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,

wherein the antisense strand comprises at least 17 contiguous nucleotides of the nucleotide sequence 5′-AAGACUGAUCAAAUAUGUUGAGU-3′ (SEQ ID NO: 543);

wherein the sense strand comprises at least 17 contiguous nucleotides of the nucleotide sequence 5′-UCAACAUAUUUGAUCAGUCUU-3′ (SEQ ID NO: 358);

wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified nucleotides,

wherein the sense strand and the antisense strand form a double stranded region of at least 17 nucleotides in length;

wherein at least one of the modified nucleotides is selected from the group consisting of a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, an abasic nucleotide, and a 2′-amino modified nucleotide, and

wherein a ligand comprising an N-acetylgalactosamine (GalNAc) derivative 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,

wherein the antisense strand comprises at least 17 contiguous nucleotides of the nucleotide sequence 5′-AAAGACUGAUCAAAUAUGUUGAG-3′ (SEQ ID NO:1199); wherein the sense strand comprises at least 17 contiguous nucleotides of the nucleotide sequence of 5′-CAACAUAUUUGAUCAGUCUUU-3′ (SEQ ID NO:1018);

wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified nucleotides,

wherein the sense strand and the antisense strand form a double stranded region of at least 17 nucleotides in length,

wherein at least one of the modified nucleotides is selected from the group consisting of a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, an abasic nucleotide, and a 2′-amino modified nucleotide, and

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

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

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 dsRNA agent comprises at least one phosphorothioate or methylphosphonate internucleotide linkage.

6. The dsRNA of claim 1 , wherein the GalNAc (N-acetylgalactosamine) derivative is attached through a bivalent or trivalent branched linker.

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

(SEQ ID NO: 387)

5′-CAUAUUUGAUCAGUCUUUUUA-3′

and

(SEQ ID NO: 572)

5′-UAAAAAGACUGAUCAAAUAUGUU-3′;

(SEQ ID NO: 287)

5′-ACAUAUUUGAUCAGUCUUUUU-3′

and

(SEQ ID NO: 472)

5′-AAAAAGACUGAUCAAAUAUGUUG-3′;

(SEQ ID NO: 303)

5′-AACAUAUUUGAUCAGUCUUUU-3′

and

(SEQ ID NO: 488)

5′-AAAAGACUGAUCAAAUAUGUUGA-3′;

(SEQ ID NO: 39)

5′-ACAUAUUUGAUCAGUCUUU-3′

and

(SEQ ID NO: 101)

5′-AAAGACUGAUCAAAUAUGU-3′;

(SEQ ID NO: 294)

5′-CAACAUAUUUGAUCAGUCUUU-3′

and

(SEQ ID NO: 479)

5′-AAAGACUGAUCAAAUAUGUUGAG-3′;

(SEQ ID NO: 358)

5′-UCAACAUAUUUGAUCAGUCUU-3′

and

(SEQ ID NO: 543)

5′-AAGACUGAUCAAAUAUGUUGAGU-3′;

and

(SEQ ID NO: 64)

5′-CAACAUAUUUGAUCAGUCU-3′

and

(SEQ ID NO: 126)

5′-AGACUGAUCAAAUAUGUUG-3′.

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

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

10. The pharmaceutical composition of claim 9 , wherein the dsRNA agent is present in a buffered solution.

11. 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.

12. The method of claim 11 , wherein the cell is within a subject.

13. 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.

14. 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.

15. The method of claim 14 , wherein the disorder is a disorder of lipid metabolism.

16. The method of claim 14 , wherein the disorder is selected from the group consisting of hypertriglyceridemia, obesity, hyperlipidemia, atherosclerosis, diabetes, cardiovascular disease, and coronary artery disease.

17. The method of claim 14 , further comprising administering an additional therapeutic to the subject.

18. The method of claim 17 , wherein the additional therapeutic is a statin.

19. The method of claim 14 , wherein the dsRNA agent is administered at a dose of about 0.5 mg/kg to about 50 mg/kg.

20. The method of claim 14 , wherein the administration of the dsRNA agent to the subject causes a decrease in one or more serum lipid and/or a decrease in ANGPTL3 protein accumulation.