Serpin family F member 2 (SERPINF2) iRNA compositions and methods of use thereof
The present invention relates to RNAi agents, e.g., double stranded RNA (dsRNA) agents, targeting the SERPINF2 gene. The invention also relates to methods of using such RNAi agents to inhibit expression of a SERPINF2 gene and to methods of preventing and treating a SERPINF2-associated disorder, e.g., a disorder associated with thrombosis.
1 . A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of serpin family F member 2 (SERPINF2) in a cell, or a salt thereof,
wherein the dsRNA agent, or a salt thereof, comprises a sense strand and an antisense strand forming a double stranded region,
wherein the antisense strand comprises the nucleotide sequence 5′-UGUGGCAUAAAAAUCACUACAAA-3′ of SEQ ID NO:128 or 5′-UAGGUGGCAUAAAAAUCACUACA-3′ of SEQ ID NO:122,
wherein at least one nucleotide comprises a nucleotide modification.
2 . The dsRNA agent, or a salt thereof, of claim 1 , wherein at least one of the nucleotide modifications is selected from the group consisting of a deoxy-nucleotide modification, a 3′-terminal deoxy-thymine (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-nucleotide modification, 2′-hydroxly-nucleotide modification, a 2′-methoxyethyl 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 5′-phosphate modification, a nucleotide comprising a 5′-phosphate mimic modification, a thermally destabilizing nucleotide modification, a glycol nucleotide (GNA) modification, and a 2-O-(N-methylacetamide) nucleotide modification; and combinations thereof.
3 . The dsRNA agent, or a salt thereof, of claim 1 , further comprising a ligand.
4 . The dsRNA agent, or a salt thereof, of claim 3 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent.
5 . The dsRNA agent, or a salt thereof, of claim 3 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.
6 . The dsRNA agent, or a salt thereof, of claim 5 , wherein the ligand is one or more GalNAc derivatives attached through a monovalent, bivalent, or trivalent branched linker.
7 . The dsRNA agent, or a salt thereof, of claim 5 , wherein the ligand is
8 . The dsRNA agent, or a salt thereof, of claim 7 , wherein the dsRNA agent, or a salt thereof, is conjugated to the ligand as shown in the following schematic
wherein X is O or S.
9 . The dsRNA agent, or a salt thereof, of claim 8 , wherein X is O.
10 . The dsRNA agent, or a salt thereof, of claim 1 , further comprising at least one phosphorothioate or methylphosphonate internucleotide linkage.
11 . An isolated cell containing the dsRNA agent, or a salt thereof, of claim 1 .
12 . A pharmaceutical composition for inhibiting expression of a gene encoding SERPINF2 comprising the dsRNA agent, or a salt thereof, of claim 1 .
13 . A method of inhibiting expression of a SERPINF2 gene in a cell, the method comprising contacting the cell with the dsRNA agent, or a salt thereof, of claim 1 , thereby inhibiting expression of the SERPINF2 gene in the cell.
14 . A method of treating a SERPINF2-associated disorder in a subject, comprising administering to the subject the dsRNA agent, or a salt thereof, of claim 1 , thereby treating the SERPINF2-associated disorder in the subject.
15 . The method of claim 14 , wherein the SERPINF2-associated disorder is selected from the group consisting of plasminogen deficiency, venous thrombosis, venous thromboembolism, deep vein thrombosis, pulmonary embolism, prosthetic valve thrombosis, post-thrombotic syndrome, atherothrombosis, heart attack, stroke, fibrinolytic disorders, hypofibrinolysis, disfibrinolysis, ischemic stroke, atrial fibrillation, myocardial infarction, peripheral arterial disease, dynamic thrombosis, coronary artery disease, microvascular thrombosis, ischemic brain injury, brain swelling, and brain hemorrhage after thromboembolic stroke.
16 . The method of claim 15 , wherein the SERPINF2-associated disorder is plasminogen deficiency.
17 . The method of claim 15 , wherein the subject is human.
18 . The method of claim 14 , wherein the dsRNA agent, or a salt thereof, is administered to the subject subcutaneously.
19 . The method of claim 14 , further comprising administering to the subject an additional therapeutic agent for treatment of thrombosis.
20 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the sense and antisense strand comprise the nucleotide sequences
(i) 5′-UGUAGUGAUUUUUAUGCCACA-3′ of SEQ ID NO:38 and 5′-UGUGGCAUAAAAAUCACUACAAA-3′ of SEQ ID NO: 128; or
(ii) 5′-UAGUGAUUUUUAUGCCACCUA-3′ of SEQ ID NO:32 and 5′-UAGGUGGCAUAAAAAUCACUACA-3′ of SEQ ID NO:122.
21 . A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of serpin family F member 2 (SERPINF2), or a salt thereof,
wherein the dsRNA agent, or a salt thereof, comprises a sense strand and an antisense strand forming a double stranded region,
wherein the antisense strand comprises the nucleotide sequence 5′-UGUGGCAUAAAAAUCACUACAAA-3′ of SEQ ID NO:128 or 5′-UAGGUGGCAUAAAAAUCACUACA-3′ of SEQ ID NO:122,
wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a nucleotide modification, and
wherein at least one strand is conjugated to a ligand.