Abstract 595: Proof-of-concept Studies for Sirna-mediated Gene Silencing for Coagulation Factors in Rat and Rabbit

Multiple coagulation factors in the intrinsic cascade are emerging targets for new anticoagulant therapies. Rat and rabbit are two commonly utilized preclinical species for studying thrombosis and hemostasis. The present study aimed at establishing feasibility of delivering short interfering RNA (siRNA) to target coagulation factors in rat and rabbit. Plasma kallikrein was selected for rat studies as plasma kallikrein knockout mouse had been described before in thrombosis and hemostasis models. Factor X (FX) was selected for rabbit studies as a rich dataset of FXa inhibitors in rabbits exists in literature. siRNAs that produced over 90% knockdown of rat plasma prekallikrein mRNA and rabbit FX mRNA in vitro were identified from cellular screens. An ionizable amino lipid based lipid nanoparticle (LNP) formulation for siRNA in vivo delivery was characterized as tolerable and exerting no appreciable effect on coagulability at day seven post dosing in both species. Both prekallikrein siRNA and FX siRNA resulte...