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),

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

wherein said antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of the complement of nucleotides 881-943 of SEQ ID NO: 1.

2. The dsRNA agent of claim 1 , wherein said dsRNA agent comprises at least one modified nucleotide.

3. The dsRNA agent of claim 2 , wherein the at least one of said modified nucleotides is selected from the group consisting of a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a 2′-deoxythymidine (dT) nucleotide, a nucleotide comprising a 5′-phosphorothioate group, and a terminal nucleotide linked to a cholesteryl derivative or a dodecanoic acid bisdecylamide group.

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

5. The dsRNA agent of claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide.

6. The dsRNA agent of claim 1 , further comprising a ligand.

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

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

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

(a) contacting the cell with the dsRNA agent of claim 1 or a pharmaceutical composition of claim 8 ; 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.

10. The method of claim 9 , wherein said cell is within a subject.

11. 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 or a pharmaceutical composition of claim 8 , thereby treating said subject.

12. The method of claim 11 , wherein the disorder is a disorder of lipid metabolism.

13. A method of inhibiting the expression of ANGPTL3 in a subject, the method comprising administering to said subject a therapeutically effective amount of the dsRNA agent of claim 1 or a pharmaceutical composition of claim 8 , thereby inhibiting the expression of ANGPTL3 in said subject.

14. A double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of Angiopoietin-like 3 (ANGPTL3),

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

wherein said antisense strand comprises at least 16 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of the complement of nucleotides 881-943 of SEQ ID NO: 1.

15. A double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of Angiopoietin-like 3 (ANGPTL3),

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

wherein said antisense strand comprises at least 17 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of the complement of nucleotides 881-943 of SEQ ID NO: 1.

16. The dsRNA agent of claim 1 , wherein each strand is independently 17-25 nucleotides in length.

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

18. The dsRNA agent of claim 1 , wherein each strand is independently 19-23 nucleotides in length.

19. The dsRNA agent of claim 1 , wherein the sense strand is 21 nucleotides in length and the antisense strand is 23 nucleotides in length.

20. The dsRNA agent of claim 1 , wherein the sense strand is 19 nucleotides in length and the antisense strand is 19 nucleotides in length.

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

22. The dsRNA agent of claim 1 , wherein the antisense strand comprises a nucleotide sequence selected from the group consisting of

5′-AAUUAAUGUCCAUGGACUACCUG-3′;

(SEQ ID NO: 1317)

5′-UUAAUGUCCAUGGACUACCUGAU-3′;

(SEQ ID NO: 1311)

5′-AUCCAUCUAUUCGAUGUUGAAUU-3′;

(SEQ ID NO: 1312)

5′-AUCUAUUCGAUGUUGAAUUAAUG-3′;

(SEQ ID NO: 1306)

5′-UAUUCGAUGUUGAAUUAAUGUCC-3′;

(SEQ ID NO: 1300)

5′-AUUCGAUGUUGAAUUAAUGUCCA-3′;

(SEQ ID NO: 1294)

5′-UUGAAUUAAUGUCCAUGGACUAC-3′;

(SEQ ID NO: 1277)

5′-UUCGAUGUUGAAUUAAUGUCCAU-3′;

(SEQ ID NO: 1288)

5′-UAAUGUCCAUGGACUACCUGAUA-3′;

(SEQ ID NO: 1305)

5′-UUUGUGAUCCAUCUAUUCGAUGU-3′;

(SEQ ID NO: 1318)

5′-UUUCAUUGAAGUUUUGUGAUCCA-3′;

(SEQ ID NO: 1289)

5′-UUCAUUGAAGUUUUGUGAUCCAU-3′;

(SEQ ID NO: 1283)

5′-AUUGAAGUUUUGUGAUCCAUCUA-3′;

(SEQ ID NO: 1278)

5′-AUCCAUCUAUUCGAUGUUG-3′;

(SEQ ID NO: 136)

5′-UUGAAUUAAUGUCCAUGGA-3′;

(SEQ ID NO: 124)

5′-UGUUGAAUUAAUGUCCAUG-3′;

(SEQ ID NO: 118)

5′-UCGAUGUUGAAUUAAUGUC-3′;

(SEQ ID NO: 95)

5′-AUUCGAUGUUGAAUUAAUG-3′;

(SEQ ID NO: 89)

5′-UGAAUUAAUGUCCAUGGAC-3′;

(SEQ ID NO: 84) and

5′-UUUGUGAUCCAUCUAUUCG-3′;

(SEQ ID NO: 121).

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

5′-GGUAGUCCAUGGACAUUAAUU-3′

(SEQ ID NO: 1136) and

5′-AAUUAAUGUCCAUGGACUACCUG-3′;

(SEQ ID NO: 1317)

5′-CAGGUAGUCCAUGGACAUUAA-3′

(SEQ ID NO: 1130) and

5′-UUAAUGUCCAUGGACUACCUGAU-3′;

(SEQ ID NO: 1311)

5′-UUCAACAUCGAAUAGAUGGAU-3′

(SEQ ID NO: 1131) and

5′-AUCCAUCUAUUCGAUGUUGAAUU-3′;

(SEQ ID NO: 1312)

5′-UUAAUUCAACAUCGAAUAGAU-3′

(SEQ ID NO: 1125) and

5′-AUCUAUUCGAUGUUGAAUUAAUG-3′;

(SEQ ID NO: 1306)

5′-ACAUUAAUUCAACAUCGAAUA-3′

(SEQ ID NO: 1119) and

5′-UAUUCGAUGUUGAAUUAAUGUCC-3′;

(SEQ ID NO: 1300)

5′-GACAUUAAUUCAACAUCGAAU-3′

(SEQ ID NO: 1116) and

5′-AUUCGAUGUUGAAUUAAUGUCCA-3′;

(SEQ ID NO: 1294)

5′-AGUCCAUGGACAUUAAUUCAA-3′

(SEQ ID NO: 1096) and

5′-UUGAAUUAAUGUCCAUGGACUAC-3′;

(SEQ ID NO: 1277)

5′-GGACAUUAAUUCAACAUCGAA-3′

(SEQ ID NO: 1107) and

5′-UUCGAUGUUGAAUUAAUGUCCAU-3′;

(SEQ ID NO: 1288)

5′-UCAGGUAGUCCAUGGACAUUA-3′

(SEQ ID NO: 1124) and

5′-UAAUGUCCAUGGACUACCUGAUA-3′;

(SEQ ID NO: 1305)

5′-AUCGAAUAGAUGGAUCACAAA-3′

(SEQ ID NO: 1137) and

5′-UUUGUGAUCCAUCUAUUCGAUGU-3′;

(SEQ ID NO: 1318)

5′-GAUCACAAAACUUCAAUGAAA-3′

(SEQ ID NO: 1108) and

5′-UUUCAUUGAAGUUUUGUGAUCCA-3′;

(SEQ ID NO: 1289)

5′-GGAUCACAAAACUUCAAUGAA-3′

(SEQ ID NO: 1102) and

5′-UUCAUUGAAGUUUUGUGAUCCAU-3′;

(SEQ ID NO: 1283)

5′-GAUGGAUCACAAAACUUCAAU-3′

(SEQ ID NO: 1097) and

5′-AUUGAAGUUUUGUGAUCCAUCUA-3′;

(SEQ ID NO: 1278)

5′-CAACAUCGAAUAGAUGGAU-3′

(SEQ ID NO: 74) and

5′-AUCCAUCUAUUCGAUGUUG-3′;

(SEQ ID NO: 136)

5′-UCCAUGGACAUUAAUUCAA-3′

(SEQ ID NO: 62) and

5′-UUGAAUUAAUGUCCAUGGA-3′;

(SEQ ID NO: 124)

5′-CAUGGACAUUAAUUCAACA-3′

(SEQ ID NO: 56) and

5′-UGUUGAAUUAAUGUCCAUG-3′;

(SEQ ID NO: 118)

5′-GACAUUAAUUCAACAUCGA-3′

(SEQ ID NO: 33) and

5′-UCGAUGUUGAAUUAAUGUC-3′;

(SEQ ID NO: 95)

5′-CAUUAAUUCAACAUCGAAU-3′

(SEQ ID NO: 27) and

5′-AUUCGAUGUUGAAUUAAUG-3′;

(SEQ ID NO: 89)

5′-GUCCAUGGACAUUAAUUCA-3′

(SEQ ID NO: 22) and

5′-UGAAUUAAUGUCCAUGGAC-3′;

(SEQ ID NO: 84) and

5′-CGAAUAGAUGGAUCACAAA-3′

(SEQ ID NO: 59) and

5′-UUUGUGAUCCAUCUAUUCG-3′;

(SEQ ID NO: 121).

24. The dsRNA agent of claim 6 , wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker.

25. The dsRNA agent of claim 24 , wherein the ligand is

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