Angiopoietin-like 3 (ANGPTL3) iRNA compositions and methods of use thereof

1. A double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of Angiopoietin-like 3 (ANGPTL3), comprising a sense strand and an antisense strand forming a duplex region,

wherein the antisense strand comprises at least 17 contiguous nucleotides which differ by no more than three nucleotides from nucleotides 1354-1422 of SEQ ID NO:1,

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

wherein at least one of the nucleotide modifications is selected from the group consisting of a 2′-O-methyl nucleotide modification, a 2′-fluoro nucleotide modification, and a nucleotide comprising a 5′-phosphorothioate group modification, and

wherein a ligand comprising an N-acetylgalactosamine (GalNAc) is conjugated to at least one strand of the dsRNA agent.

2. A double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of Angiopoietin-like 3 (ANGPTL3), comprising a sense strand and an antisense strand forming a duplex region,

wherein the antisense strand comprises at least 17 contiguous nucleotides which differ by no more than three nucleotides from nucleotides 1354-1410 of SEQ ID NO:1,

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

wherein at least one of the nucleotide modifications is selected from the group consisting of a 2′-O-methyl nucleotide modification, a 2′-fluoro nucleotide modification, and a nucleotide comprising a 5′-phosphorothioate group modification, and

wherein a ligand comprising an N-acetylgalactosamine (GalNAc) is conjugated to at least one strand of the dsRNA agent.

3. A double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of Angiopoietin-like 3 (ANGPTL3), comprising a sense strand and an antisense strand forming a duplex region,

wherein the antisense strand comprises at least 17 contiguous nucleotides which differ by no more than three nucleotides from nucleotides 1354-1406 of SEQ ID NO:1,

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

wherein at least one of the nucleotide modifications is selected from the group consisting of a 2′-O-methyl nucleotide modification, a 2′-fluoro nucleotide modification, and a nucleotide comprising a 5′-phosphorothioate group modification, and

wherein a ligand comprising an N-acetylgalactosamine (GalNAc) is conjugated to at least one strand of the dsRNA agent.

4. The dsRNA agent of claim 1 , wherein each strand is independently 19-25 nucleotides in length.

5. The dsRNA agent of claim 1 , wherein the duplex region is 15-30 base pairs in length.

6. The dsRNA agent of claim 1 , wherein the duplex region is 18-21 base pairs in length.

7. The dsRNA agent of claim 1 , wherein the duplex region is 20 base pairs in length.

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

9. The dsRNA of claim 1 , wherein the GalNAc (N-acetylgalactosamine) is conjugated to at least one strand of the dsRNA agent through a linker.

10. The dsRNA of claim 9 , wherein the GalNAc (N-acetylgalactosamine) is conjugated through a bivalent or trivalent branched linker.

11. The dsRNA of claim 9 , wherein the linker comprises C(O)NH.

12. The dsRNA of claim 11 , wherein the linker comprises between 1-24 atoms.

13. The dsRNA of claim 11 , wherein the linker comprises between 6-24 atoms.

14. The dsRNA agent of claim 1 , wherein the sense and antisense strands comprise nucleotide sequences selected from the group consisting of

(SEQ ID NO: 1182)

5′-UACUCUAUAAAAUCAACCAAAA-3′

and

(SEQ ID NO: 1363)

5′-UUUGGUUGAUUUUAUAGAGUAUA-3′;

(SEQ ID NO: 1177)

5′-AUACUCUAUAAAAUCAACCAA-3′

and

(SEQ ID NO: 1358)

5′-UUGGUUGAUUUUAUAGAGUAUAA-3′;

(SEQ ID NO: 1166)

5′-AUGGAAGGUUAUACUCUAUAA-3′

and

(SEQ ID NO: 1347)

5′-UUAUAGAGUAUAACCUUCCAUUU-3′;

(SEQ ID NO: 43)

5′-CAACCAAAAUGUUGAUCCA-3′

and

(SEQ ID NO: 105)

5′-UGGAUCAACAUUUUGGUUG-3′;

(SEQ ID NO: 28)

5′-CAAAAUGUUGAUCCAUCCA-3′

and

(SEQ ID NO: 90)

5′-UGGAUGGAUCAACAUUUUG-3′;

(SEQ ID NO: 1172)

5′-UGGAAGGUUAUACUCUAUAAA-3′

and

(SEQ ID NO: 1353)

5′-UUUAUAGAGUAUAACCUUCCAUU-3′;

(SEQ ID NO: 1160)

5′-GUCUCAAAAUGGAAGGUUAUA-3′

and

(SEQ ID NO: 1341)

5′-UAUAACCUUCCAUUUUGAGACUU-3′;

and

(SEQ ID NO: 1144)

5′-AUCCAUCCAACAGAUUCAGAA-3′

and

(SEQ ID NO: 325)

5′-UUCUGAAUCUGUUGGAUGGAUCA-3′.

15. An isolated cell containing the dsRNA agent of claim 1 .

16. A pharmaceutical composition for inhibiting expression of an ANGPTL3 gene, comprising the dsRNA agent of claim 1 .

17. The pharmaceutical composition of claim 16 , wherein the dsRNA agent is present in a buffered solution.

18. A method of inhibiting ANGPTL3 expression in a cell, the method comprising:

(a) contacting the cell with the dsRNA agent of claim 1 ; and

(b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of an ANGPTL3 gene, thereby inhibiting expression of the ANGPTL3 gene in the cell.

19. The method of claim 18 , wherein the cell is within a subject.

20. A method of inhibiting the expression of ANGPTL3 in a subject, the method comprising administering to the subject a therapeutically effective amount of the dsRNA agent of claim 1 , thereby inhibiting the expression of ANGPTL3 in the subject.

21. A method of treating a subject having a disorder that would benefit from reduction in ANGPTL3 expression, comprising administering to the subject a therapeutically effective amount of the dsRNA agent of claim 1 , thereby treating the subject.

22. The method of claim 21 , wherein the disorder is a disorder of lipid metabolism.

23. The method of claim 21 , wherein the disorder is selected from the group consisting of hypertriglyceridemia, obesity, hyperlipidemia, atherosclerosis, diabetes, cardiovascular disease, and coronary artery disease.

24. The method of claim 23 , wherein the disorder is hyperlipidemia.

25. The method of claim 21 , further comprising administering an additional therapeutic to the subject.

26. The method of claim 25 , wherein the additional therapeutic is a statin.

27. The method of claim 21 , wherein the administration of the dsRNA agent to the subject causes a decrease in one or more serum lipid.

28. The method of claim 21 , wherein the administration of the dsRNA agent to the subject causes a decrease in ANGPTL3 protein accumulation.

29. The method of claim 21 , wherein the subject is a human subject.