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, 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.