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Inhibition of the intrinsic coagulation pathway factor XI by antisense oligonucleotides: a novel antithrombotic
Hong Zhang1, Ester C Löwenberg, Jeffrey R Crosby
1Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc, Carlsbad, CA, USA.
Abstract:
Existing anticoagulants effectively inhibit the activity of coagulation factors of the extrinsic and common pathway but have substantial limitations and can cause severe bleeding complications. Here we describe a novel therapeutic approach to thrombosis treatment. We have developed and characterized the efficacy and safety of selective second-generation antisense oligonucleotides (ASOs) targeting coagulation factor XI (FXI), a member of the intrinsic coagulation pathway. Systemic treatment of mice with FXI ASO led to a potent, specific, and dose-dependent reduction of FXI mRNA levels in the liver with corresponding reductions in plasma levels of FXI protein and activity. FXIASO treatment produced potent, dose-dependent antithrombotic activity in various venous and arterial thrombosis models, comparable with warfarin or enoxaparin. However, unlike warfarin or enoxaparin, FXI inhibition did not cause bleeding. Coadministration of FXI ASO with enoxaparin or the antiplatelet drug clopidogrel produced improved antithrombotic activity without increased bleeding. Finally, plasma-derived FXI concentrate was shown to effectively and rapidly reverse the anticoagulant effect of FXI antisense therapy. These results support the concept that inhibition of FXI through antisense therapy might serve as a new and effective strategy for the treatment and prevention of venous thromboembolism with improved specificity and safety.
Insights
Novel antisense oligonucleotides targeting coagulation factor XI (FXI) show potent antithrombotic effects without increased bleeding. This FXI antisense therapy offers a safer alternative for treating and preventing venous thromboembolism.
Area of Science:
- Biochemistry
- Pharmacology
- Thrombosis Research
Background:
- Current anticoagulants targeting the extrinsic and common coagulation pathways have limitations, including severe bleeding risks.
- Factor XI (FXI) is part of the intrinsic coagulation pathway, presenting a potential target for novel antithrombotic strategies.
Purpose of the Study:
- To develop and evaluate the efficacy and safety of second-generation antisense oligonucleotides (ASOs) targeting FXI for thrombosis treatment.
- To assess the antithrombotic activity and bleeding risk associated with FXI inhibition compared to existing anticoagulants.
Main Methods:
- Systemic administration of FXI ASOs in mouse models.
- Measurement of FXI mRNA, protein levels, and plasma activity.
- Evaluation of antithrombotic efficacy in venous and arterial thrombosis models.
- Assessment of bleeding complications and reversal of anticoagulant effects.
Main Results:
- FXI ASO treatment resulted in dose-dependent reduction of FXI mRNA, protein, and activity.
- FXI ASO demonstrated potent antithrombotic activity comparable to warfarin and enoxaparin.
- FXI inhibition did not increase bleeding risk, and FXI concentrate rapidly reversed the anticoagulant effect.
Conclusions:
- FXI inhibition via antisense therapy is a promising strategy for treating and preventing venous thromboembolism.
- This approach offers improved specificity and safety compared to existing anticoagulants.
- Combination therapy with FXI ASO and other antithrombotics enhanced efficacy without increasing bleeding.
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