An antioxidant enzyme to suppress hyperinflammation induced by SARS-CoV-2

PROJECT SUMMARY The COVID-19 pandemic has taken a significant toll on people worldwide, and current treatment is mainly supportive. While the pathogenesis of COVID-19 remains elusive, accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have virally driven hyperinflammation and immune dysregulation. We propose herein reactive oxygen species contribute to hyperinflammation and immune dysregulation in severe COVID-19 patients, which can be treated by an antioxidant enzyme-catalase that regulates cytokine production, protects against oxidative injury, and represses replication of SARS-CoV-2. This therapeutic based on catalase, the most abundant antioxidant enzyme ubiquitously present in the liver, erythrocytes and alveolar epithelial cells, is the most effective catalyst to breakdown hydrogen peroxide and minimize the downstream reactive oxygen species. The potential of catalase as a therapeutic agent has been explored for different diseases in vitro and in mouse models, including influenza-associated pneumonia, respiratory infections caused by respiratory syncytial virus (RSV), and inflammatory disease associated with oxidative stress. However, the efficacy of catalase has been hampered by its poor stability and short plasma half-life. Particularly, in the context of COVID-19 patients, death of the alveolar cells and inflammation could result in high local concentrations of proteases, further deteriorating the stability of catalase. We recently published an effective delivery system of catalase using the nanocapsule technology. Catalase delivered by nanocapsules assists to regulate production of cytokines and protect oxidative injury, as demonstrated in human leukocytes and alveolar epithelial cells, and repress replication of SARS-CoV-2 in rhesus macaques, without noticeable toxicity. In this proposal, we will further investigate the immunoregulatory effect of catalase nanocapsules on hyperinflammation induced by SARS-CoV-2 ex vivo, further optimize their biodistribution, pharmacokinetics, and delivery efficiency to SARS-CoV-2 infected organs, and test their therapeutic efficacy in the SARS-CoV-2 infection mice developing respiratory disease resembling severe COVID-19. Success of this project may provide an effective therapeutic solution for the pandemic, as well as treatment of hyperinflammation induced by virus infection in general.