1区 · 医学
Article
作者: Theodorou, Marina ; Dhindsa, Navreet ; Xu, Zhenghong Hannah ; Huang, Zhaohua Richard ; Voegelin, Manon ; Banerjee, Mainak ; Velten, Michel ; Detappe, Alexandre ; Diringer, Marie-Charlotte ; Chaban, Vitaliy ; Mertes, Paul-Michel ; Roche, Anne ; Laurent, Nina ; Sartori, Valérie ; Defuria, Jason ; Kim, Gwangseong ; Gizzi, Patrick ; Moyo, Victor ; Geng, Bolin ; Villa, Pascal ; Niyikiza, Clet ; Coliat, Pierre ; Khalifa, Kaniz ; Bernard, Alexandre ; Collange, Olivier ; Delabranche, Xavier ; Pivot, Xavier
Current therapeutic treatments improving the impaired transportation of oxygen in acute respiratory distress syndrome (ARDS) have been found to be relevant and beneficial for the therapeutic treatment of COVID-19 patients suffering from severe respiratory complications. Hence, we report the preclinical and the preliminary results of the Phase I/II clinical trial of LEAF-4L6715, a liposomal nanocarrier encapsulating the kosmotropic agent trans-crocetin (TC), which, once injected, enhance the oxygenation of vascular tissue and therefore has the potential to improve the clinical outcomes of ARDS and COVID-19 in severely impacted patients. We demonstrated that the liposomal formulation enabled to increase from 30 min to 48 h the reoxygenation properties of free TCs in vitro in endothelial cells, but also to improve the half-life of TC by 6-fold in healthy mice. Furthermore, we identified 25 mg/kg as the maximum tolerated dose in mice. This determined concentration led to the validation of the therapeutic efficacy of LEAF-4 L6715 in a sepsis mouse model. Finally, we report the preliminary outcomes of an open-label multicenter Phase I/II clinical trial (EudraCT 2020-001393-30; NCT04378920), which was aimed to define the appropriate schedule and dosage of LEAF-4L6715 and to confirm its tolerability profile and preliminary clinical activity in COVID-19 patients treated in intensive care unit.