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 which differ by no more than three nucleotides from the nucleotide sequence of 5′-AAAGACUGAUCAAAUAUGUUGAG-3′ (nucleotides 274-296 of SEQ ID NO:1),

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

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, 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 which differ by no more than three nucleotides from the nucleotide sequence of 5′-AAGACUGAUCAAAUAUGUUGAGU-3′ (nucleotides 273-295 of SEQ ID NO:1),

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

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, 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. 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 which differ by no more than three nucleotides from the nucleotide sequence of 5′-AGACUGAUCAAAUAUGUUG-3′ (nucleotides 276-294 of SEQ ID NO:1),

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

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, 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.

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 and antisense strands 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.