Абстрактный

Prophylactic administration of a clinically safe low dose of the COVID-19 drug candidate Rejuveinix (RJX) effectively prevents fatal cytokine storm and mitigates inflammatory organ injury in a mouse model of sepsis

Fatih M. Uckun, Cemal Orhan, Ibrahim H. Ozercan, Nurhan Sahin, Joy Powell, Natalie Pizzimenti, Michael Volk, Kazim Sahin

Severe viral sepsis of coronavirus disease 2019 (COVID-19) is associated with a Cytokine Release Syndrome (CRS) and a high case fatality rate due to the development of Acute Respiratory Distress Syndrome (ARDS) and multi-organ failure in high-risk COVID-19 patients, including cancer patients undergoing chemotherapy. Here, we demonstrate that our COVID-19 drug candidate Rejuveinix (RJX) exhibits potent protective anti-inflammatory activity in the LPS-GalN mouse model of fatal sepsis and multi-organ failure at a dose level >10x lower than its maximum tolerated dose (MTD) for human subjects. In BALB/c mice challenged with an otherwise invariably fatal dose of LPS-GalN, prophylactic administration of 0.7 mL/kg RJX (Human equivalent dose=0.057 mL/ kg), corresponding to 7.5% of its clinical Maximum Tolerated Dose (MTD), prevented the cytokine storm, mitigated the oxidative stress and inflammatory tissue injury in lungs, liver, and heart, and significantly improved the survival outcome. Furthermore, RJX increased the levels of antioxidant enzymes SOD, CAT, and GSH-Px, and reduced oxidative stress in the brain. These results indicate that RJX has clinical potential as a prophylactic anti-inflammatory agent against severe sepsis, including viral sepsis in COVID-19 patients.