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.

2017 Scientific Sessions Sol Sherry Distinguished Lecture in Thrombosis

“…25,26 In the same model, FXI knockdown with an antisense oligonucleotide (ASO) reduced thrombosis in a concentration-dependent manner once FXI levels were <50% of normal. 27 Results in rodent models are different; in these models, FXI and FXII seem to be equally important drivers of thrombosis. Thus, in arterial or venous injury models, mice deficient in FXII Figure 2.…”

“…Strategies to inhibit FXI are illustrated in Table 2 and include (1) ASOs that reduce hepatic synthesis of the clotting protein 27,33,44 ; (2) monoclonal antibodies that block FXI activation, FXIa activity, or both 25,45,46 ; (3) aptamers that block FXI activation or activity 47,48 ; and (4) small molecules that block the active site of FXIa [49][50][51] or induce allosteric modulation.…”

Recent insights into the role of the contact pathway in thrombo-inflammatory disorders

“…Without exception, these approaches showed thromboprotective effects in rodent thrombosis models using ferric chloride or vena cava ligation. [22][23][24][25][26] For example, inhibitory factor XI antibodies, which prevent the activation of factor XI by factor XII, protected mice from ferric chloride-induced arterial and venous thrombosis. 27,28 Furthermore, factor XI and factor XI antisense oligonucleotides have been studied in higher species using a vascular graft occlusion model in primates, 29,30 which paved the way for human studies using factor XI antisense oligonucleotides.…”

Inhibition of factor XI activation attenuates inflammation and coagulopathy while improving the survival of mouse polymicrobial sepsis

“…Despite its apparently modest hemostatic role, persons with high plasma FXI levels are at an increased risk for arterial and venous thrombosis, [12][13][14] and FXI-deficient patients are protected against ischemic stroke and deep vein thrombosis. 15,16 In various animal models, decreasing or eliminating FXI procoagulant activity through gene knockout, pharmacologic inhibition, or antisense oligonucleotidemediated knockdown is also antithrombotic without significantly impairing hemostasis, [17][18][19][20][21] suggesting that FXI is an important driver of pathologic coagulation with only a supportive function in normal hemostasis. Interestingly, FXII and prekallikrein have also been shown to contribute to the development of experimental thrombosis in mice, 22,23 despite the normal to possibly prothrombotic phenotype associated with deficiency of either of these proteins (Hagemen trait and Fletcher trait, respectively) in humans.…”