METABOLIC DISORDER-ASSOCIATED TARGET GENE IRNA COMPOSITIONS AND METHODS OF USE THEREOF

1 . A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of a metabolic disorder-associated target gene selected from the group consisting of inhibin subunit beta E (INHBE), activin A receptor type 1C (ACVR1C), perilipin-1 (PLIN1), phosphodiesterase 3B (PDE3B), and inhibin subunit beta C (INHBC) in a cell,

wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region,

a) wherein the metabolic disorder-associated target gene is INHBE and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the antisense strand nucleotide sequences selected from the group consisting of

SEQ ID NO: 6245

5′-AAAGACGGCAGAAUGGAAAGAGG-3′ of;

SEQ ID NO: 64

5′-AAGAAAGUAUAAAUGCUUGUCUC-3′ of;

SEQ ID NO: 63

5′-ACAGACAAGAAAGUGCCCAUUUG-3′ of;

SEQ ID NO: 58

5′-AGUUAUTCUGGGACGACUGGUCU-3′ of;

and

SEQ ID NO: 6403

5′-AAAGCCAGAGUCUCAGACAAGAA-3′ of.

 and

wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a nucleotide modification

b) wherein the metabolic disorder-associated target gene is INHBE and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than three nucleotides from the complement of any one of the nucleotide sequence of nucleotides 400-422, 1430-1452, 1863-1885, 410-432, 518-540, 519-541, 640-662, or 1864-1886 of SEQ ID NO: 1;

c) wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, or 55, and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the corresponding portion of the nucleotide sequence of any one of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, or 56;

d) wherein the antisense strand comprises a region of complementarity to an mRNA encoding the target gene, and wherein the region of complementarity comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the antisense nucleotide sequences in any one of Tables 2-17, 19 and 20.

2 .- 22 . (canceled)

23 . The dsRNA agent of claim 1 , wherein at least one of the nucleotides of the dsRNA agent comprises a nucleotide modification.

24 . (canceled)

25 . The dsRNA agent of claim 1 , wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a nucleotide modification.

26 . The dsRNA agent of claim 23 , wherein at least one of the nucleotide modifications is selected from the group consisting of a deoxy-nucleotide modification, a 3′-terminal deoxythimidine (dT) nucleotide modification, a 2′-O-methyl nucleotide modification, a 2′-fluoro nucleotide modification, a 2′-deoxy-nucleotide modification, a locked nucleotide modification, an unlocked nucleotide modification, a conformationally restricted nucleotide modification, a constrained ethyl nucleotide modification, an abasic nucleotide modification, a 2′-amino-nucleotide modification, a 2′-O-allyl-nucleotide modification, 2′-C-alkyl-nucleotide modification, 2′-hydroxly-nucleotide modification, a 2′-methoxyethyl nucleotide modification, a 2′-O-alkyl-nucleotide modification, a morpholino nucleotide modification, a phosphoramidate modification, a non-natural base comprising nucleotide modification, a tetrahydropyran nucleotide modification, a 1,5-anhydrohexitol nucleotide modification, a cyclohexenyl nucleotide modification, a nucleotide comprising a phosphorothioate group modification, a nucleotide comprising a methylphosphonate group modification, a nucleotide comprising a 5′-phosphate modification, a nucleotide comprising a 5′-phosphate mimic modification, a thermally destabilizing nucleotide modification, a glycol nucleotide (GNA) modification, a nucleotide comprising a 2′ phosphate modification, and a 2-O—(N-methylacetamide) nucleotide modification; and combinations thereof.

27 .- 30 . (canceled)

31 . The dsRNA agent of claim 1 , further comprising a phosphate or phosphate mimic at the 5′-end of the antisense strand.

32 . (canceled)

33 . The dsRNA agent of claim 1 , wherein the 3′ end of the sense strand is protected via an end cap which is a cyclic group having an amine, said cyclic group being selected from the group consisting of pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, [1,3]dioxolanyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, tetrahydrofuranyl, and decalinyl.

34 . The dsRNA agent of claim 1 , wherein the double stranded region is 19-30 nucleotide pairs in length.

35 .- 38 . (canceled)

39 . The dsRNA agent of claim 1 , wherein each strand is independently no more than 30 nucleotides in length.

40 .- 43 . (canceled)

44 . The dsRNA agent of claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide; or at least one strand comprises a 3′ overhang of at least 2 nucleotides.

45 . (canceled)

46 . The dsRNA agent of claim 1 , wherein one or more C22 hydrocarbon chains is conjugated to one or more internal positions on at least one strand.

47 .- 69 . (canceled)

70 . The dsRNA agent of claim 1 , further comprising a targeting ligand that targets a receptor which mediates delivery to adipose tissue.

71 . (canceled)

72 . The dsRNA agent of claim 1 , further comprising a targeting ligand that targets a liver tissue.

73 . The dsRNA agent of claim 72 , wherein the targeting ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent.

74 . The dsRNA agent of claim 72 , wherein the targeting ligand is an N-acetylgalactosamine (GalNAc) derivative.

75 . The dsRNA agent of claim 72 , wherein the targeting ligand is one or more GalNAc derivatives attached through a monovalent, bivalent, or trivalent branched linker.

76 . The dsRNA agent of claim 72 , wherein the targeting ligand is

77 . The dsRNA agent of claim 76 , wherein the dsRNA agent is conjugated to the targeting ligand as shown in the following schematic

and, wherein X is O or S.

78 . The dsRNA agent of claim 77 , wherein the X is O.

79 . (canceled)

80 . The dsRNA agent of claim 1 , wherein the dsRNA agent further comprises at least one phosphorothioate or methylphosphonate internucleotide linkage.

81 .- 121 . (canceled)

122 . A cell containing the dsRNA agent of claim 1 .

123 . A pharmaceutical composition for inhibiting expression of a metabolic disorder-associated target gene selected from the group consisting of inhibin subunit beta E (INHBE), activin A receptor type 1C (ACVR1C), perilipin-1 (PLIN1), phosphodiesterase 3B (PDE3B), and inhibin subunit beta C (INHBC) comprising the dsRNA agent of claim 1 and a pharmaceutically acceptable carrier.

124 .- 128 . (canceled)

129 . A method of inhibiting expression of a metabolic disorder-associated target gene selected from the group consisting of inhibin subunit beta E (INHBE), activin A receptor type 1C (ACVR1C), perilipin-1 (PLIN1), phosphodiesterase 3B (PDE3B), and inhibin subunit beta C (INHBC) in a cell, the method comprising contacting the cell with the dsRNA agent of claim 1 , thereby inhibiting expression of the metabolic disorder-associated target gene in the cell.

130 .- 144 . (canceled)

145 . A method of treating a subject having a metabolic disorder, comprising administering to the subject a therapeutically effective amount of the dsRNA agent of claim 1 , thereby treating the subject having the metabolic disorder.

146 .- 169 . (canceled)

170 . A kit, a vial, or a syringe comprising the dsRNA agent of claim 1 .

171 .- 173 . (canceled)