Editors' ChoiceCORONAVIRUS

An ACE therapy for COVID-19

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Science Translational Medicine  29 Apr 2020:
Vol. 12, Issue 541, eabb5676
DOI: 10.1126/scitranslmed.abb5676

Abstract

Recombinant human soluble ACE2 inhibits SARS-CoV-2 viral infection in human organoids in vitro.

To cause infection, a virus must gain entry into host cells to replicate. COVID-19 infection is caused by the severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2), which gains entry to host cells by attaching to a membrane-bound protein, angiotensin-converting enzyme 2 (ACE2). ACE2 is expressed mainly in the lung, which is the primary site of SARS-CoV-2 infection. However, it is also present at varying levels in the heart, vasculature, kidneys, and intestine. The pattern of multiorgan dysfunction seen in COVID-19 patients is likely related to this pattern of ACE2 expression and resultant widespread infection.

Monteil et al. sought to determine if human recombinant soluble ACE2 (hrsACE2) could be used to inhibit infection, presumably by viral binding to proteins in solution rather than those on host cells. In vitro, hrsACE2 drastically reduced viral recovery from host cell cultures, indicating prevention of host cell binding. Disease etiology and therapeutic potential of hrsACE2 were next examined in two human organoid models. First, the quantity of viral RNA expressed in infected capillary organoids increased over time, indicative of active tissue infection. This is crucial, as infection of blood vessels must occur for the virus to disseminate to tissues throughout the body. Kidney organoids were similarly susceptible to infection, as they expressed ACE2 in tubular cells (similar to known patterns in vivo). Although infection was not completely halted by hrsACE2 in vitro, treatment slowed viral replication in both organoid models, indicating the soluble enzyme may inhibit the spread of infection and lower viral loads which may correlate with disease severity.

Due to the present pandemic, there is an unprecedented call to arms among the scientific community. Many of us are working on shields to protect our frontline essential workers and medical professionals, while others are in a race for weapons to fight the virus more directly. The approach described here is of particular interest, as hrsACE2 has already passed through phase I and II clinical trials (NCT00886353, NCT01597635) for acute respiratory distress syndrome and has received regulatory approval (NCT04335136) for continued study in the fight against COVID-19.

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