Coagulation factor V (F5) iRNA compositions and methods of use thereof
Inventors
Keating, Mark • McIninch, James D. • Schlegel, Mark K.
Assignees
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Publication Number
US-12331297-B2
Publication Date
2025-06-17
Expiration Date
Abstract
The present invention relates to RNAi agents, e.g., dsRNA agents, targeting the Coagulation Factor V (F5) gene. The invention also relates to methods of using such RNAi agents to inhibit expression of an F5 gene and to methods of treating or preventing an F5-associated disease, e.g., a disorder associated with thrombosis, in a subject.
Core Innovation
The invention relates to double stranded ribonucleic acid (dsRNA) agents for inhibiting expression of coagulation Factor V (F5) in a cell, including pharmaceutically acceptable salts. The dsRNA agents include a sense strand and an antisense strand with defined nucleotide sequences and limited differences from SEQ ID NO:2739 and SEQ ID NO:2940, or consist of those sequences. The agent uses defined chemical modifications, including 2′-O-methyl A, G, C, and U, 2′-fluoro A and C, phosphorothioate linkages, and deoxyguanosine-3-phosphate and deoxyadenosine-3-phosphate components.
The invention further includes conjugation of the dsRNA agent to a ligand at the 3′-end of the sense strand, with X being O in the schematic. Dependent refinement also specifies an N-acetylgalactosamine (GalNAc) derivative as the ligand, and the document presents carbohydrate ligand concepts for targeting RNAi agents through mono-, bi-, or trivalent branched linkers, with attachment to strand termini or unpaired nucleotides in a hairpin loop.
The document addresses inhibition of F5 gene expression by RNAi agents and describes evaluation of F5 mRNA and F5 protein. It provides single-dose screening and in vivo pharmacodynamic study results for selected Factor V dsRNA duplexes, including RT-qPCR readouts and ELISA measurement of Factor V protein levels over time, supporting evaluation of Factor V knockdown.
Claims Coverage
The provided claims content includes 3 independent claims directed to dsRNA agents for inhibiting coagulation Factor V (F5) expression in a cell. The inventive features center on sequence-constrained sense and antisense strands, defined chemical modifications, and 3′-end ligand conjugation of the sense strand, with dependent refinements including salt form, isolated cell, and pharmaceutical composition context.
Sequence-constrained dsRNA agent for F5 inhibition
A dsRNA agent for inhibiting expression of coagulation Factor V (F5) in a cell, comprising a sense strand differing by no more than 4 unmodified or modified bases from SEQ ID NO:2739 and an antisense strand differing by no more than 4 unmodified or modified bases from SEQ ID NO:2940, or consisting of these sequences, and a pharmaceutically acceptable salt thereof.
Defined nucleotide chemical modifications in dsRNA strands
The sense and antisense strands are defined wherein a, g, c and u are 2′-O-methyl A, G, C, and U; Af and Cf are 2′-fluoro A and C; s is a phosphorothioate linkage; dG is 2-deoxyguanosine-3′-phosphate; and dA is 2-deoxyadenosine-3′-phosphate.
3′-end ligand conjugation with X=O
The 3′-end of the sense strand is conjugated to a ligand as shown in a schematic, wherein X is O, and dependent coverage includes an N-acetylgalactosamine (GalNAc) derivative.
Across the independent claims, the coverage centers on dsRNA agents that inhibit coagulation Factor V (F5) expression using tightly defined sense and antisense strands, specified chemical modifications, and 3′-end ligand conjugation of the sense strand with X defined as O.
Stated Advantages
The in vivo results indicate durable and potent Factor V knockdown.
Inhibits expression of coagulation Factor V (F5) in a cell.
Reduces F5 protein level in serum/plasma, including Factor V reduction after subcutaneous dosing in non-human primates.
Used for treating or preventing thrombosis-associated diseases, including thrombosis and prophylaxis.
Enables combination therapy with additional anticoagulant and thrombolytic agents.
Documented Applications
Single-dose screening and measurement of F5 knockdown in primary human hepatocytes using RT-qPCR readouts and reporting F5 message remaining.
Non-human primate pharmacodynamic study of selected Factor V dsRNA duplexes with Factor V protein level measurement over time by ELISA.
In vitro and in vivo inhibition of coagulation Factor V (F5) expression by dsRNA/siRNA RNAi agents, with effects measured on F5 mRNA and F5 protein.
Use in a cell for inhibiting expression of coagulation Factor V (F5).
A pharmaceutical composition comprising the dsRNA agent, or a pharmaceutically acceptable salt thereof.
An isolated cell containing the dsRNA agent, or a pharmaceutically acceptable salt thereof.
Treatment and/or prevention of thrombosis-associated diseases including venous thromboembolism, deep vein thrombosis, pulmonary embolism, atherothrombosis, and Factor V Leiden.
Prophylaxis of thrombosis-associated disease via in vivo inhibition of F5 expression.
Combination therapy contexts with additional anticoagulant agents and thrombolytics (tPA/urokinase/antistreplase) for thrombosis-associated treatment.
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