Abstract 17159: Targeting Factor XII (F12) With a Novel RNAi Delivery Platform as a Prophylactic Treatment for Thromboembolism

Introduction: Current anticoagulants effectively prevent thromboembolic (TBE) events, but unmet need remains due to an elevated risk of major bleeding events. Factor XII (F12) autoactivation initiates the intrinsic coagulation pathway. F12 deficient mice show protection from thrombosis without increased bleeding risk. Also, F12 deficiency in individuals is not associated with increased bleeding risk, suggesting F12 is not essential for hemostasis. Hypothesis: We hypothesized that an RNA interference (RNAi) based approach for reducing liver F12 production using our Dynamic Polyconjugate (DPC)™ delivery platform may provide a new prophylactic therapy for TBE without increased risk of bleeding events. Methods: Highly specific mouse/human/non-human primate (NHP) cross-reactive RNAi triggers were designed in silico and screened for F12 knockdown activity in vitro and in mice. Structure activity relationship (SAR) studies of the most active RNAi triggers identified optimal modifications enabling lead identifica...