PROJECT SUMMARY There is an urgent need for the development of new approaches to treat patients suffering from pulmonary injury from viral infections, as demonstrated by the severe impact of COVID-19, which is a global pandemic that, at the time of writing, is estimated have impacted approximately 50 million people in the United States, leading to morbidity, substantial hospital and intensive care utilization, and mortality. In multiple preclinical studies, we and others have defined the therapeutic potential of low dose exogenous carbon monoxide (CO) in acute lung injury, including in virus-induced pulmonary injury, by reducing inflammation and promoting viral clearance. To date, inhaled CO gas (iCO) and CO bound to carrier molecules (CORMs) have been the modalities of choice in the majority of animal and in all the clinical studies, and the safety and tolerability of CO has been demonstrated in 23 successful Phase 1 and 2 clinical studies, including in patients with pulmonary conditions such as ARDS and COPD. However, iCO and CORMS are not expected to be pharmaceutically acceptable and viable therapeutic options in COVID patients due to, for iCO, the risk of accidental inhalation exposure from the presence of compressed CO gas cylinders and imprecise dosing, especially in COVID-19 patients that have limited and variable respiratory function, and, for CORMs, problematic release kinetics and toxicological concerns with carrier molecules. The objective of the proposed project is to investigate HBI-002, a novel oral low dose CO drug product that enables the use of low dose CO in viral infections associated with acute pulmonary injury, such as COVID-19. HBI-002 is an oral liquid drug product containing CO. An IND is in place for HBI-002, with a Phase 1 clinical trial in healthy volunteers planned in 2022. The next step in development is to demonstrate that HBI-002 is effective in clinically relevant animal models of viral acute lung injury as has been shown with other forms of CO and to better understand the potential mechanism(s) of action. Based upon the substantial literature of CO in acute lung injury and our and others findings in virus-induced lung injury, our central hypothesis that will be tested in this project is: HBI-002 modulates the immune response to regulate inflammation and improve viral clearance in experimental models of virally induced lung injury sufficiently to warrant a Phase 2 clinical trial.