FXII Antisense Oligonucleotide Mediated Depletion Results In Effective Anticoagulation without Bleeding Risk.

Abstract 1149

Human clinical efficacy has been demonstrated with antisense oligonucleotides (ASOs) in several disease indications, including dyslipidemia, cancer, diabetes and multiple sclerosis. Coagulation factors are attractive targets for antisense therapeutics for several reasons. The liver is principally responsible for production of coagulation factors and is an organ which is highly sensitive to ASO drugs. ASOs are highly specific, and thus we can selectively evaluate multiple coagulation factors to determine their roles in thrombosis, bleeding, and other processes. Employing antisense technology we selectively reduced levels of several individual clotting factors and compared the relative risk/benefit profiles. Antithrombotic activity was determined following ferric chloride induced thrombosis in the inferior vena cava and bleeding tendency was measured by blood volume loss following tail nick. ASOs targeting several clotting factors were studied, including factors FII, FVII, FIX, FXI and FXII. Previously we characterized the beneficial effects of targeting FXI, demonstrating antithrombotic effects without increased bleeding risk. Here, we describe the effects of targeting another member of the intrinsic pathway, FXII. FXII ASO treatment resulted in a dose-dependent and specific reduction in FXII mRNA levels in liver. These reductions in FXII levels correlated well with a prolongation of aPTT with no effects on PT prolongation. The anticoagulant effect of FXII ASO treatment also correlated well with antithrombotic activity in a FeCl3 induced IVC thrombosis mouse model across a wide dose range. In addition to the venous thrombosis model, FXII ASO treatment was effective across a wide dose range in a model of arterial thrombosis. Furthermore, FXII ASO treatment was well tolerated and no prolongation of tail bleeding time was observed at any dose tested, indicating a broad safety margin for FXII ASO targeting (in mice). In addition, FXII inhibition was protective in a mouse TF driven pulmonary embolism model. Inhibiting coagulation factors with ASOs is highly specific and offers an attractive approach to identifying optimal antithrombotic targets as well as human therapeutics for the treatment of coagulation related disorders with the potential for improved safety profiles.