Systematic Evaluation of Coagulation Factors as Targets for Anti-Thrombotic Therapy Using Antisense Technology.

Abstract

Abstract 4181Human clinical efficacy has been demonstrated with antisense oligonucleotides (ASOs) in several disease indications, including dyslipidemia, cancer, diabetes and multiple sclerosis. Second generation ASOs show potent pharmacology in many tissues, with liver being one of the most sensitive to ASO action. As the liver is responsible for production of many of the factors involved in blood coagulation we systematically designed and evaluated ASOs selective for several members of the coagulation cascade. ASOs targeting coagulation cascade members of both the intrinsic and extrinsic pathway produced highly specific target knockdown in liver. An overall aim of this study was to evaluate the contribution of the various factors to the coagulation process as well as to assess their relative risk/benefit relationships. The “risk” component was determined by bleeding tendency as measured by blood volume loss following tail nick, and the “benefit” component was determined by antithrombotic effect following ferric chloride induced thrombosis in the inferior vena cava. We have previously reported the activity of FVII and FXI ASOs in a ferric chloride mouse model without increased bleeding risk. Here we identify additional promising new antithrombotic targets. FII and FIX ASOs were able to reduce thrombosis, but inhibition of these targets had deleterious effects on the bleeding tendency. The ASO effects on PT and aPTT will be presented. The approach used in this study will be used to further characterize targets for antithrombotic potential and determine their ability to be combined with antiplatelet therapies. In addition to the characterization of antithrombotic targets, these ASOs will be evaluated and developed as potent, selective and potentially safer human antithrombotic therapeutics. Disclosures:Crosby:Isis Pharmaceuticals, Inc.: Employment. Gao:Isis Pharmaceuticals, Inc.: Employment. Zhao:Isis Pharmaceuticals, Inc.: Employment. Bhattacharjee:Isis Pharmaceuticals, Inc.: Employment. May:Isis Pharmaceuticals, Inc.: Employment. Zhang:Isis Pharmaceuticals, Inc.: Consultancy. MacLeod:Isis Pharmaceuticals: Employment. Monia:Isis Pharmaceuticals, Inc.: Employment.