title: Inhibition of the intrinsic coagulation pathway factor XI by antisense oligonucleotides: a novel antithrombotic strategy with lowered bleeding risk.
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.
authors.affiliation: Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc, Carlsbad, CA, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Ester C
authors.initials: EC
authors.lastname: Löwenberg
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Crosby
authors.forename: A Robert
authors.initials: AR
authors.lastname: MacLeod
authors.forename: Chenguang
authors.initials: C
authors.lastname: Zhao
authors.forename: Dacao
authors.initials: D
authors.lastname: Gao
authors.forename: Chris
authors.initials: C
authors.lastname: Black
authors.forename: Alexey S
authors.initials: AS
authors.lastname: Revenko
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Meijers
authors.forename: Erik S
authors.initials: ES
authors.lastname: Stroes
authors.forename: Marcel
authors.initials: M
authors.lastname: Levi
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000077144:Clopidogrel; D004338:Drug Combinations; D017984:Enoxaparin / Q000627:therapeutic use; D005172:Factor XI / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006470:Hemorrhage / Q000209:etiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016376:Oligonucleotides, Antisense / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D013927:Thrombosis / Q000188:drug therapy*; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D004338:Drug Combinations; D017984:Enoxaparin; D016376:Oligonucleotides, Antisense; D005172:Factor XI; D000077144:Clopidogrel; D013988:Ticlopidine