COAGULATION FACTOR X (F10) iRNA COMPOSITIONS AND METHODS OF USE THEREOF
The present invention relates to RNAi agents, e.g., dsRNA agents, targeting the Coagulation Factor X (F10) gene. The invention also relates to methods of using such RNAi agents to inhibit expression of an F10 gene and to methods of treating or preventing an F10-associated disease, e.g., a disorder associated with thrombosis, in a subject.
1 . A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of coagulation Factor X (F10) in a cell,
a) wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region,
wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:1 and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:8; or
b) wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand comprises a region of complementarity to an mRNA encoding F10, and wherein the region of complementarity comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the antisense nucleotide sequences in any one of Tables 2-3.
2 .- 6 . (canceled)
7 . The dsRNA agent of claim 1 , wherein at least one nucleotide of the dsRNA agent comprises a nucleotide modification.
8 . (canceled)
9 . The dsRNA agent of claim 1 , wherein all of the nucleotides of the sense strand comprise a nucleotide modification; all of the nucleotides of the antisense strand comprise a nucleotide modification; or all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a nucleotide modification.
10 . The dsRNA agent of claim 7 , wherein at least one of the nucleotide modifications is selected from the group consisting of a deoxy-nucleotide modification, a 3′-terminal deoxythimidine (dT) nucleotide modification, a 2′-O-methyl nucleotide modification, a 2′-fluoro nucleotide modification, a 2′-deoxy-nucleotide modification, a locked nucleotide modification, an unlocked nucleotide modification, a conformationally restricted nucleotide modification, a constrained ethyl nucleotide modification, an abasic nucleotide modification, a 2′-amino-nucleotide modification, a 2′-O-allyl-nucleotide modification, 2′-C-alkyl-modified nucleotide modification, 2′-hydroxyl-nucleotide modification, a 2′-methoxyethyl modified nucleotide modification, a 2′-O-alkyl-nucleotide modification, a morpholino nucleotide modification, a phosphoramidate modification, a non-natural base comprising nucleotide modification, a tetrahydropyran nucleotide modification, a 1,5-anhydrohexitol nucleotide modification, a cyclohexenyl nucleotide modification, a nucleotide comprising a phosphorothioate group modification, a nucleotide comprising a methylphosphonate group modification, a nucleotide comprising a 5′-phosphate modification, a nucleotide comprising a 5′-phosphate mimic modification, a thermally destabilizing nucleotide modification, a glycol modified nucleotide (GNA) modification, and a 2-O-(N-methylacetamide) modified nucleotide modification; and combinations thereof.
11 .- 14 . (canceled)
15 . The dsRNA agent of claim 1 , wherein the double stranded region is 19-30 nucleotide pairs in length.
16 .- 19 . (canceled)
20 . The dsRNA agent of claim 1 , wherein each strand is independently no more than 30 nucleotides in length.
21 .- 24 . (canceled)
25 . The dsRNA agent of claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide.
26 . (canceled)
27 . The dsRNA agent of claim 1 , further comprising a ligand.
28 . The dsRNA agent of claim 27 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent.
29 . The dsRNA agent of claim 27 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.
30 . The dsRNA agent of claim 27 , wherein the ligand is one or more GalNAc derivatives attached through a monovalent, bivalent, or trivalent branched linker.
31 . The dsRNA agent of claim 29 , wherein the ligand is
32 . The dsRNA agent of claim 31 , wherein the dsRNA agent is conjugated to the ligand as shown in the following schematic
and, wherein X is O or S.
33 . The dsRNA agent of claim 32 , wherein X is O.
34 . The dsRNA agent of claim 1 , wherein the dsRNA agent further comprises at least one phosphorothioate or methylphosphonate internucleotide linkage.
35 .- 43 . (canceled)
44 . A cell containing the dsRNA agent of claim 1 .
45 . A pharmaceutical composition for inhibiting expression of a gene encoding coagulation Factor X (F10) comprising the dsRNA agent of claim 1 .
46 .- 50 . (canceled)
51 . An in vitro method of inhibiting expression of a coagulation Factor X (F10) gene in a cell, the method comprising contacting the cell with the dsRNA agent of claim 1 , thereby inhibiting expression of the F10 gene in the cell.
52 .- 58 . (canceled)
59 . A method of treating a subject having a disorder that would benefit from reduction in coagulation Factor X (F10) expression, the method comprising administering to the subject a therapeutically effective amount of the dsRNA agent of claim 1 , thereby treating the subject having the disorder that would benefit from reduction in F10 expression.
60 . (canceled)
61 . The method of claim 59 , wherein the disorder is an F10-associated disorder.
62 . The method of claim 61 , wherein the F10-associated disorder is a disorder associated with thrombosis.
63 .- 70 . (canceled)