LAUSR

Thrombotic disorders are prevalent and dangerous. Thrombosis involves the formation of unwanted blood clots inside blood vessels, which can impair blood flow and lead to severe cardiovascular events, such as heart attack, stroke, and pulmonary embolism. Current therapies for thrombosis are unsatisfactory in that they require frequent re-administration, and are associated with a significant bleeding risk, a consequence of inhibiting the coagulation cascade upstream of fibrin generation. Coagulation proteins factor XIII (FXIII) and thrombin activatable fibrinolysis inhibitor (TAFI) are enzymes that act to stabilize clots, downstream of fibrin generation and polymerization. Though this makes them ideal targets to reduce the burden of thrombosis while maintaining hemostasis, no inhibitors for either protein are currently available in the clinic. As we have recently published (Strilchuk, et al. Blood. 2020), lipid nanoparticles can be used to deliver siRNA to knock-down FXIII-B and achieve depletion of FXIII-A from circulation in mice and rabbits. FXIII-A depletion causes less antiplasmin to be crosslinked to clots, resulting in clots that are more susceptible to fibrinolysis. In the current abstract, we have expanded on preliminary data showing that while clots are weaker, bleeding is not enhanced in mice or rabbits after minor or major injury. We have also leveraged the same biological tools to knock-down TAFI for days after a single administration. In the short term, these novel RNA agents will be valuable tools in investigating the biology of thrombotic disorders. The ultimate goal is to develop these agents into precise and long-acting prophylactic therapies for thrombotic disorders, that are safer and more effective than current standards of care. No relevant conflicts of interest to declare.