Compositions and methods for inhibiting expression of TMPRSS6 gene

Patent metadata

Field	Value
Publication number	US-10100312-B2
Application number	US-201514866148-A
Country	US
Kind code	B2
Filing date	Sep 25, 2015
Priority date	Mar 29, 2011
Publication date	Oct 16, 2018
Grant date	Oct 16, 2018

Abstract

The invention relates to double-stranded ribonucleic acid (dsRNA) compositions targeting the TMPRSS6 gene, and methods of using such dsRNA compositions to inhibit expression of TMPRSS6.

First claim

We claim:

1. A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of TMPRSS6, wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to nucleotides 2045-2063 of a TMPRSS6 transcript comprising the sequence of SEQ ID NO: 1, wherein the sense strand comprises cuGGAGAGGuGuccuucAAdTsdT (SEQ ID NO: 492) and the antisense strand comprises UUGAAGGAcACCUCUCcAGdTsdT (SEQ ID NO: 493), wherein A is adenosine, C is cytidine, G is guanosine, U is uridine, c is 2′-O-methylcytidine, u is 2′-O′-methyluridine, dT is 2′-deoxythymidine, and s is phosphorothioate linkage.

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

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

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

5. The dsRNA of claim 4 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA.

6. A cell containing the dsRNA of claim 1 .

7. A pharmaceutical composition for inhibiting expression of a TMPRSS6 gene comprising the dsRNA of claim 1 .

8. The pharmaceutical composition of claim 7 , further comprising a lipid formulation.

9. A method of inhibiting TMPRSS6 expression in a cell, the method comprising:
(a) introducing into the cell 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 a TMPRSS6 gene, thereby inhibiting expression of the TMPRSS6 gene in the cell.

10. The method of claim 9 , wherein the TMPRSS6 expression is inhibited by at least 30%.

11. A method of treating hemochromatosis or a β-thalassemia, comprising administering to a human in need of such treatment a therapeutically effective amount of the dsRNA of claim 1 .

12. The method of claim 11 , wherein the β-thalassemia is β-thalassemia intermedia.

13. The method of claim 11 , wherein the human has a β-thalassemia and wherein the administration of the dsRNA to the subject causes a decrease in iron in the serum of the subject by at least 10%.

14. The method of claim 11 , wherein the dsRNA is administered at a concentration of 0.01 mg/kg-5 mg/kg bodyweight of the subject.

15. The dsRNA of claim 1 , wherein at least one end of the dsRNA is blunt.

16. The dsRNA of claim 1 , wherein the dsRNA comprises a duplex region between 19-30 base pairs.

17. The dsRNA of claim 4 , wherein the ligand is a cell or tissue targeting group chosen from a lectin, a glycoprotein, a lipid, or an antibody that binds to a specified cell type.

18. The dsRNA of claim 4 , wherein the ligand is a multivalent galactose, N-acetyl-galactosamine, an N-acetyl-galacosamine multivalent mannose, or a cholesterol.

19. The dsRNA of claim 1 , wherein the dsRNA comprises a sense strand consisting of the sequence of SEQ ID NO: 492.

20. The dsRNA of claim 1 , wherein the dsRNA comprises an antisense strand consisting of the sequence of SEQ ID NO: 493.

21. The dsRNA of claim 1 , wherein the dsRNA comprises a sense strand consisting of the sequence of SEQ ID NO: 492 and an antisense strand consisting of the sequence of SEQ ID NO: 493.

Assignees

• Alnylam Pharmaceuticals Inc

Inventors

• Bumcrot David A
• Bettencourt Brian
• Toudjarska Ivanka

Classifications

• A61P43/00

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

• A61P7/06

  Antianaemics · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P3/12

  for electrolyte homeostasis · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title