Grant: Doctoral Research Award: Canada Graduate Scholarships

Approximately 100,000 Canadians annually suffer an adverse blood clot, the underlying cause of many cardiovascular pathologies, including pulmonary embolism, heart attack, and stroke. Pathological clot formation inside intact blood vessels (thrombosis) accounts for >10,000 Canadian deaths every year. Currently, the only preventative treatment option for at-risk patients is continuous anticoagulant therapy, which requires daily dosing, frequent monitoring, and often increases the risk of uncontrolled and spontaneous major bleeding. Plasminogen activator inhibitor 1 (PAI-1) is a blood protein that slows the breakdown of blood clots, thereby promoting clot stabilization and thrombosis. PAI-1 levels are high in stroke patients and in other diseases with high risk of thrombosis, such as COVID-19. Furthermore, PAI-1 is also a marker and mediator of cell aging; circulating levels of PAI-1 increase with age and the progression of age-associated diseases, such as Alzheimer's disease, diabetes, cancer, and obesity. Decreasing circulating PAI-1 levels has both experimental and therapeutic value, but there is a lack of clinically suitable and long-lasting approaches. RNA gene therapy represents an alternate option to regulate the levels of target proteins, such as PAI-1 that have major limitations to traditional small-molecule or protein-based therapies. This project aims to develop long-lasting and semi-permanent gene therapy agents to decrease circulating PAI-1 levels. The therapeutic potential of these agents in decreasing and/or preventing thrombosis will be assessed. Advancing RNA gene therapy may provide a novel tool to reduce the risk of morbidity and mortality in thrombosis as well as in other PAI-1 - related diseases.