Compositions and methods for inhibition of expression of apolipoprotein C-III (APOC3) genes

Patent metadata

Field	Value
Publication number	US-9315813-B2
Application number	US-201214125567-A
Country	US
Kind code	B2
Filing date	Jun 21, 2012
Priority date	Jun 21, 2011
Publication date	Apr 19, 2016
Grant date	Apr 19, 2016

Abstract

The invention relates to double-stranded ribonucleic acid (dsRNA) targeting an APOC3 gene, and methods of using the dsRNA to inhibit expression of APOC3.

First claim

We claim:

1. A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of an APOC3 gene, wherein the dsRNA comprises a sense strand and an antisense strand, the sense strand consisting of SEQ ID NO:232 (GcuuAAAAGGGAcAGuAuudTsdT) and the antisense strand consisting of SEQ ID NO:313 (AAuACUGUCCCUUUuAAGCdTsdT) wherein each strand includes a 2′-O-methyl ribonucleotide as indicated by a lower case letter “c” or “u,” a 2′-deoxythymidine-3′-phosphate as indicated by a “dT,” and a 2′-deoxy-thymidine-5′phosphate-phosphorothioate as indicated by a “sdT.”.

2. The dsRNA of claim 1 , further comprising a ligand.

3. The dsRNA of claim 2 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA.

4. The dsRNA of claim 1 , further comprising at least one N-Acetyl-Galactosamine.

5. A cell comprising the dsRNA of claim 1 .

6. A vector encoding at least one strand of the dsRNA of claim 1 .

7. A cell comprising the vector of claim 6 .

8. A pharmaceutical composition for inhibiting expression of an APOC3 gene comprising the dsRNA of claim 1 .

9. The pharmaceutical composition of claim 8 , comprising a lipid formulation.

10. The pharmaceutical composition of claim 8 , comprising a lipid formulation comprising MC3.

11. A method of inhibiting APOC3 expression in a cell, the method comprising:
(a) contacting the cell with the dsRNA 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 APOC3 gene, thereby inhibiting expression of the APOC3 gene in the cell.

12. The method of claim 11 , wherein the APOC3 expression is inhibited by at least 30%.

13. A method of treating a disorder mediated by APOC3 expression comprising administering to a human in need of such treatment a therapeutically effective amount of the APOC3 dsRNA of claim 1 .

14. A method of inhibiting APOC3 expression in a cell, the method comprising:
(a) contacting the cell with the dsRNA of claim 4 ; and
(b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of an APOC3 gene, thereby inhibiting expression of the APOC3 gene in the cell.

15. A method of treating a disorder mediated by APOC3 expression comprising administering to a human in need of such treatment a therapeutically effective amount of the APOC3 dsRNA of claim 4 .

16. A method of inhibiting APOC3 expression in a cell, the method comprising:
(a) contacting the cell with the dsRNA of claim 9 ; and
(b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of an APOC3 gene, thereby inhibiting expression of the APOC3 gene in the cell.

17. A method of treating a disorder mediated by APOC3 expression comprising administering to a human in need of such treatment a therapeutically effective amount of the APOC3 dsRNA of claim 9 .

Assignees

• Bettencourt Brian
• Fitzgerald Kevin
• Milstein Stuart
• Maier Martin
• Charisse Klaus
• Rajeev Kallanthottathil
• Kuchimanchi Satyanarayana
• Manoharan Muthiah
• Nguyen Tuyen
• Alnylam Pharmaceuticals Inc

Inventors

• Bettencourt Brian
• Fitzgerald Kevin
• Milstein Stuart
• Maier Martin
• Charisse Klaus
• Rajeev Kallanthottathil
• Kuchimanchi Satyanarayana
• Manoharan Muthiah
• Nguyen Tuyen

Classifications

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• C12N2310/3515

  Lipophilic moiety, e.g. cholesterol · CPC title

• C12N15/113 Primary

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title