Mechanistic studies on ACE2 as a rational therapy for COVID-19

The COVID-19 pandemic has already killed 100,000s of people worldwide, and triggered a massive global effort to develop vaccines and therapeutics. We will build on our previous research to test a front-line candidate drug, human recombinant soluble ACE2 (hrsACE2), as a treatment for COVID-19. There is a strong rationale for hrsACE2 to be effective: first, hrsACE2 is a modified version of the human protein (ACE2) that SARS-CoV-2 uses to infect cells in the lungs and other organs. We have already shown that hrsACE2 blocks SARS-CoV-2 infection by acting as a decoy. Second, in animal models, hrsACE2 helps to reduce tissue damage in lung, heart, and kidney, and therefore could help prevent multi-organ failure in COVID-19 patients. hrsACE2 is already known to be safe to use, and is currently being tested in clinical trials for COVID-19. While there is an urgent need to understand how SARS-CoV-2 causes disease, evaluate drug efficacy, and optimize treatment conditions, there are limitations to testing in human patients. The goal of our project is to test the effects of hrsACE2 in a living organism and optimize rhsACE2 treatment (dose, drug delivery methods, and timing) to get maximal benefits. For this we will use our novel, improved, mouse model that expresses the human ACE2 gene in the correct location in the lung and other organs, and develops disease after infection. We will also use this mouse to test combination therapies of hrsACE2 with two other front-line drugs remdesivir, an antiviral, and chloroquine, an antimalarial drug. We anticipate that a combination of hrsACE2 treatment with these drugs would allow a reduction in the dosage of remdesivir (known to have liver toxicity at high dose) and chloroquine (heart toxicity at high dose) to a safer range.