity may be at least 85% complementary to the nucleotide sequence of at least a portion of an antisense strand. The nucleotide sequence of the region of complementarity may be at least 90% complementary to the nucleotide sequence of at least a portion of an antisense strand. The nucleotide sequence of the region of complementarity may be at least 95% complementary to the nucleotide sequence of at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to the nucleotide sequence of at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity is at least 95%, 96%, 97%, 98%, 99%, or 100% complementary to the nucleotide sequence of at least a portion of an antisense strand.

[0223] In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of one or more non-complementary nucleotide mismatches relative to the nucleotide sequence of the at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 5 (e.g., 4, 3, 2, 1, or 0) non-complementary nucleotide mismatches relative to the nucleotide sequence of the at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 3 (e.g., 2, 1, or 0) non-complementary nucleotide mismatches relative to the nucleotide sequence of the at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 2 (e.g., 1 or 0) non-complementary nucleotide mismatches relative to the nucleotide sequence of the at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 1 (e.g., 0) non-complementary nucleotide mismatches relative to the nucleotide sequence of the at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity comprises 0 non-complementary nucleotide mismatches relative to the nucleotide sequence of the at least a portion of an antisense strand. In some embodiments, the region of complementarity comprises one or more (e.g., 2, 3, or more) non-complementary nucleotide mismatches relative to the nucleotide sequence of the at least a portion of an antisense strand, wherein the one or more non-complementary nucleotide mismatch is within the last 5 (e.g., 4, 3, 2, or 1) nucleotides from either the 5'- and / or 3'-end of the region ofAttorney Docket No. 62801.94WO01complementarity. In some embodiments, the region of complementarity comprises at least one but not more than 3 (e.g., 1, 2, or 3) non-complementary nucleotide mismatches relative to the nucleotide sequence of the at least a portion of an antisense strand, wherein the one or more non-complementary nucleotide mismatch is within the last 5 e.g., 4, 3, 2, or 1) nucleotides from either the 5'- and / or 3 '-end of the region of complementarity.

[0224] In some embodiments, the region of complementarity comprises from about 15-30 nucleotides, e.g., 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotides. In some embodiments, the region of complementarity comprises from about 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-25, 20-24, 20-23, 20-22, 20-21, 21-25, 21-24, 21-23, 21-22, 22-25, 22-24, 22-23, 23-25, 23-24 or 24-25 nucleotides. In some embodiments, the region of complementarity comprises from about 19-21 (e.g., 19-20) nucleotides. In some embodiments, the region of complementarity comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the region of complementarity comprises or consists of about 19, 20, or 21 nucleotides. In some embodiments, the region of complementarity comprises or consists of about 19 nucleotides. In some embodiments, the region of complementarity comprises or consists of about 20 nucleotides. In some embodiments, the region of complementarity comprises or consists of about 21 nucleotides. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.4.2.2.2 Overall Length

[0225] In some embodiments, the sense strand comprises or consists of from about 15-30 nucleotides (e.g., 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30. 18-29, 18-28, 18-27, 18-26, 18-25, 18-24. 18-23. 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotides). In some embodiments, the sense strand comprises or consists of from about 18-25 nucleotides (e.g., 18-24, 18-23, 18-22, 18-21, 18-20, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-25, 20-24, 20-23, 20-22, 20-21, 21-25, 21-24, 21-23, 21-22, 22-25, 22-24, 22-23, 23-25,Attorney Docket No. 62801.94WO0123-24 or 24-25 nucleotides). In some embodiments, the sense strand comprises or consists of from about 19-25 nucleotide (e.g., 19-20, 19-21, 19-22, 19-23, 19-24, 19-25, 20-21, 20-22, 20-23, 20-24, 20-25, 21-22, 21-23, 21-24, 21-25. 22-23. 22-24. 22-25, 23-24, 23-25, 24-25 nucleotides). In some embodiments, the sense strand comprises or consists of from about 15-30, 16-30, 17-30, 18-30, 19-30, 20-30, 21-30, 22-30, 23-30, 24-30, 25-30, 26-30, 27-30, 28-30, 29-30, 19-20, 19-21. 19-22, 19-23, 19-24, or 19-25 nucleotides.

[0226] In some embodiments, the sense strand comprises or consists of not more than about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the sense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides, hi some embodiments, the sense strand comprises or consists of about 19, 20, 21, 22, 23 nucleotides. In some embodiments, the sense strand comprises or consists of about 19, 20, 21 nucleotides. In some embodiments, the sense strand comprises or consists of about 20 nucleotides. In some embodiments, the sense strand comprises or consists of about 21 nucleotides. In some embodiments, the sense strand comprises or consists of about 21 nucleotides. In some embodiments, the sense strand comprises or consists of about 23 nucleotides. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.4.2.2.3 Exemplary Sense Strands

[0227] In some embodiments, the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3. 4, or 5) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence of any one of the sense strands set forth in Table 2.

[0228] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in Table 2 differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the sense strand set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence ofAttorney Docket No. 62801.94WO01any one of the sense strands set forth in Table 2 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in Table 2 differing by no more than 2 (e.g., 0, 1, or 2) nucleotides from the sense strand set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in Table 2 differing by no more than 1 (e.g., 0 or 1) nucleotide from the sense strand set forth in Table 2.

[0229] In some embodiments, the nucleotide sequence of the sense strand is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand is at least 95%, 96%, 97%, 98%. 99% or 100% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand is at least 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand is at least 97% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand is at least 98% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand is at least 99% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand is 100% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2.

[0230] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand consists of the nucleotide sequence of any one of the sense strands set forth in Table 2.

[0231] Table 2 further identifies the target nucleic acid molecule within the cited reference GPAM mRNA transcript (SEQ ID NO: 1) targeted by each of the sense strands. As such, the disclosure further provides sense strands wherein the nucleotide sequence of the sense strandAttorney Docket No. 62801.94WO01differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5 (e.g., no more than 3 (e.g., 0, 1, 2, or 3))) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially complementary to the region contiguous (e.g., either at the 3'-end, the 5'-end, or both the 3' and 5'-end) of the GPAM mRNA transcript targeted by the select sense strand.

[0232] In some embodiments, the sense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the sense strand comprises at least 19 (e.g., 20. 21, 22, 23, 24, 25. 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the sense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2.

[0233] In some embodiments, the sense strand comprises from about 15-23 (e.g., 15-22, 15- 21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-21, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19. 17-18, 18-23, 18-22, 18-21, 18-20, 18-19. 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the sense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2.

[0234] In some embodiments, the nucleotide sequence of the sense strand comprises theAttorney Docket No. 62801.94WO01nucleotide sequence of any one of the sense strands set forth in Table 2 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in Table 2.

[0235] Table 2 further identifies the target nucleic acid molecule within the reference GPAM mRNA transcript at least partially identical to each of the sense strands. As such, the disclosure further provides sense strands comprising at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially identical to the region contiguous (e.g., either at the 3 '-end, the 5 '-end, or both the 3' and 5 '-end) of the GPAM mRNA transcript identical to the select sense strand.

[0236] In some embodiments, the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152.

[0237] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152 differing by no more than 5 (e.g., 0, 1, 2, 3. 4, or 5) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152 differing by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152. In some embodiments,Attorney Docket No. 62801.94WO01the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152 differing by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152.

[0238] In some embodiments, the nucleotide sequence of the sense strand is at least 85%, 86%, 87%, 88%, 89%. 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the nucleotide sequence of the sense strand is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the nucleotide sequence of the sense strand is at least 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the nucleotide sequence of the sense strand is at least 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the nucleotide sequence of the sense strand is at least 97% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the nucleotide sequence of the sense strand is at least 98% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the nucleotide sequence of the sense strand is at least 99% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the nucleotide sequence of the sense strand is 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152.

[0239] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the nucleotide sequence of the sense strand consists of the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152.

[0240] Table 2 further identifies the target nucleic acid molecule within the cited reference GPAM mRNA transcript (SEQ ID NO: 1) targeted by each of the sense strands. As such, the disclosure further provides sense strands wherein the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5 e.g., no more than 3 (e.g., 0, 1, 2, or 3))) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152 and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3. or 1-2 nucleotides) at least partially complementary to the region contiguous (e.g., either at the 3 '-end, the 5 '-end, or both the 3' and 5 '-end) of the GPAM mRNA transcript targetedAttorney Docket No. 62801.94WO01by the select sense strand.

[0241] In some embodiments, the sense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the sense strand comprises at least 19 (e.g., 20.21.22. 23.24.25.26.27.28.29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the sense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2.

[0242] In some embodiments, the sense strand comprises from about 15-23 (e.g., 15-22, 15- 21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-21, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the sense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2.

[0243] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in Table 2 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in Table 2.

[0244] Table 2 further identifies the target nucleic acid molecule within the reference GPAMAttorney Docket No. 62801.94WO01mRNA transcript at least partially identical to each of the sense strands. As such, the disclosure further provides sense strands comprising at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29. 30 e.g., 19. 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially identical to the region contiguous (e.g., either at the 3 '-end, the 5 '-end, or both the 3' and 5 '-end) of the GPAM mRNA transcript identical to the select sense strand.

[0245] In some embodiments, the sense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in SEQ ID NOS: 4-152. In some embodiments, the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the sense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29. 30) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152.

[0246] In some embodiments, the sense strand comprises from about 15-23 (e.g., 15-22, 15- 21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-21, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23. 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the sense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from theAttorney Docket No. 62801.94WO01nucleotide sequence set forth in any one of SEQ ID NOS: 4-152.

[0247] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152.

[0248] As described above, Table 2 further identifies the target nucleic acid molecule within the reference GPAM mRNA transcript at least partially identical to each of the sense strands. As such, disclosure further provides sense strands comprising at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152 and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially identical to the region contiguous (e.g., either at the 3 '-end, the 5 '-end, or both the 3' and 5 '-end) of the GPAM mRNA transcript identical to the select sense strand.

[0249] In some embodiments, the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149.

[0250] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149 differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the sense strand of any one of dsRNA agents 1-149. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand of any one of dsRNA agentsAttorney Docket No. 62801.94WO011-149. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149 differing by no more than 2 (e.g., 0, 1, or 2) nucleotides from the sense strand of any one of dsRNA agents 1-149. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149 differing by no more than 1 (e.g., 0 or 1) nucleotide from the sense strand of any one of dsRNA agents 1-149.

[0251] In some embodiments, the nucleotide sequence of the sense strand is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149. In some embodiments, the nucleotide sequence of the sense strand is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149. In some embodiments, the nucleotide sequence of the sense strand is at least 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149. In some embodiments, the nucleotide sequence of the sense strand is at least 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149. In some embodiments, the nucleotide sequence of the sense strand is at least 97% identical to the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149. In some embodiments, the nucleotide sequence of the sense strand is at least 98% identical to the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149. In some embodiments, the nucleotide sequence of the sense strand is at least 99% identical to the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149. In some embodiments, the nucleotide sequence of the sense strand is 100% identical to the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149.

[0252] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149. In some embodiments, the nucleotide sequence of the sense strand consists of the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149.

[0253] Table 2 further identifies the target nucleic acid molecule within the cited reference GPAM mRNA transcript (SEQ ID NO: 1) targeted by each of the sense strands. As such, the disclosure further provides sense strands wherein the nucleotide sequence of the sense strandAttorney Docket No. 62801.94WO01differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5 (e.g., no more than 3 (e.g., 0, 1, 2, or 3))) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149 and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially complementary to the region contiguous (e.g., either at the 3'-end, the 5'-end, or both the 3' and 5'-end) of the GPAM mRNA transcript targeted by the select sense strand.

[0254] In some embodiments, the sense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149 set forth in Table 2. In some embodiments, the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149 set forth in Table 2. In some embodiments, the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149 set forth in Table 2. In some embodiments, the sense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149 set forth in Table 2.

[0255] In some embodiments, the sense strand comprises from about 15-23 (e.g., 15-22, 15- 21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-21, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149 set forth in Table 2. In some embodiments, the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20. 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149 set forth in Table 2. In some embodiments, the sense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from theAttorney Docket No. 62801.94WO01nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149 set forth in Table 2.

[0256] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149 set forth in Table 2 differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the sense strand set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149 set forth in Table 2.

[0257] As described above, Table 2 further identifies the target nucleic acid molecule within the reference GPAM mRNA transcript at least partially identical to each of the sense strands. As such, disclosure further provides sense strands comprising at least 15 (e.g., 15, 16. 17. 18. 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-149 set forth in Table 2 and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially identical to the region contiguous (e.g., either at the 3'-end, the 5'-end, or both the 3' and 5'-end) of the GPAM mRNA transcript identical to the select sense strand.

[0258] In some embodiments, the sense strand comprises at least 15 (e.g., 16, 17, 18. 19. 20, 21) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from 350-388, 392-420, 430-482, 481-509, 508-536, 530-560, 606-634, 640-668, 668-704, 735-766, 768-796. 850-879, 871-923, 937-980, 1037-1067, 1077-1127, 1144-1172, 1187-1217, 1249-1277, 1269-1301, 1360-1398, 1430-1457, 1469-1501, 1613-1666, 1691-1816, 1894-2001, 1905-1945, 1946-1990, 2005-2038, 2095-2123, 2163-2191, 2291-2335, 2489-2517, 2620-2647, 2669-2702, 2894-2922. 2918-2946. 3083-3113, 3237-3265, 3318-3356. 3586-3624, 3676-3704, 3725-3769, 3836-3864, 3889-3930, 4325-4355, 4422-4451, 4511-4546, 5003-5035, 5501-5542, 5565-5593, 5662-5710, 5805-5835, or 6015-6043 of SEQ ID NO: 1. In some embodiments, the sense strand comprises at least 19 (e.g., 20, 21) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 350-388, 392-420, 430-482, 481-509, 508-536, 530-560, 606-634, 640-668. 668-704, 735-766. 768-796, 850-879, 871-923, 937-980, 1037-1067, 1077-1127, 1144-1172, 1187-1217, 1249-1277, 1269-1301, 1360-1398, 1430-1457, 1469-1501, 1613-Attorney Docket No. 62801.94WO011666, 1691-1816, 1894-2001, 1905-1945, 1946-1990, 2005-2038, 2095-2123, 2163-2191, 2291 -2335, 2489-2517, 2620-2647, 2669-2702, 2894-2922, 2918-2946, 3083-3113, 3237-3265, 3318-3356, 3586-3624, 3676-3704, 3725-3769. 3836-3864, 3889-3930, 4325-4355. 4422-4451, 4511-4546, 5003-5035, 5501-5542, 5565-5593, 5662-5710, 5805-5835, or 6015-6043 of SEQ ID NO: 1. In some embodiments, the sense strand comprises at least 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 350-388, 392-420. 430-482, 481-509, 508-536, 530-560, 606-634, 640-668, 668-704, 735-766, 768-796, 850-879, 871-923, 937-980, 1037-1067, 1077-1127, 1144-1172, 1187-1217, 1249-1277, 1269-1301, 1360-1398, 1430-1457, 1469-1501, 1613-1666, 1691-1816, 1894-2001, 1905-1945, 1946-1990, 2005-2038, 2095-2123, 2163-2191, 2291-2335, 2489-2517, 2620-2647, 2669-2702, 2894-2922, 2918-2946, 3083-3113. 3237-3265, 3318-3356, 3586-3624, 3676-3704. 3725-3769, 3836-3864, 3889-3930, 4325-4355, 4422-4451, 4511-4546, 5003-5035, 5501-5542, 5565-5593, 5662-5710, 5805-5835, or 6015-6043 of SEQ ID NO: 1.

[0259] In some embodiments, the sense strand comprises from about 15-23 (e.g., 15-22, 15- 21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-21, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) from nucleotides 350-388, 392-420, 430-482, 481-509, 508-536, 530-560, 606-634, 640-668, 668-704, 735-766, 768-796, 850-879. 871-923, 937-980, 1037-1067. 1077-1127, 1144-1172, 1187-1217, 1249-1277, 1269-1301, 1360-1398, 1430-1457, 1469-1501, 1613-1666, 1691-1816, 1894-2001, 1905-1945, 1946-1990, 2005-2038, 2095-2123, 2163-2191, 2291-2335, 2489-2517, 2620-2647. 2669-2702, 2894-2922, 2918-2946, 3083-3113. 3237-3265, 3318-3356, 3586-3624, 3676-3704, 3725-3769, 3836-3864, 3889-3930, 4325-4355, 4422-4451, 4511-4546, 5003-5035, 5501-5542, 5565-5593, 5662-5710, 5805-5835, or 6015-6043 of SEQ ID NO: 1. In some embodiments, the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23. 20- 22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 350-388, 392-420, 430-482, 481-509, 508-536, 530-560, 606-634, 640-668, 668-704, 735-766, 768-796, 850-879, 871-923, 937-980, 1037-1067, 1077-1127, 1144-1172, 1187-1217, 1249-1277, 1269-1301, 1360-1398, 1430-1457, 1469-1501, 1613-1666, 1691-1816. 1894-2001, 1905-1945, 1946-1990, 2005-2038. 2095-2123, 2163-2191, 2291-2335, 2489-2517, 2620-2647, 2669-2702, 2894-2922, 2918-2946, 3083-3113, 3237-3265, 3318-3356,Attorney Docket No. 62801.94WO013586-3624, 3676-3704, 3725-3769, 3836-3864, 3889-3930, 4325-4355, 4422-4451, 4511-4546, 5003-5035, 5501-5542, 5565-5593, 5662-5710, 5805-5835, or 6015-6043 of SEQ ID NO: 1. In some embodiments, the sense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 e.g., 0, 1, 2, or 3) nucleotides from nucleotides 350-388, 392-420, 430-482, 481-509, 508-536, 530-560, 606-634, 640-668, 668-704, 735-766, 768-796, 850-879, 871-923. 937-980, 1037-1067, 1077-1127, 1144-1172. 1187-1217. 1249-1277, 1269-1301, 1360-1398, 1430-1457, 1469-1501, 1613-1666, 1691-1816, 1894-2001, 1905-1945, 1946-1990, 2005-2038, 2095-2123, 2163-2191, 2291-2335, 2489-2517, 2620-2647, 2669-2702, 2894-2922, 2918-2946, 3083-3113, 3237-3265, 3318-3356, 3586-3624, 3676-3704, 3725-3769, 3836-3864, 3889-3930, 4325-4355, 4422-4451, 4511-4546, 5003-5035, 5501-5542, 5565-5593, 5662-5710, 5805-5835, or 6015-6043 of SEQ ID NO: 1.

[0260] As described above, Table 2 further identifies the target nucleic acid molecule within the reference GPAM mRNA transcript at least partially identical to each of the sense strands. As such, the disclosure further provides sense strands comprising at least 15 (e.g., 15. 16. 17. 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 350-388, 392-420, 430-482, 481-509, 508-536, 530-560, 606-634, 640-668, 668-704, 735-766, 768-796, 850-879, 871-923, 937-980, 1037-1067, 1077-1127, 1144-1172, 1187-1217, 1249-1277, 1269-1301, 1360-1398, 1430-1457, 1469-1501, 1613-1666, 1691-1816, 1894-2001, 1905-1945, 1946-1990, 2005-2038, 2095-2123, 2163-2191, 2291-2335, 2489-2517, 2620-2647, 2669-2702, 2894-2922, 2918-2946, 3083-3113, 3237-3265, 3318-3356, 3586-3624, 3676-3704, 3725-3769, 3836-3864, 3889-3930, 4325-4355, 4422-4451, 4511-4546. 5003-5035, 5501-5542, 5565-5593. 5662-5710, 5805-5835, or 6015-6043 of SEQ ID NO: 1 and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially identical to the region contiguous (e.g., either at the 3'-end, the 5'-end, or both the 3' and 5 '-end) of the GPAM mRNA transcript identical to the select sense strand.

[0261] It is to be understood, that although the sense strands set forth in Table 2 are not described as being modified (e.g., comprising chemically modified nucleotides), conjugated, etc., the disclosure includes any sense strand set forth in Table 2 that is unmodified, unconjugated, modified (e.g., as described herein), or conjugated (e.g., as described herein).4.2.3 dsRNA AgentsAttorney Docket No. 62801.94WO01

[0262] In some embodiments, the agent (e.g., RNAi agent) comprises a dsRNA agent comprising an antisense strand (e.g., described herein, e.g., described in § 4.2.1) and a sense strand (e.g., described herein, e.g., described in § 4.2.2) that hybridize to form a double stranded region (e.g., under conditions in which the dsRNA will be used (e.g., under physiological (e.g., mammalian, e.g., human) conditions within a cell)).

[0263] As described above, antisense strands (e.g., described herein) comprise a region of complementarity that comprises a nucleotide sequence that is at least partially (e.g., substantially, fully) complementary to the nucleotide sequence of a target nucleic acid molecule (e.g., a target mRNA (e.g., a GPAM mRNA), a portion of a target mRNA (e.g., a GPAM mRNA)); and the sense strands comprise a region of complementarity that comprises a nucleotide sequence that is at least partially (e.g., substantially, fully) complementary to the nucleotide sequence of at least a portion of an antisense strand.4.2.3.1 Single & Multiple Nucleic Acid Molecules

[0264] As described herein, and known in the art, the sense strand and the antisense strand can be part of a single larger nucleic acid molecule (connected as a single stranded nucleic acid molecule) or separate nucleic acid molecules (only connected through the double stranded region). In some embodiments, the sense strand and the antisense strand are separate nucleic acid molecules. In some embodiments, sense strand and the antisense strand are part of a single larger (e.g., longer) nucleic acid molecule.

[0265] In embodiments wherein the sense and antisense strands are part of a single nucleic acid molecule, the nucleic acid molecule may comprise a hairpin loop between the antisense strand and the sense strand to allow for formation of the double stranded region. In some embodiments, the hairpin loop comprises at least 1 (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20. 23. 25 or more) unpaired nucleotides (non-complementary nucleotide mismatches). In some embodiments, the hairpin loop comprises at least one but less than 25, 23, 20, 10, 9, 8, 7, 6, 5, 4, 3, or 2 unpaired nucleotides (non-complementary nucleotide mismatches). In some embodiments, the hairpin loop comprises about 25, 23, 20, 9, 8, 7, 6, 5, 4, 3, or 1 unpaired nucleotide (non-complementary nucleotide mismatch).

[0266] Without wishing to be bound by theory, in embodiments wherein the sense strand and the antisense strand are part of a single nucleic acid molecule, after introduction into a suitable cell (e.g., a mammalian cell, e.g., a human cell), the nucleic acid molecule may be cleaved into aAttorney Docket No. 62801.94WO01dsRNA molecule wherein the two strands of the dsRNA molecule are no longer part of the same nucleic acid molecule e.g., by a Type III endonuclease (e.g., Dicer) (see, e.g., Sharp et al. (2001) Genes Dev. 15:485, the entire contents of which are incorporated by herein by reference for all purposes).4.2.3.2 Length of Double Stranded Region

[0267] In some embodiments, the double stranded region is about 15-30 base pairs in length (e.g., 15-29, 15-28, 15-27, 15-26, 15-25. 15-24. 15-23. 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 base pairs in length). In some embodiments, the double stranded region is about 18-25 base pairs in length (e.g., 18-25, 18-24, 18-23. 18-22, 18-21, 18-20, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-25, 20-24, 20-23, 20-22, 20-21, 21-25, 21-24, 21-23, 21-22, 22-25, 22-24, 22-23, 23-25, 23-24 or 24-25 base pairs in length (e.g., 19-21 base pairs in length)). In some embodiments, the double stranded region is about 15-30, 15-29, 15-28, 15-27. 15-26. 15-25, 15-24, 15-23, 15-22, 15-21. 15-20, 15-19, 15-18, 15-17, 15-16, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-20, 19-21. 23-30, 23-29, 23-28, 23-27, 23-26, 23-25, 23-24, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 base pairs in length. In some embodiments, the double stranded region is about 19-21 (e.g., 19-20) base pairs in length.

[0268] In some embodiments, the double stranded region is not more than about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 base pairs in length. In some embodiments, the double stranded region is about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 base pairs in length. In some embodiments, the double stranded region is about 19, 20, or 21 base pairs in length. In some embodiments, the double stranded region is about 19 base pairs in length. In some embodiments, the double stranded region is about 20 base pairs in length. In some embodiments, the double stranded region is about 21 base pairs in length. In some embodiments, the double stranded region is about 23 base pairs in length. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.4.2.3.3 Nucleotide Overhangs & Blunt Ends

[0269] In some embodiments, the dsRNA agent comprises one or more (e.g., 1 or 2) nucleotide overhang. As is clear from the disclosure, but for the sake of clarity, the nucleotides of a nucleotideAttorney Docket No. 62801.94WO01overhang can include one or more a modified (e.g., chemically modified) nucleotide e.g., described herein, e.g., described in §§ 4.3, 4.3.1).

[0270] In some embodiments, the nucleotide overhang comprises from about 1-5 nucleotides, e.g., 1-4, 1-3, 1-2, 2-5, 2-4, 2-3, 3-5, 3-4, 4-5 nucleotides. In some embodiments, the nucleotide overhang comprises or consists of about 1, 2, 3, 4, or 5 nucleotides. In some embodiments, the nucleotide overhang comprises or consists of about 1 nucleotide. In some embodiments, the nucleotide overhang comprises or consists of about 2 nucleotides.

[0271] The nucleotide overhang(s) can be on the sense strand, the antisense strand, or both the sense strand and the antisense strand. In some embodiments, the sense strand comprises a nucleotide overhang. In some embodiments, the antisense strand comprises a nucleotide overhang. In some embodiments, the sense strand and the antisense strand both comprise a nucleotide overhang.

[0272] Furthermore, the nucleotide(s) of an overhang can be present on the 5'-end, 3'-end, or both the 5'-end, 3'-end of an antisense or sense strand. In some embodiments, the sense strand comprises a nucleotide overhang at the 5'-end. In some embodiments, the sense strand comprises a nucleotide overhang at the 3'-end. In some embodiments, the sense strand comprises a nucleotide overhang at the 5'-end and the 3'-end. In some embodiments, the antisense strand comprises a nucleotide overhang at the 5’-end. In some embodiments, the antisense strand comprises a nucleotide overhang at the 3'-end. In some embodiments, the antisense strand comprises a nucleotide overhang at the 5'-end and the 3'-end. In some embodiments, the antisense strand comprises a nucleotide overhang at the 3'-end; and the sense strand comprises a nucleotide overhang at the 3’-end. In some embodiments, the antisense strand comprises a nucleotide overhang at the 5'-end; and the sense strand comprises a nucleotide overhang at the 5'-end.

[0273] In some embodiments, the dsRNA agent comprises one or more blunt end. In some embodiments, the dsRNA agent comprises a blunt end at the end of the agent comprising the 3'-end of the sense strand and the 5'-end of the antisense strand. In some embodiments, the dsRNA agent comprises a blunt end at the end of the agent comprising the 5 '-end of the sense strand and the 3'-end of the antisense strand. In some embodiments, both ends of the dsRNA agent are blunt ends.4.2.3.4 Exemplary Structural Combinations of Sense & Antisense Strands

[0274] In some embodiments, the antisense strand and the sense strand contain the sameAttorney Docket No. 62801.94WO01number of nucleotides. In some embodiments, the antisense strand and the sense strand contain different numbers of nucleotides. In some embodiments, the nucleotide sequence of the sense strand is from about 1-5, 1-3. 1-4, or 1-2 nucleotides shorter than the nucleotide sequence of the antisense strand. In some embodiments, the nucleotide sequence of the sense strand is about 1, 2, 3, 4, or 5 nucleotides shorter than the nucleotide sequence of the antisense strand. In some embodiments, the nucleotide sequence of the sense strand is about 2 nucleotides shorter than the nucleotide sequence of the antisense strand. In some embodiments, the nucleotide sequence of the antisense strand is from about 1-5, 1-3, 1-4, or 1-2 nucleotides shorter than the nucleotide sequence of the sense strand. In some embodiments, the nucleotide sequence of the antisense strand is about 1, 2, 3, 4, or 5 nucleotides shorter than the nucleotide sequence of the sense strand. In some embodiments, the nucleotide sequence of the antisense strand is about 2 nucleotides shorter than the nucleotide sequence of the sense strand.

[0275] In some embodiments, the sense strand comprises or consists of 21 nucleotides. In some embodiments, the antisense strand comprises or consists of 23 nucleotides. In some embodiments, the sense strand comprises or consists of 21 nucleotides; and the antisense strand comprises or consists of 23 nucleotides. In some embodiments, the double stranded region comprises or consists of 21 nucleotides. In some embodiments, the antisense strand comprises a 2-nucleotide overhang at the 3'-end. In some embodiments, the 5'-end of the antisense strand and 3'-end of the sense strand form a blunt end. In some embodiments, the sense strand comprises or consists of 21 nucleotides; the antisense strand comprises or consists of 23 nucleotides; the double stranded region comprises or consists of 21 nucleotides; the antisense strand comprises a 2-nucleotide overhang at the 3 '-end; and the 5 '-end of the antisense strand and 3 '-end of the sense strand form a blunt end.

[0276] In some embodiments, the sense strand comprises or consists of 19 nucleotides. In some embodiments, the antisense strand comprises or consists of 21 nucleotides. In some embodiments, the sense strand comprises or consists of 19 nucleotides; and the antisense strand comprises or consists of 21 nucleotides. In some embodiments, the double stranded region comprises or consists of 19 nucleotides. In some embodiments, the antisense strand comprises a 2-nucleotide overhang at the 3'-end. In some embodiments, the 5'-end of the antisense strand and 3'-end of the sense strand form a blunt end. In some embodiments, the sense strand comprises or consists of 19 nucleotides; the antisense strand comprises or consists of 21 nucleotides; the double strandedAttorney Docket No. 62801.94WO01region comprises or consists of 19 nucleotides; the antisense strand comprises a 2-nucleotide overhang at the 3'-end; and the 5'-end of the antisense strand and 3'-end of the sense strand form a blunt end.

[0277] In some embodiments, the sense strand comprises or consists of 21 nucleotides. In some embodiments, the antisense strand comprises or consists of 21 nucleotides. In some embodiments, the sense strand comprises or consists of 21 nucleotides; and the antisense strand comprises or consists of 21 nucleotides. In some embodiments, the double stranded region comprises or consists of 19 nucleotides. In some embodiments, the antisense strand comprises a 2-nucleotide overhang at the 3 '-end. In some embodiments, the sense strand comprises a 2-nucleotide overhang at the 3'-end. In some embodiments, the sense strand comprises or consists of 21 nucleotides; the antisense strand comprises or consists of 21 nucleotides; the double stranded region comprises or consists of 19 nucleotides; the antisense strand comprises a 2-nucleotide overhang at the 3 '-end; and the sense strand comprises a 2-nucleotide overhang at the 3 '-end.

[0278] In some embodiments, the sense strand comprises or consists of 20 nucleotides. In some embodiments, the antisense strand comprises or consists of 19 nucleotides. In some embodiments, the sense strand comprises or consists of 20 nucleotides; and the antisense strand comprises or consists of 19 nucleotides. In some embodiments, the double stranded region comprises or consists of 20 nucleotides. In some embodiments, the sense strand comprises a 1-nucleotide overhang at the 5 '-end. In some embodiments, the 5 '-end of the antisense strand and 3 '-end of the sense strand form a blunt end. In some embodiments, the sense strand comprises or consists of 20 nucleotides; the antisense strand comprises or consists of 19 nucleotides; the double stranded region comprises or consists of 20 nucleotides: the sense strand comprises a 1-nucleotide overhang at the 5 '-end; and the 5 '-end of the antisense strand and 3 '-end of the sense strand form a blunt end.

[0279] In some embodiments, the sense strand comprises or consists of 21 nucleotides. In some embodiments, the antisense strand comprises or consists of 19 nucleotides. In some embodiments, the sense strand comprises or consists of 21 nucleotides; and the antisense strand comprises or consists of 19 nucleotides. In some embodiments, the double stranded region comprises or consists of 19 nucleotides. In some embodiments, the sense strand comprises a 1-nucleotide overhang at the 3 '-end. In some embodiments, the sense strand comprises a 1-nucleotide overhang at the 5'-end. In some embodiments, the sense strand comprises or consists of 21 nucleotides; the antisense strand comprises or consists of 19 nucleotides; the double stranded region comprises or consistsAttorney Docket No. 62801.94WO01of 19 nucleotides; the sense strand comprises a 1 -nucleotide overhang at the 3'-end; and the sense strand comprises a 1 -nucleotide overhang at the 5 '-end.

[0280] In some embodiments, the sense strand comprises or consists of 24 nucleotides. In some embodiments, the antisense strand comprises or consists of 23 nucleotides. In some embodiments, the sense strand comprises or consists of 24 nucleotides; and the antisense strand comprises or consists of 23 nucleotides. In some embodiments, the double stranded region comprises or consists of 21 nucleotides. In some embodiments, the antisense strand comprises a 2-nucleotide overhang at the 3 '-end. In some embodiments, the sense strand comprises a 3-nucleotide overhang at the 3'-end. In some embodiments, the sense strand comprises or consists of 24 nucleotides; the antisense strand comprises or consists of 23 nucleotides; the double stranded region comprises or consists of 21 nucleotides; the antisense strand comprises a 2-nucleotide overhang at the 3'-end; and the sense strand comprises a 3-nucleotide overhang at the 3'-end.

[0281] In some embodiments, the sense strand comprises or consists of 19 nucleotides. In some embodiments, the antisense strand comprises or consists of 19 nucleotides. In some embodiments, the sense strand comprises or consists of 19 nucleotides; and the antisense strand comprises or consists of 19 nucleotides. In some embodiments, the double stranded region comprises or consists of 19 nucleotides. In some embodiments, the 5'-end of the antisense strand (and 3'-end of the sense strand) form a blunt end. In some embodiments, the 3'-end of the antisense strand (and 5'-end of the sense strand) form a blunt end. In some embodiments, the sense strand comprises or consists of 19 nucleotides; the antisense strand comprises or consists of 19 nucleotides; the double stranded region comprises or consists of 19 nucleotides; the 5 '-end of the antisense strand (and 3 '-end of the sense strand) form a blunt end; and the 3 '-end of the antisense strand (and 5 '-end of the sense strand) form a blunt end

[0282] In some embodiments, the antisense strand and the sense strand are part of the same larger nucleic acid molecule, wherein the nucleic acid molecule comprises or consists of 44 nucleotides, the antisense portion comprises or consists of 21 nucleotides, the sense strand portion of the nucleic acid molecule comprises 19 nucleotides, the double stranded region comprises or consists of 19 nucleotides, the antisense strand comprises a 2-nucleotide overhang at the 3'-end, and the intervening nucleotide sequence between the antisense strand and the sense strand comprises or consists of 4 unpaired nucleotides that create a hairpin loop.4.2.3.5 Exemplary Antisense Strands & Sense StrandsAttorney Docket No. 62801.94WO01

[0283] In some embodiments, the antisense strand is an antisense strand described herein. In some embodiments, the sense strand is a sense strand described herein. In some embodiments, the antisense strand is an antisense strand described in § 4.2.1. In some embodiments, the sense strand is a sense strand described in § 4.2.2. In some embodiments, the antisense strand is an antisense strand described in § 4.2.1; and the sense strand is a sense strand described in § 4.2.2. It is to be understood that any sense strand described herein (e.g., in § 4.2.2); and be utilized in combination with any antisense strand in a dsRNA agent described herein (e.g., in § 4.2.1). For the sake of clarity, the entire contents of in § 4.2.1 and § 4.2.2, are incorporated by reference into the instant section in § 4.2.3.5.

[0284] In some embodiments, the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3. 4, or 5) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2; and the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2; and the nucleotide sequence of the antisense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2; and the nucleotide sequence of the antisense strand differs by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence of any one of the sense strands set forth in Table 2; and the nucleotide sequence of the antisense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence of any one of the antisense strands set forth in Table 2.

[0285] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in Table 2 differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the sense strand set forth in Table 2; and the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2 differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides fromAttorney Docket No. 62801.94WO01the antisense strand set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in Table 2 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in Table 2; and the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in Table 2 differing by no more than 2 (e.g., 0, 1, or 2) nucleotides from the sense strand set forth in Table 2; and the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2 differing by no more than 2 (e.g., 0, 1, or 2) nucleotides from the antisense strand set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in Table 2 differing by no more than 1 (e.g., 0 or 1) nucleotide from the sense strand set forth in Table 2; and the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2 differing by no more than 1 (e.g., 0 or 1) nucleotide from the antisense strand set forth in Table 2.

[0286] In some embodiments, the nucleotide sequence of the sense strand is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2; and the nucleotide sequence of the antisense strand is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2; and the nucleotide sequence of the antisense strand is at least 90%. 91%, 92%, 93%, 94%, 95%, 96%, 97%. 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand is at least 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2; and the nucleotide sequence of the antisense strand is at least 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand is at least 96%,Attorney Docket No. 62801.94WO0197%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2; and the nucleotide sequence of the antisense strand is at least 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand is at least 97% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2; and the nucleotide sequence of the antisense strand is at least 97% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand is at least 98% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2; and the nucleotide sequence of the antisense strand is at least 98% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand is at least 99% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2; and the nucleotide sequence of the antisense strand is at least 99% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand is 100% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2; and the nucleotide sequence of the antisense strand is 100% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2.

[0287] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in Table 2; and the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand consists of the nucleotide sequence of any one of the sense strands set forth in Table 2; and the nucleotide sequence of the antisense strand consists of the nucleotide sequence of any one of the antisense strands set forth in Table 2.

[0288] In some embodiments, the antisense strand comprises at least 15 (e.g., 15. 16. 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2. In someAttorney Docket No. 62801.94WO01embodiments, the antisense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the antisense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2.

[0289] In some embodiments, the antisense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-21, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20. 15-19. 15-18, 15-17, 15-16, 16-22, 16-21, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19,Attorney Docket No. 62801.94WO0117-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the antisense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the antisense strand comprises from about from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the antisense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2.

[0290] In some embodiments, the antisense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23. 24. 25. 26, 27, 28, 29, or 30 (e.g., 19. 20. 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25. 26. 27. 28. 29. or 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the antisense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises or consists of 19, 20, 21, 22, 23, 24, 25, 26,Attorney Docket No. 62801.94WO0127, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1,2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises or consists of about 19. 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the antisense strand comprises or consists of about 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the antisense strand comprises or consists of about 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2. In some embodiments, the antisense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises or consists of about 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2.

[0291] In some embodiments, the nucleotide sequence of the antisense strand comprises orAttorney Docket No. 62801.94WO01consists of the nucleotide sequence of any one of the antisense strands set forth in Table 2 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in Table 2; and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of any one of the sense strands set forth in Table 2 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in Table 2.

[0292] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of any one of the sense strands set forth in Table 2.

[0293] In some embodiments, the antisense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21. 22, 23, 24, 25. 26, 27, 28, 29. 30 (e.g., 19, 20, 21. 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises at least 15 (e.g., 15, 16, 17. 18. 19. 20. 21, 22, 23, 24, 25, 26, 27, 28. 29. 30 (e.g., 19. 20. 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2. In some embodiments, the antisense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forthAttorney Docket No. 62801.94WO01in Table 2; and the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2. In some embodiments, the antisense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2.

[0294] In some embodiments, the antisense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19. 15-18, 15-17, 15-16, 16-22, 16-21, 16-20. 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-21, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2. In some embodiments, the antisense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20- 22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2. In some embodiments, the antisense strand comprises from about from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2. In some embodiments,Attorney Docket No. 62801.94WO01the antisense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2.

[0295] In some embodiments, the antisense strand comprises or consists of about 15. 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2. In some embodiments, the antisense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises or consists of 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2. In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises or consists of about 19. 20. 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2. In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2. In some embodiments, the antisense strandAttorney Docket No. 62801.94WO01comprises or consists of about 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1,2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2. In some embodiments, the antisense strand comprises or consists of about 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2. In some embodiments, the antisense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the sense strand comprises or consists of about 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2.

[0296] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence of any one of the antisense strands set forth in Table 2 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in Table 2; and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of the corresponding sense strand set forth in Table 2 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding sense strand set forth in Table 2.

[0297] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence of any one of the antisense strands set forth in Table 2; and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of the corresponding sense strand set forth in Table 2.

[0298] In some embodiments, the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152; and the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301 differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301.Attorney Docket No. 62801.94WO01In some embodiments, the nucleotide sequence of the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152; and the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 2 e.g., 0, 1, or 2) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152; and the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301 differing by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152; and the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301 differing by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301.

[0299] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152 differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152; and the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152 differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152; and the nucleotide sequence of the antisense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152 differing by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152; and the nucleotide sequence of the antisense strand differs by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152 differing byAttorney Docket No. 62801.94WO01no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152; and the nucleotide sequence of the antisense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301.

[0300] In some embodiments, the nucleotide sequence of the sense strand is at least 85%, 86%, 87%, 88%, 89%. 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152; and the nucleotide sequence of the antisense strand is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the nucleotide sequence of the sense strand is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152; and the nucleotide sequence of the antisense strand is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the nucleotide sequence of the sense strand is at least 95%, 96%, 97%. 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152; and the nucleotide sequence of the antisense strand is at least 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the nucleotide sequence of the sense strand is at least 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152; and the nucleotide sequence of the antisense strand is at least 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the nucleotide sequence of the sense strand is at least 97% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152; and the nucleotide sequence of the antisense strand is at least 97% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the nucleotide sequence of the sense strand is at least 98% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152; and the nucleotide sequence of the antisense strand is at least 98% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the nucleotide sequence of the sense strand is at least 99% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152; and the nucleotide sequence of the antisense strand is at least 99% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301. In some embodiments, the nucleotide sequence of the sense strand is 100% identical toAttorney Docket No. 62801.94WO01the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152; and the nucleotide sequence of the antisense strand is 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 153-301.

[0301] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152; and the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS; 153-301. In some embodiments, the nucleotide sequence of the sense strand consists of the nucleotide sequence set forth in any one of SEQ ID NOS: 4-152; and the nucleotide sequence of the antisense strand consists of the nucleotide sequence set forth in any one of SEQ ID NOS; 153-301.

[0302] In some embodiments, the antisense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21. 22, 23, 24, 25. 26, 27, 28, 29. 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises at least 15 (e.g., 15. 16. 17. 18, 19, 20, 21, 22, 23, 24, 25. 26. 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the antisense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26. 27. 28. 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30Attorney Docket No. 62801.94WO01(e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises at least 21 (e.g., 22, 23. 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the antisense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-152.

[0303] In some embodiments, the antisense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19. 15-18. 15-17, 15-16, 16-22, 16-21, 16-20. 16-19. 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-21, 16-20. 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the antisense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21. 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises from about 19-23 (e.g., 19-22. 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the antisense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from theAttorney Docket No. 62801.94WO01nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises from about 19-23 {e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 {e.g., 0, 1. 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the antisense strand comprises from about 21-23 e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises from about 21-23 {e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-152.

[0304] In some embodiments, the antisense strand comprises or consists of about 15. 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 {e.g., 19, 20, 21, 22, 23 {e.g., 23)) contiguous nucleotides differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 {e.g., 19, 20, 21, 22, 23 {e.g., 21)) contiguous nucleotides differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the antisense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27. 28. 29, 30 {e.g., 19, 20, 21, 22, 23 {e.g., 23)) contiguous nucleotides differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises or consists of 19. 20. 21, 22, 23, 24, 25, 26. 27, 28, 29, 30 {e.g., 19, 20, 21, 22, 23 {e.g., 21)) contiguous nucleotides differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 {e.g., 21, 22, 23 {e.g., 23)) contiguous nucleotides differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 {e.g., 19, 20, 21, 22, 23 {e.g., 21)) contiguous nucleotides differing by no more than 3 {e.g., 0. 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-Attorney Docket No. 62801.94WO01152. In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the antisense strand comprises or consists of about 23, 24, 25, 26, 27. 28, 29, 30 (e.g., 23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28. 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the antisense strand comprises or consists of about 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-152. In some embodiments, the antisense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises or consists of about 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-152.

[0305] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in any one of SEQ ID NOS: 153-301; and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-152 differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from the sense strand set forth in any one of SEQ ID NOS: 4-152.Attorney Docket No. 62801.94WO01

[0306] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301: and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-152.

[0307] In some embodiments, the antisense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21. 22, 23, 24, 25. 26, 27, 28, 29. 30 (e.g., 19, 20, 21. 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-152). In some embodiments, the antisense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-152). In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-152). In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., asAttorney Docket No. 62801.94WO01set forth in one of SEQ ID NOS: 4-152). In some embodiments, the antisense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises at least 21 e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-152).

[0308] In some embodiments, the antisense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-21, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23. 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19. 15-18. 15-17, 15-16, 16-22, 16-21, 16-20. 16-19. 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-152). In some embodiments, the antisense strand comprises from about 19-23 (e.g., 19-22, 19-21. 19-20. 20-23. 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21. 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-152). In some embodiments, the antisense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-152). In some embodiments, the antisense strand comprisesAttorney Docket No. 62801.94WO01from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-152).

[0309] In some embodiments, the antisense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises or consists of about 15, 16. 17, 18, 19, 20, 21, 22, 23, 24, 25. 26, 27, 28, 29, or 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-152). In some embodiments, the antisense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises or consists of 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-152). In some embodiments, the antisense strand comprises or consists of about 21, 22, 23. 24, 25, 26, 27, 28. 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises or consists of about 19, 20, 21, 22, 23. 24, 25. 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-152). In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strandAttorney Docket No. 62801.94WO01comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand e.g., as set forth in one of SEQ ID NOS: 4-152). In some embodiments, the antisense strand comprises or consists of about 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-152). In some embodiments, the antisense strand comprises or consists of about 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-152). In some embodiments, the antisense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the sense strand comprises or consists of about 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-152).

[0310] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in any one of SEQ ID NOS: 153-301; and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-152) differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in any one of SEQ ID NOS: 4-152.

[0311] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 153-301; and the nucleotide sequence of the sense strand comprises or consists of theAttorney Docket No. 62801.94WO01nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-152).

[0312] In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149; and the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0. 1, 2, 3. 4, or 5) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149; and the nucleotide sequence of the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149; and the nucleotide sequence of the sense strand differs by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149; and the nucleotide sequence of the sense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent.

[0313] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149 differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the antisense strand of any one of dsRNA agents 1-149; and the nucleotide sequence of the sense strand comprises the nucleotide sequence of the corresponding (the same) dsRNA agent differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand of any one of dsRNA agents 1-149; and the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strand of the corresponding (the same) dsRNA agent differing byAttorney Docket No. 62801.94WO01no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149 differing by no more than 2 (e.g., 0, 1, or 2) nucleotides from the antisense strand of any one of dsRNA agents 1-149; and the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands of the corresponding (the same) dsRNA agent differing by no more than 2 (e.g., 0, 1, or 2) nucleotides from the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149 differing by no more than 1 (e.g., 0 or 1) nucleotide from the antisense strand of any one of dsRNA agents 1-149; and the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strand of the corresponding (the same) dsRNA agent differing by no more than 1 (e.g., 0 or 1) nucleotide from the sense strand of the corresponding (the same) dsRNA agent.

[0314] In some embodiments, the nucleotide sequence of the antisense strand is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149; and the nucleotide sequence of the sense strand is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149; and the nucleotide sequence of the sense strand is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand is at least 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149; and the nucleotide sequence of the sense strand is at least 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand is at least 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands of any oneAttorney Docket No. 62801.94WO01of dsRNA agents 1-149; and the nucleotide sequence of the sense strand is at least 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand is at least 97% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149; and the nucleotide sequence of the sense strand is at least 97% identical to the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand is at least 98% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149; and the nucleotide sequence of the sense strand is at least 98% identical to the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand is at least 99% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149; and the nucleotide sequence of the sense strand is at least 99% identical to the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand is 100% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149; and the nucleotide sequence of the sense strand is 100% identical to the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent.

[0315] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149; and the nucleotide sequence of the sense strand comprises the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand consists of the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149; and the nucleotide sequence of the sense strand consists of the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent.

[0316] In some embodiments, the antisense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-149; and the sense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19. 20, 21, 22, 23, 24, 25, 26, 27, 28, 29. 30 (e.g., 19. 20. 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotidesAttorney Docket No. 62801.94WO01from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-149; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-149; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-149; and the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-149; and the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent.

[0317] In some embodiments, the antisense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-21, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23. 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNAAttorney Docket No. 62801.94WO01agents 1-149; and the sense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-21, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22. 18-21, 18-20, 18-19, 19-23, 19-22, 19-21. 19-20. 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-149; and the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-149; and the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-149; and the sense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent.

[0318] In some embodiments, the antisense strand comprises or consists of about 15, 16. 17, 18, 19, 20, 21. 22. 23. 24. 25, 26, 27, 28, 29, or 30 (e.g., 19. 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-149; and the sense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25,Attorney Docket No. 62801.94WO0126, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-149; and the sense strand comprises or consists of 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-149; and the sense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-149; and the sense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises or consists of about 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-149; and the sense strand comprises or consists of about 21, 22, 23, 24, 25. 26. 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises or consists of about 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-149; and the sense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides fromAttorney Docket No. 62801.94WO01the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-149; and the sense strand comprises or consists of about 19 contiguous nucleotides differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent.

[0319] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-149 differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in any one of the dsRNA agents 1-149; and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent differing by no more than 3 e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in the corresponding (the same) dsRNA agent.

[0320] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence the antisense strand of any one of dsRNA agents 1-149; and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent.

[0321] In some embodiments, the sense strand comprises at least 15 {e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from nucleotides 350-388, 392-420, 430-482, 481-509, 508-536, 530-560, 606-634, 640-668, 668-704, 735-766, 768-796. 850-879, 871-923, 937-980, 1037-1067, 1077-1127, 1144-1172, 1187-1217, 1249-1277, 1269-1301, 1360-1398, 1430-1457, 1469-1501, 1613-1666, 1691-1816, 1894-2001, 1905-1945, 1946-1990, 2005-2038, 2095-2123, 2163-2191, 2291-2335, 2489-2517, 2620-2647, 2669-2702. 2894-2922, 2918-2946, 3083-3113, 3237-3265. 3318-3356, 3586-3624, 3676-3704, 3725-3769, 3836-3864, 3889-3930, 4325-4355, 4422-4451, 4511-4546, 5003-5035, 5501-5542, 5565-5593, 5662-5710, 5805-5835, or 6015-6043 of SEQ ID NO: 1; and the antisense strand comprises at least 15 {e.g., 16, 17. 18. 19. 20, 21, 22, or 23) contiguous nucleotides differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises at least 19 {e.g., 20, 21) contiguous nucleotides differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from nucleotides 350-388, 392-420, 430-482, 481-509, 508-536, 530-560, 606-634, 640-668, 668-704, 735-766, 768-796. 850-879, 871-923, 937-980, 1037-1067. 1077-1127, 1144-1172, 1187-1217, 1249-1277, 1269-1301, 1360-1398, 1430-1457, 1469-1501, 1613-1666, 1691-1816, 1894-2001,Attorney Docket No. 62801.94WO011905-1945, 1946-1990, 2005-2038, 2095-2123, 2163-2191, 2291-2335, 2489-2517, 2620-2647, 2669-2702, 2894-2922, 2918-2946, 3083-3113, 3237-3265, 3318-3356, 3586-3624, 3676-3704, 3725-3769. 3836-3864, 3889-3930, 4325-4355, 4422-4451. 4511-4546, 5003-5035, 5501-5542, 5565-5593, 5662-5710, 5805-5835, or 6015-6043 of SEQ ID NO: 1; and the antisense strand comprises at least 19 (e.g., 20, 21, 22, or 23) contiguous nucleotides differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises at least 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 350-388, 392-420, 430-482, 481-509, 508-536, 530-560, 606-634, 640-668, 668-704, 735-766, 768-796, 850-879, 871-923, 937-980, 1037-1067, 1077-1127, 1144-1172, 1187-1217, 1249-1277, 1269-1301, 1360-1398, 1430-1457, 1469-1501, 1613-1666, 1691-1816, 1894-2001, 1905-1945. 1946-1990, 2005-2038, 2095-2123, 2163-2191, 2291-2335, 2489-2517, 2620-2647, 2669-2702, 2894-2922, 2918-2946, 3083-3113, 3237-3265, 3318-3356, 3586-3624, 3676-3704, 3725-3769, 3836-3864, 3889-3930. 4325-4355, 4422-4451, 4511-4546. 5003-5035, 5501-5542, 5565-5593. 5662-5710, 5805-5835, or 6015-6043 of SEQ ID NO: 1; and the antisense strand comprises at least 21 (e.g., 22 or 23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises at least 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 350-388, 392-420, 430-482, 481-509, 508-536, 530-560, 606-634, 640-668, 668-704, 735-766, 768-796, 850-879, 871-923, 937-980, 1037-1067, 1077-1127, 1144-1172, 1187-1217, 1249-1277, 1269-1301, 1360-1398, 1430-1457, 1469-1501, 1613-1666, 1691-1816, 1894-2001, 1905-1945. 1946-1990, 2005-2038, 2095-2123. 2163-2191, 2291-2335, 2489-2517, 2620-2647, 2669-2702, 2894-2922, 2918-2946, 3083-3113, 3237-3265, 3318-3356, 3586-3624, 3676-3704, 3725-3769, 3836-3864, 3889-3930, 4325-4355, 4422-4451, 4511-4546. 5003-5035, 5501-5542, 5565-5593. 5662-5710, 5805-5835, or 6015-6043 of SEQ ID NO: 1; and the antisense strand comprises at least 21 (e.g., 22 or 23) contiguous nucleotides differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises at least 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 350-388, 392-420, 430-482, 481-509. 508-536, 530-560, 606-634, 640-668. 668-704, 735-766, 768-796, 850-879, 871-923, 937-980, 1037-1067, 1077-1127, 1144-1172, 1187-1217,Attorney Docket No. 62801.94WO011249-1277, 1269-1301, 1360-1398, 1430-1457, 1469-1501, 1613-1666, 1691-1816, 1894-2001, 1905-1945, 1946-1990, 2005-2038, 2095-2123, 2163-2191, 2291-2335, 2489-2517, 2620-2647, 2669-2702. 2894-2922, 2918-2946, 3083-3113, 3237-3265. 3318-3356, 3586-3624, 3676-3704, 3725-3769, 3836-3864, 3889-3930, 4325-4355, 4422-4451, 4511-4546, 5003-5035, 5501-5542, 5565-5593, 5662-5710, 5805-5835, or 6015-6043 of SEQ ID NO: 1; and the antisense strand comprises at least 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2.

[0322] In some embodiments, the sense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-21, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23. 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 350-388, 392-420, 430-482, 481-509, 508-536, 530-560, 606-634, 640-668, 668-704, 735-766, 768-796, 850-879, 871-923, 937-980, 1037-1067, 1077-1127. 1144-1172, 1187-1217, 1249-1277. 1269-1301, 1360-1398, 1430-1457. 1469-1501, 1613-1666, 1691-1816, 1894-2001, 1905-1945, 1946-1990, 2005-2038, 2095-2123, 2163-2191, 2291-2335, 2489-2517, 2620-2647, 2669-2702, 2894-2922, 2918-2946, 3083-3113, 3237-3265, 3318-3356, 3586-3624, 3676-3704, 3725-3769, 3836-3864, 3889-3930, 4325-4355, 4422-4451, 4511-4546, 5003-5035, 5501-5542, 5565-5593, 5662-5710, 5805-5835, or 6015-6043 of SEQ ID NO: 1; and the antisense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-21, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 350-388, 392-420, 430-482, 481-509, 508-536, 530-560, 606-634, 640-668, 668-704, 735-766, 768-796, 850-879, 871-923, 937-980, 1037-1067, 1077-1127, 1144-1172, 1187-1217, 1249-1277, 1269-1301, 1360-1398, 1430-1457, 1469-1501, 1613-1666, 1691-1816, 1894-2001, 1905-1945, 1946-1990, 2005-2038, 2095-2123, 2163-2191, 2291-2335, 2489-2517, 2620-2647, 2669-2702, 2894-2922, 2918-2946, 3083-3113, 3237-3265, 3318-3356. 3586-3624, 3676-3704, 3725-3769, 3836-3864, 3889-3930, 4325-4355, 4422-4451, 4511-4546, 5003-5035, 5501-Attorney Docket No. 62801.94WO015542, 5565-5593, 5662-5710, 5805-5835, or 6015-6043 of SEQ ID NO: 1; and the antisense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises from about from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from nucleotides 350-388. 392-420, 430-482, 481-509, 508-536, 530-560, 606-634, 640-668, 668-704, 735-766, 768-796, 850-879, 871-923, 937-980, 1037-1067, 1077-1127, 1144-1172, 1187-1217, 1249-1277, 1269-1301, 1360-1398, 1430-1457, 1469-1501, 1613-1666, 1691-1816, 1894-2001, 1905-1945, 1946-1990, 2005-2038, 2095-2123, 2163-2191, 2291-2335, 2489-2517, 2620-2647, 2669-2702, 2894-2922, 2918-2946, 3083-3113, 3237-3265, 3318-3356, 3586-3624, 3676-3704, 3725-3769. 3836-3864, 3889-3930, 4325-4355, 4422-4451, 4511-4546, 5003-5035, 5501-5542, 5565-5593, 5662-5710, 5805-5835, or 6015-6043 of SEQ ID NO: 1; and the antisense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23. 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from 350-388, 392-420, 430-482, 481-509, 508-536, 530-560, 606-634, 640-668, 668-704, 735-766, 768-796, 850-879, 871-923, 937-980, 1037-1067, 1077-1127, 1144-1172, 1187-1217, 1249-1277, 1269-1301, 1360-1398, 1430-1457, 1469-1501, 1613-1666, 1691-1816, 1894-2001, 1905-1945, 1946-1990, 2005-2038, 2095-2123, 2163-2191, 2291-2335, 2489-2517, 2620-2647. 2669-2702, 2894-2922, 2918-2946, 3083-3113. 3237-3265, 3318-3356, 3586-3624, 3676-3704, 3725-3769, 3836-3864, 3889-3930, 4325-4355, 4422-4451, 4511-4546, 5003-5035, 5501-5542, 5565-5593, 5662-5710, 5805-5835, or 6015-6043 of SEQ ID NO: 1; and the antisense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2.

[0323] In some embodiments, the sense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 350-388, 392-420, 430-482, 481-509, 508-536, 530-560, 606-634, 640-668, 668-704, 735-766, 768-796,Attorney Docket No. 62801.94WO01850-879, 871-923, 937-980, 1037-1067, 1077-1127, 1144-1172, 1187-1217, 1249-1277, 1269-1301, 1360-1398, 1430-1457, 1469-1501, 1613-1666, 1691-1816, 1894-2001, 1905-1945, 1946-1990, 2005-2038, 2095-2123, 2163-2191. 2291-2335, 2489-2517, 2620-2647. 2669-2702, 2894-2922, 2918-2946, 3083-3113, 3237-3265, 3318-3356, 3586-3624, 3676-3704, 3725-3769, 3836-3864, 3889-3930, 4325-4355, 4422-4451, 4511-4546, 5003-5035, 5501-5542, 5565-5593, 5662-5710. 5805-5835, or 6015-6043 of SEQ ID NO: 1; and the antisense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 e.g., 0, 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 e.g., 19, 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from nucleotides 350-388, 392-420, 430-482, 481-509, 508-536, 530-560, 606-634, 640-668, 668-704, 735-766, 768-796, 850-879, 871-923, 937-980, 1037-1067, 1077-1127, 1144-1172. 1187-1217, 1249-1277, 1269-1301. 1360-1398, 1430-1457, 1469-1501. 1613-1666, 1691-1816, 1894-2001, 1905-1945, 1946-1990, 2005-2038, 2095-2123, 2163-2191, 2291-2335, 2489-2517, 2620-2647, 2669-2702, 2894-2922, 2918-2946, 3083-3113, 3237-3265, 3318-3356, 3586-3624, 3676-3704, 3725-3769, 3836-3864, 3889-3930, 4325-4355, 4422-4451, 4511-4546, 5003-5035, 5501-5542, 5565-5593, 5662-5710, 5805-5835, or 6015-6043 of SEQ ID NO: 1; and the antisense strand comprises or consists of 19, 20. 21. 22. 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises or consists of about 21, 22, 23. 24, 25. 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 350-388, 392-420, 430-482, 481-509, 508-536, 530-560, 606-634, 640-668, 668-704. 735-766, 768-796, 850-879. 871-923, 937-980. 1037-1067, 1077-1127, 1144-1172, 1187-1217, 1249-1277, 1269-1301, 1360-1398, 1430-1457, 1469-1501, 1613-1666, 1691-1816, 1894-2001, 1905-1945, 1946-1990, 2005-2038, 2095-2123, 2163-2191, 2291-2335, 2489-2517, 2620-2647, 2669-2702, 2894-2922, 2918-2946, 3083-3113, 3237-3265, 3318-3356, 3586-3624, 3676-3704, 3725-3769, 3836-3864, 3889-3930, 4325-4355, 4422-4451, 4511-4546, 5003-5035. 5501-5542, 5565-5593, 5662-5710. 5805-5835, or 6015-6043 of SEQ ID NO: 1; and the antisense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30Attorney Docket No. 62801.94WO01(e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 350-388, 392-420, 430-482, 481-509, 508-536, 530-560, 606-634, 640-668, 668-704, 735-766, 768-796. 850-879, 871-923. 937-980, 1037-1067, 1077-1127, 1144-1172, 1187-1217, 1249-1277, 1269-1301, 1360-1398, 1430-1457, 1469-1501, 1613-1666, 1691-1816, 1894-2001, 1905-1945, 1946-1990, 2005-2038, 2095-2123, 2163-2191, 2291-2335, 2489-2517, 2620-2647, 2669-2702, 2894-2922, 2918-2946, 3083-3113, 3237-3265, 3318-3356, 3586-3624, 3676-3704, 3725-3769, 3836-3864, 3889-3930, 4325-4355, 4422-4451, 4511-4546. 5003-5035, 5501-5542, 5565-5593. 5662-5710, 5805-5835, or 6015-6043 of SEQ ID NO: 1; and the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises or consists of about 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 350-388, 392-420, 430-482, 481-509, 508-536, 530-560, 606-634, 640-668, 668-704, 735-766, 768-796, 850-879, 871-923, 937-980, 1037-1067, 1077-1127, 1144-1172, 1187-1217, 1249-1277. 1269-1301, 1360-1398, 1430-1457, 1469-1501. 1613-1666, 1691-1816, 1894-2001, 1905-1945, 1946-1990, 2005-2038, 2095-2123, 2163-2191, 2291-2335, 2489-2517, 2620-2647, 2669-2702, 2894-2922, 2918-2946, 3083-3113, 3237-3265, 3318-3356, 3586-3624, 3676-3704, 3725-3769. 3836-3864, 3889-3930, 4325-4355, 4422-4451. 4511-4546, 5003-5035, 5501-5542, 5565-5593, 5662-5710, 5805-5835, or 6015-6043 of SEQ ID NO: 1; and the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises or consists of about 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 350-388, 392-420, 430-482, 481-509, 508-536, 530-560, 606-634, 640-668, 668-704, 735-766, 768-796, 850-879, 871-923, 937-980, 1037-1067, 1077-1127. 1144-1172, 1187-1217, 1249-1277, 1269-1301. 1360-1398, 1430-1457, 1469-1501, 1613-1666, 1691-1816, 1894-2001, 1905-1945, 1946-1990, 2005-2038, 2095-2123, 2163-2191,Attorney Docket No. 62801.94WO012291-2335, 2489-2517, 2620-2647, 2669-2702, 2894-2922, 2918-2946, 3083-3113, 3237-3265, 3318-3356, 3586-3624, 3676-3704, 3725-3769, 3836-3864, 3889-3930, 4325-4355, 4422-4451, 4511-4546. 5003-5035, 5501-5542, 5565-5593. 5662-5710, 5805-5835, or 6015-6043 of SEQ ID NO: 1; and the antisense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 350-388, 392-420, 430-482, 481-509, 508-536, 530-560, 606-634, 640-668, 668-704, 735-766, 768-796, 850-879, 871-923, 937-980, 1037-1067, 1077-1127, 1144-1172, 1187-1217, 1249-1277, 1269-1301, 1360-1398, 1430-1457, 1469-1501, 1613-1666, 1691-1816, 1894-2001, 1905-1945, 1946-1990, 2005-2038, 2095-2123, 2163-2191. 2291-2335, 2489-2517, 2620-2647, 2669-2702, 2894-2922, 2918-2946, 3083-3113, 3237-3265, 3318-3356, 3586-3624, 3676-3704, 3725-3769, 3836-3864, 3889-3930, 4325-4355, 4422-4451, 4511-4546, 5003-5035. 5501-5542, 5565-5593, 5662-5710. 5805-5835, or 6015-6043 of SEQ ID NO: 1; and the antisense strand comprises or consists of about 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2.4.2.3.6 Exemplary dsRNA Agents

[0324] The nucleotide sequence of exemplary unmodified dsRNA agents comprising a sense and antisense strand (e.g., suitable for targeting hGPAM, suitable for inhibiting hGPAM expression)) are set forth in Table 2. More specifically, Table 2 sets forth the nucleotide sequence of exemplary sense strands, antisense strands, and dsRNA agent pairs of sense and antisense strands. It is to be understood that while the sense and antisense strands are set forth in pairs in Table 2, the...

Claims

Attorney Docket No. 62801.94WO01CLAIMSWhat is claimed is:

1. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM) (e.g., human GPAM (hGPAM)), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region,wherein the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1. 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or set forth in any one of SEQ ID NOS: 153-301.

2. The dsRNA agent of claim 1, wherein the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or the corresponding sense strand set forth in any one of SEQ ID NOS: 4-152.

3. The dsRNA agent of claim 1 or 2, wherein the nucleotide sequence of the antisense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or set forth in any one of SEQ ID NOS: 153-301; and the nucleotide sequence of the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or the corresponding sense strand set forth in one of SEQ ID NOS: 4-152.

4. The dsRNA agent of any one of claims 1-3, wherein the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2 or set forth in any one of SEQ ID NOS: 153-301; and the nucleotide sequence of the sense strand comprises the nucleotide sequence of the corresponding sense strand set forth in Table 2 or the corresponding sense strand set forth in one of SEQ ID NOS: 4-152.

5. A dsRNA agent for inhibiting expression of GPAM (e.g., hGPAM),wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, andwherein the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149 set forth in Table 2; andAttorney Docket No. 62801.94WO01the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the sense strand of the corresponding dsRNA agent set forth in Table 2.

6. The dsRNA agent of claim 5, wherein the nucleotide sequence of the antisense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149 set forth in Table 2; and the nucleotide sequence of the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding dsRNA agent set forth in Table 2.

7. A dsRNA agent for inhibiting expression of GPAM (e.g., hGPAM),wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, andwherein the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3. 4 or 5 (e.g., 3 (e.g., 0. 1, 2, or 3))) nucleotides from nucleotides 350-388, 392-420, 430-482, 481-509, 508-536, 530-560, 606-634, 640-668, 668-704, 735-766, 768-796, 850-879, 871-923, 937-980, 1037-1067, 1077-1127, 1144-1172, 1187-1217, 1249-1277, 1269-1301, 1360-1398, 1430-1457, 1469-1501, 1613-1666, 1691-1816, 1894-2001, 1905-1945, 1946-1990, 2005-2038, 2095-2123, 2163-2191, 2291-2335, 2489-2517, 2620-2647, 2669-2702, 2894-2922, 2918-2946, 3083-3113. 3237-3265, 3318-3356, 3586-3624, 3676-3704, 3725-3769, 3836-3864, 3889-3930, 4325-4355, 4422-4451, 4511-4546, 5003-5035, 5501-5542, 5565-5593, 5662-5710, 5805-5835, or 6015-6043 of SEQ ID NO: 1;wherein the nucleotide sequence of the antisense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5 (e.g., 2 or 3)) nucleotides from the nucleotide sequence of the corresponding complementary nucleotide sequence of SEQ ID NO: 2.

8. The dsRNA agent of claim 7, wherein the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5 (e.g., 3 (e.g., 0, 1, 2, or 3))) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or set forth in any one of SEQ ID NOS: 153-301.Attorney Docket No. 62801.94WO019. The dsRNA agent of claim 7 or 8, wherein the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or set forth in any one of SEQ ID NOS: 4-152.

10. A dsRNA agent for inhibiting expression of GPAM (e.g., hGPAM),wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region,wherein the nucleotide sequence of the antisense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or set forth in any one of SEQ ID NOS: 153-301.

11. The dsRNA agent of claim 10, wherein the nucleotide sequence of the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or the corresponding sense strand set forth in one of SEQ ID NOS: 4-152.

12. The dsRNA agent of claim 10 or 11, wherein the nucleotide sequence of the antisense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or set forth in any one of SEQ ID NOS: 153-301; and wherein the nucleotide sequence of the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or the corresponding sense strand set forth in one of SEQ ID NOS: 4-152.

13. The dsRNA agent of any one of claims 10-12, wherein the nucleotide sequence of the antisense strand comprises at least 21 (e.g., 21, 22, or 23) contiguous nucleotides of the nucleotide sequence of any one of the antisense strands set forth in Table 2 or set forth in any one of SEQ ID NOS: 153-301; and wherein the nucleotide sequence of the sense strand comprises at least 18 (e.g., 18, 19, 20, 21) contiguous nucleotides of the nucleotide sequence of the corresponding sense strand set forth in Table 2 or the corresponding sense strand set forth in one of SEQ ID NOS: 4-152.

14. A dsRNA agent for inhibiting expression of GPAM (e.g., hGPAM),Attorney Docket No. 62801.94WO01wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region,wherein the nucleotide sequence of the antisense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strand of any one of dsRNA agents 1-149.

15. The dsRNA agent of claim 14, wherein the nucleotide sequence of the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the corresponding sense strand of the dsRNA agent.

16. The dsRNA agent of claim 14 or 15, wherein the nucleotide sequence of the antisense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strand of any one of dsRNA agents 1-149: and wherein the nucleotide sequence of the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand of the dsRNA agent.

17. The dsRNA agent of any one of claims 14-16, wherein the nucleotide sequence of the antisense strand comprises at least 21 (e.g., 21, 22, or 23) contiguous nucleotides of the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-149; and wherein the nucleotide sequence of the sense strand comprises at least 18 (e.g., 18, 19, 20, 21) contiguous nucleotides of the nucleotide sequence of the corresponding sense strand of the dsRNA agent.

18. The dsRNA agent of any one of the preceding claims, wherein the sense strand comprises at least one modified nucleotide and / or the antisense strand comprises at least one modified nucleotide.

19. The dsRNA agent of any one of the preceding claims, wherein at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the nucleotides of the sense strand and / or antisense strand are modified.

20. The dsRNA agent of any one of the preceding claims, wherein substantially all (or all) of the nucleotides in the sense strand and / or antisense strand are modified.Attorney Docket No. 62801.94WO0121. The dsRNA agent of any one of the preceding claims, wherein at least one of the modified nucleotides comprises a modified sugar (e.g., ribose moiety).

22. The dsRNA agent of any one of the preceding claims, wherein at least one of the modified nucleotides comprises a modified nucleobase.

23. The dsRNA agent of any one of the preceding claims, wherein the sense strand comprises at least one modified internucleoside linkage and / or the antisense strand comprises at least one modified internucleoside linkage.

24. The dsRNA agent of any one of the preceding claims, wherein each of the antisense strand and the sense strand are not more than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 nucleotides in length.

25. The dsRNA agent of any one of the preceding claims, wherein the antisense strand comprises from about 15-30, 16-30, 17-30, 18-30, 19-30, 20-30, 21-30, 22-30, 23-30, 24-30, 25-30, 26-30, 27-30, 28-30, 29-30, 19-20, 19-21, 19-22, 19-23, 19-24, or 19-25 nucleotides; and / or the sense strand comprises from about 15-30, 16-30, 17-30, 18-30, 19-30, 20-30, 21-30, 22-30, 23-30, 24-30, 25-30, 26-30, 27-30, 28-30, 29-30, 19-20, 19-21, 19-22, 19-23, 19-24, or 19-25 nucleotides.

26. The dsRNA agent of any one of the preceding claims, wherein antisense strand comprises from about 19-23 nucleotides; and / or the sense strand comprises from about 19-23 nucleotides.

27. The dsRNA agent of any one of the preceding claims, wherein antisense strand comprises or consists of about 23 nucleotides; and / or the sense strand comprises or consists of about 21 nucleotides.

28. The dsRNA agent of any one of the preceding claims, wherein the sense strand and / or the antisense strand comprises a 3' and / or 5' overhang of 1, 2, or 3 nucleotides.

29. The dsRNA agent of any one of the preceding claims, wherein the antisense strand comprises a 3' overhang of 1. 2, or 3 nucleotides (e.g., 2 nucleotides).

30. The dsRNA agent of any one of the preceding claims, wherein the double stranded region is from about 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22. 19-20, 19-21, 23- 30, 23-29, 23-28, 23-27, 23-26, 23-25, 23-24, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotide pairs in length.

31. The dsRNA agent of any one of the preceding claims, wherein the double stranded region is from about 19-23 or 19-21 nucleotide pairs in length.Attorney Docket No. 62801.94WO0132. The dsRNA agent of any one of the preceding claims, wherein the double stranded region is about 21 nucleotide pairs in length.

33. The dsRNA agent of any one of the preceding claims, wherein the sense strand and the antisense strand are part of a single nucleic acid molecule (e.g., wherein a hairpin loop is between the sense strand and the antisense strand of the single nucleic acid molecule.

34. The dsRNA agent of any one of the preceding claims, wherein the sense strand and the antisense strand are separate nucleic acid molecules (z.e., connected only through the double stranded region).

35. A conjugate comprising the dsRNA agent of any one of claims 1-34 and a heterologous moiety.

36. The conjugate of claim 35, wherein the heterologous moiety is a peptide, protein, carbohydrate, lipid, polymer, or small molecule.

37. The conjugate of claim 36, wherein the heterologous moiety is carbohydrate.

38. The conjugate of claim 37, wherein the heterologous moiety comprises one or more GalNac.

39. The conjugate of claim 38, wherein the GalNac is triantennary GalNac.

40. The conjugate of any one of claims 35-39, wherein the heterologous moiety is a targeting moiety.

41. The conjugate of claim 40, wherein the targeting moiety specifically binds to a moiety expressed by hepatocytes (e.g., on the surface of the hepatocytes).

42. The conjugate of any one of claims 40-41, wherein the targeting moiety comprises GalNac.

43. The conjugate of claim 42, wherein the GalNac is triantennary GalNac.

44. The conjugate of any one of claims 40-43, wherein the targeting moiety directs the agent to hepatocytes through specific binding to the asialoglycoprotein receptor (e.g., expressed on the surface of hepatocytes).

45. The conjugate of any one of claims 35-44, wherein the heterologous moiety is attached to the dsRNA agent via a linker.

46. The conjugate of claim 45, wherein the linker is cleavable.Attorney Docket No. 62801.94WO0147. The conjugate of any one of claims 35-46, wherein the heterologous moiety attached to the 3 '-end of the sense and / or antisense strand and / or the 5 '-end of the sense and / or antisense strand, and / or at an internal site of the sense and / or antisense strand.

48. A vector (e.g., a viral vector, a non-viral vector) encoding the antisense strand, the sense strand, or both the antisense and sense strand of any one of claims 1-34.

49. A earner comprising the dsRNA agent of any one of claims 1-34 or the vector of claim 48.

50. The carrier of claim 49, wherein the carrier comprises a nanoparticle, a polymer, a lipid-based delivery system, a dendrimer, a cationic delivery system, or a hydrogel.

51. The carrier of claim 50, wherein the lipid-based delivery system is a lipid nanoparticle (LNP), liposome, lipoplex, nanoliposome, an exosome. or a micelle.

52. A cell (or population of cells) comprising the dsRNA of any one of claims 1-34, the conjugate of any one of claims 35-47, the vector of claim 48, or the carrier of any one of claims 49-51.

53. A pharmaceutical composition comprising the dsRNA of any one of claims 1-34, the conjugate of any one of claims 35-47, the vector of claim 48, the carrier of any one of claims 49-51, or the cell (or population of cells) of claim 52, and a pharmaceutically acceptable excipient.

54. A kit comprising the dsRNA of any one of claims 1-34, the conjugate of any one of claims 35-47, the vector of claim 48, the carrier of any one of claims 49-51, the cell (or population of cells) of claim 52, or the pharmaceutical composition of claim 53.

55. A method of delivering a dsRNA, conjugate, vector, carrier, or pharmaceutical composition to a cell, the method comprising introducing into a cell the dsRNA of any one of claims 1-34, the conjugate of any one of claims 35-47, the vector of claim 48, the carrier of any one of claims 49-51, or the pharmaceutical composition of claim 53, to thereby deliver the dsRNA, conjugate, vector, carrier, or pharmaceutical composition into the cell.

56. The method of claim 55, wherein the cell is in vitro, ex vivo, or in vivo.

57. The method of claim 55 or 56, wherein the cell is a subject (e.g., a human subject).

58. A method of delivering a dsRNA, conjugate, vector, carrier, or pharmaceutical composition to a subject, the method comprising administering to the subject the dsRNA of any one of claims 1-34, the conjugate of any one of claims 35-47, the vector of claim 48, the carrierAttorney Docket No. 62801.94WO01of any one of claims 49-51, or the pharmaceutical composition of claim 53, to thereby deliver the dsRNA, conjugate, vector, carrier, or pharmaceutical composition to the subject.

59. A method of reducing or inhibiting expression of GPAM (e.g., hGPAM) in a cell, the method comprising delivering into the cell the dsRNA of any one of claims 1-34, the conjugate of any one of claims 35-47, the vector of claim 48, the carrier of any one of claims 49-51, or the pharmaceutical composition of claim 53, to thereby reduce or inhibit expression of GPAM (e.g., hGPAM) in the cell.

60. A method of reducing or inhibiting expression of GPAM (e.g., hGPAM) in a cell in a subject, the method comprising administering to the subject the dsRNA of any one of claims 1-34, the conjugate of any one of claims 35-47, the vector of claim 48, the carrier of any one of claims 49-51, or the pharmaceutical composition of claim 53, to thereby reduce or inhibit expression of GPAM (e.g., hGPAM) in the cell in the subject.

61. A method of treating, ameliorating, or preventing a GPAM (e.g., hGPAM) associated disease in a subject, the method comprising administering to the subject the dsRNA of any one of claims 1-34, the conjugate of any one of claims 35-47, the vector of claim 48, the carrier of any one of claims 49-51, or the pharmaceutical composition of claim 53, to thereby treat, ameliorate, or prevent the GPAM (e.g., hGPAM) associated disease in the subject.

62. The method of claim 61, wherein the treating, ameliorating, or preventing of the GPAM (e.g., hGPAM) associated disease is mediated (at least in part) through the by reducing or inhibiting expression of GPAM (e.g., hGPAM) in the subject (e.g., a population of cells within the subject).

63. The method of claim 61 or 62, wherein the GPAM (e.g., hGPAM) associated disease is fatty liver disease, steatotic liver disease, liver inflammation, NASH, NAFLD, MASLD, MASH, MAFLD, MetALD, SLD, or cryptogenic SLD.

64. The method of claim 61 or 62, wherein the GPAM (e.g., hGPAM) associated disease is liver fibrosis, cirrhosis, liver failure, jaundice, AFLD, obesity-induced metabolic syndrome, insulin insensitivity, or type-2 diabetes.

65. A method of treating, ameliorating, or preventing a liver disease in a subject, the method comprising administering to the subject the dsRNA of any one of claims 1-34, the conjugate of any one of claims 35-47, the vector of claim 48. the carrier of any one of claims 49-51, or theAttorney Docket No. 62801.94WO01pharmaceutical composition of claim 53, to thereby treat, ameliorate, or prevent the liver disease in the subject.

66. The method of claim 65, wherein the treating, ameliorating, or preventing of the liver disease is mediated (at least in part) through the by reducing or inhibiting expression of GPAM (e.g., hGPAM) in the subject (e.g., a population of cells within the subject).

67. The method of claim 65 or 66, wherein the liver disease is fatty liver disease, steatotic liver disease, liver inflammation, NASH, NAFLD, MASLD, MASH, MAFLD, MetALD, SLD, or cryptogenic SLD.

68. The method of claim 65 or 66, wherein the GPAM (e.g., hGPAM) associated disease is liver fibrosis, cirrhosis, liver failure, jaundice, AFLD, obesity-induced metabolic syndrome, insulin insensitivity, or type-2 diabetes.

69. A method of diagnosing a GPAM (e.g., hGPAM) associated disease in a subject, the method comprising(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject;(b) detecting, or having detected, the presence or absence of one or more somatic GPAM mutation in the DNA, RNA, or protein,wherein the presence of the one or more somatic mutation indicates that the subject has a GPAM (e.g., hGPAM) associated disease.

70. The method of claim 69, wherein the GPAM e.g., hGPAM) associated disease is a liver disease.

71. The method of any one of claims 69-70, wherein the GPAM (e.g., hGPAM) associated disease is fatty liver disease, steatotic liver disease, liver inflammation, NASH, NAFLD, MASLD, MASH, MAFLD, MetALD, SLD, or cryptogenic SLD.

72. The method of any one of claims 69-70. wherein the GPAM (e.g., hGPAM) associated disease is liver fibrosis, cirrhosis, liver failure, jaundice, AFLD, obesity-induced metabolic syndrome, insulin insensitivity, or type-2 diabetes.

73. A method of diagnosing a liver disease in a subject, the method comprising(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject;Attorney Docket No. 62801.94WO01(b) detecting, or having detected, the presence or absence of one or more somatic GPAM mutation in the DNA, RNA, or protein,wherein the presence of the one or more somatic mutation indicates that the subject has a liver disease.

74. The method of claim 73, wherein the liver disease is fatty liver disease, steatotic liver disease, liver inflammation. NASH, NAFLD, MASLD, MASH. MAFLD, MetALD. SLD, or cryptogenic SLD.

75. The method of claim 73, wherein the liver disease is liver fibrosis, cirrhosis, liver failure, jaundice, AFLD, obesity-induced metabolic syndrome, insulin insensitivity, or type-2 diabetes.

76. The method of any one of claims 69-75, wherein (a) comprises isolating and purifying DNA, or having DNA isolated and purified, from a sample obtained from the subject; and (b) comprises detecting, or having detected, the presence or absence of the one or more somatic GPAM mutation in the DNA.

77. The method of any one of claims 69-76. further comprising administering to the subject an inhibitory nucleic acid molecule that inhibits expression of GPAM if a GPAM somatic mutation is detected in the DNA, RNA, or protein.

78. The method of claim 77, wherein the inhibitory nucleic acid molecule comprises the dsRNA of any one of claims 1-34, the conjugate of any one of claims 35-47, the vector of claim 48, the carrier of any one of claims 49-51, or the pharmaceutical composition of claim 53.

79. A method of selecting a subject for administration of an inhibitory nucleic acid molecule that inhibits expression of GPAM, the method comprising(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject;(b) detecting, or having detected, the presence or absence of one or more somatic GPAM mutation in the DNA, RNA, or protein,wherein the subject is selected for administration of the inhibitory nucleic acid molecule if the one or more somatic mutation is present.

80. The method of claim 79, wherein (a) comprises isolating and purifying DNA, or having DNA isolated and purified, from a sample obtained from the subject; and (b) comprises detecting, or having detected, the presence or absence of the one or more somatic GPAM mutation in the DNA.Attorney Docket No. 62801.94WO0181. The method of any one of claims 79-80, further comprising administering to the subject the inhibitory nucleic acid molecule if the subject is selected.

82. The method of claim 81, wherein the inhibitory nucleic acid molecule comprises the dsRNA of any one of claims 1-34, the conjugate of any one of claims 35-47, the vector of claim 48, the carrier of any one of claims 49-51, or the pharmaceutical composition of claim 53.

83. A method of treating, ameliorating, or preventing a GPAM (e.g., hGPAM) associated disease in a subject, the method comprising(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject;(b) detecting, or having detected, the presence or absence of one or more somatic GPAM mutation in the DNA, RNA, or protein, and(c) administering to the subject an inhibitory nucleic acid that inhibits expression of GPAM if the one or more GPAM somatic mutation is detected in the DNA, RNA, or protein.

84. The method of claim 83, wherein the GPAM (e.g., hGPAM) associated disease is a liver disease.

85. The method of any one of claims 83-84, wherein the liver disease is fatty liver disease, steatotic liver disease, liver inflammation, NASH, NAFLD, MASLD, MASH, MAFLD, MetALD, SLD, or cryptogenic SLD.

86. The method of any one of claims 83-84, wherein the liver disease is liver fibrosis, cirrhosis, liver failure, jaundice, AFLD, obesity-induced metabolic syndrome, insulin insensitivity, or type-2 diabetes.

87. A method of treating, ameliorating, or preventing a liver disease in a subject, the method comprising(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject;(b) detecting, or having detected, the presence or absence of one or more somatic GPAM mutation in the DNA, RNA, or protein, and(c) administering to the subject an inhibitory nucleic acid that inhibits expression of GPAM if the one or more GPAM somatic mutation is detected in the DNA, RNA, or protein.Attorney Docket No. 62801.94WO0188. The method of claim 87, wherein the liver disease is fatty liver, liver inflammation, NASH, NAFLD, obesity-induced metabolic syndrome, insulin insensitivity, obesity, type-2 diabetes, AFLD, cirrhosis, MASLD, MASH, MetALD, SLD, or cryptogenic SLD.

89. The method of claim 87, wherein the liver disease is liver fibrosis, cirrhosis, liver failure, jaundice, AFLD, obesity-induced metabolic syndrome, insulin insensitivity, or type-2 diabetes.

90. The method of any one of claims 83-89. wherein (a) comprises isolating and purifying DNA, or having DNA isolated and purified, from a sample obtained from the subject; and (b) comprises detecting, or having detected, the presence or absence of the one or more somatic GPAM mutation in the DNA.

91. The method of any one of claims 83-90, wherein the inhibitory nucleic acid molecule comprises the dsRNA of any one of claims 1-34, the conjugate of any one of claims 35-47, the vector of claim 48, the carrier of any one of claims 49-51, or the pharmaceutical composition of claim 53.

92. An in vitro method of screening a sample from a subject for one or more somatic GPAM mutation, the method comprising(a) isolating and purifying DNA, RNA, or protein from a sample obtained from the subject; and(b) detecting the presence or absence of one or more somatic GPAM mutation in the DNA, RNA, or protein.

93. The method of any one of claims 69-92, wherein the sample is a blood, tissue, or cell sample.

94. The method of any one of claims 69-93, wherein the sample is biopsy.

95. The method of any one of claims 69-94, wherein the sample is a liver biopsy.

96. The method of any one of claims 69-95, wherein at least one of the one or more somatic mutation is a loss of function mutation.

97. The method of any one of claims 69-96, wherein at least one of the one or more somatic mutation is a gain of function mutation.

98. The method of any one of claims 69-97, wherein the subject is a human.

99. A dsRNA of any one of claims 1-34, conjugate of any one of claims 35-47, vector of claim 48, carrier of any one of claims 49-51, cell (or population of cells) of claim 52, or pharmaceutical composition of claim 53 for use in a method of treating, ameliorating, orAttorney Docket No. 62801.94WO01preventing a GPAM associated disease (e.g., a GPAM associated disease described herein) in a subject.

100. A dsRNA of any one of claims 1-34, conjugate of any one of claims 35-47, vector of claim 48, carrier of any one of claims 49-51, cell (or population of cells) of claim 52, or pharmaceutical composition of claim 53 for use in a method of treating, ameliorating, or preventing a liver disease (e.g., a liver disease described herein) in a subject.

101. Use of a dsRNA of any one of claims 1-34, conjugate of any one of claims 35-47, vector of claim 48, carrier of any one of claims 49-51, cell (or population of cells) of claim 52, or pharmaceutical composition of claim 53 for the manufacture of a medicament for the treatment, amelioration, or prevention of a GPAM associated disease (e.g., a GPAM associated disease described herein) in a subject.

102. Use of a dsRNA of any one of claims 1-34, conjugate of any one of claims 35-47, vector of claim 48, carrier of any one of claims 49-51, cell (or population of cells) of claim 52, or pharmaceutical composition of claim 53 for the manufacture of a medicament for the treatment, amelioration, or prevention of a liver disease (e.g., a liver disease described herein) in a subject.

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