To develop a universal strategy to block SARS-CoV-2 cellular entry and
infection represents a central aim for effective
COVID-19 therapy. The growing impact of emerging variants of concern increases the urgency for development of effective interventions. Since ACE2 is the critical SARS-CoV-2 receptor and all tested variants bind to ACE2, some even at much increased affinity (see accompanying paper), we hypothesized that
aerosol administration of clinical grade soluble human recombinant ACE2 (APN01) will neutralize SARS-CoV-2 in the airways, limit spread of
infection in the lung and mitigate lung damage caused by deregulated signaling in the
renin-
angiotensin (RAS) and
Kinin pathways. Here we show that
intranasal administration of APN01 in a mouse model of
SARS-CoV-2 infection dramatically reduced
weight loss and prevented animal death. As a prerequisite to a clinical trial, we evaluated both virus binding activity and enzymatic activity for cleavage of Ang II following aerosolization. We report successful aerosolization for APN01, retaining viral binding as well as catalytic RAS activity. Dose range-finding and IND-enabling repeat-dose
aerosol toxicology testing were conducted in dogs. Twice daily
aerosol administration for two weeks at the maximum feasible concentration revealed no notable toxicities. Based on these results, a Phase I clinical trial in healthy volunteers can now be initiated, with subsequent Phase II testing in individuals with
SARS-CoV-2 infection. This strategy could be used to develop a viable and rapidly actionable
therapy to prevent and treat
COVID-19, against all current and future SARS-CoV-2 variants.