Fibrinolytic granulocyte-derived extracellular vesicles as an innovative therapeutic strategy in septic shock-associated cerebral thromboembolic stroke – FIGRAVIS

Ischemic stroke in sepsis shock is associated with increased mortality and long-term cognitive impairment. Due to its critical position, the brain vessel recanalization is an emergency. However, in sepsis context, the therapeutic strategies available are limited. Thus, innovative approaches targeting the fibrinolysis impairment are absolutely warranted. Granulocyte-derived Extracellular Vesicles (Gran-EVs) are circulating fibrinolytic carriers whose binding molecules allow them to reach the fibrin clot. The fibrinolytic Gran-EVs were associated with less coagulopathy and a better prognosis in sepsis shock patients. Consistently, in a murine model of sepsis, it was recently observed that the repeated injection of fibrinolytic Gran-EVs significantly 1/increased the mouse fibrinolytic circulating activity 2/reduced the number of thrombi in vital organs and 3/improved mouse survival. In addition, it was shown that Gran-EVs from septic patients lyse a thrombus according to their fibrinolytic potential. Therefore, our hypothesis is that injection of granulocyte-derived EVs with a highly fibrinolytic activity may improve the septic shock prognosis by participating to the organ thrombi resolution in vivo. Two research groups, respectively renowned in EV biology and their impact in the cardiovascular system (C2VN) and neurovascular diseases (PhIND) will join their force to carry out this project whose aims are 1/to produce and characterize gran-EVs with a highly fibrinolytic activity; 2/to evaluate their effect on thrombus resolution in vivo in mouse models of sepsis, and 3/to evaluate their therapeutic potential on sepsis-associated thromboembolic stroke compared to currently available thrombolytic therapies. The ultimate goal of this project is to pave the ground of an innovative therapeutic EV-based strategy in septic shock-associated cerebral stroke relevant for future clinical translation.