Compositions and methods for inhibiting expression of TMPRSS6 gene
View Patent ↗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.
1. A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of TMPRSS6, wherein said dsRNA comprises a sense strand and an antisense strand, wherein said antisense strand comprises a region of complementarity to a TMPRSS6 RNA transcript comprising a sequence selected from the group consisting of SEQ ID NO:420, SEQ ID NO:112, SEQ ID NO:110, SEQ ID NO:90, and SEQ ID NO:48, and wherein said dsRNA comprises at least one modified nucleotide.
2. The dsRNA of claim 1 , wherein the sense strand comprises a sequence selected from the group consisting of SEQ ID NO:419, SEQ ID NO:111, SEQ ID NO:109, SEQ ID NO:89, and SEQ ID NO:47.
3. The dsRNA of claim 1 , wherein said modified nucleotide is chosen from a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, or a terminal nucleotide linked to a cholesteryl derivative or dodecanoic acid bisdecylamide group.
4. The dsRNA of claim 1 , wherein said modified nucleotide is chosen from a 2′-deoxy-2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, 2′-amino-modified nucleotide, 2′-alkyl-modified nucleotide, morpholino nucleotide, a phosphoramidate, and a non-natural base comprising nucleotide.
5. The dsRNA of claim 1 , wherein the antisense strand has a region of complementarity to a TMPRSS6 RNA transcript of at least 17 nucleotides in length.
6. The dsRNA of claim 5 , wherein the region of complementarity is between 19 and 21 nucleotides in length.
7. The dsRNA of claim 1 , wherein each strand is no more than 30 nucleotides in length.
8. The dsRNA of claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide or at least 2 nucleotides.
9. The dsRNA of claim 1 , further comprising a ligand.
10. The dsRNA of claim 9 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA.
11. The dsRNA of claim 1 , wherein the antisense strand is between 19 and 24 nucleotides in length.
12. The dsRNA of claim 1 , wherein the dsRNA comprises a sense strand comprising a sequence selected from the group consisting of SEQ ID NO:419, SEQ ID NO:111, SEQ ID NO:109, SEQ ID NO:89, and SEQ ID NO:47 and an antisense strand comprising a sequence selected from the group consisting of SEQ ID NO:420, SEQ ID NO:112, SEQ ID NO:110, SEQ ID NO:90, and SEQ ID NO:48, and wherein each strand is between 19 and 24 nucleotides in length.
13. A cell containing the dsRNA of claim 1 .
14. A pharmaceutical composition for inhibiting expression of a TMPRSS6 gene comprising the dsRNA of claim 1 .
15. The pharmaceutical composition of claim 14 , further comprising a lipid formulation.
16. 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.
17. The method of claim 16 , wherein the TMPRSS6 expression is inhibited by at least 30%.
18. A method of treating a disorder mediated by TMPRSS6 expression comprising administering to a human in need of such treatment a therapeutically effective amount of the dsRNA of claim 1 .
19. The method of claim 18 , wherein the human has a disorder associated with hemochromatosis, a β-thalassemia, or β-thalassemia intermedia.
20. The method of claim 18 , wherein the human has aβ-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%.
21. The method of claim 18 , wherein the dsRNA is administered at a concentration of 0.01 mg/kg-5 mg/kg bodyweight of the subject.
22. The dsRNA of claim 1 , wherein the dsRNA comprises a sense strand consisting of a sequence selected from the group consisting of SEQ ID NO:562, SEQ ID NO:455, SEQ ID NO:524, SEQ ID NO:494, and SEQ ID NO:540; and an antisense strand consisting of a sequence selected from the group consisting of SEQ ID NO:563, SEQ ID NO:456, SEQ ID NO:525, SEQ ID NO:495, and SEQ ID NO:541.
23. A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of TMPRSS6, wherein the dsRNA comprises a sense strand consisting of the sequence of SEQ ID NO:419; and an antisense strand consisting of the sequence of SEQ ID NO:420.
24. The dsRNA of claim 23 , wherein at least one end of the dsRNA is blunt.
25. The dsRNA of claim 23 , wherein the dsRNA comprises a duplex region between 15-30 base pairs.
26. The dsRNA of claim 23 , further comprising a ligand.
27. The dsRNA of claim 26 , 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.
28. The dsRNA of claim 26 , wherein the ligand is a multivalent galactose, N-acetyl-galactosamine, an N-acetyl-galactosamine multivalent mannose, or a cholesterol.
29. The dsRNA of claim 1 , wherein the dsRNA comprises a sense strand consisting of the sequence of SEQ ID NO:562; and an antisense strand consisting of the sequence of SEQ ID NO:563.
30. The dsRNA of claim 1 , wherein the dsRNA comprises a sense strand consisting of the sequence of SEQ ID NO:455; and an antisense strand consisting of the sequence of SEQ ID NO:456.
31. The dsRNA of claim 1 , wherein the dsRNA comprises a sense strand consisting of the sequence of SEQ ID NO:524; and an antisense strand consisting of the sequence of SEQ ID NO:525.
32. The dsRNA of claim 1 , wherein the dsRNA comprises a sense strand consisting of the sequence of SEQ ID NO:494; and an antisense strand consisting of the sequence of SEQ ID NO:495.
33. The dsRNA of claim 1 , wherein the dsRNA comprises a sense strand consisting of the sequence of SEQ ID NO:540; and an antisense strand consisting of the sequence of SEQ ID NO:541.
34. The dsRNA of claim 1 , wherein at least one end of the dsRNA is blunt.
35. The dsRNA of claim 1 , wherein the dsRNA comprises a duplex region between 15-30 base pairs.
36. The dsRNA of claim 9 , 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.
37. The dsRNA of claim 9 , wherein the ligand is a multivalent galactose, N-acetyl-galactosamine, an N-acetyl-galactosamine multivalent mannose, or a cholesterol.