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Several drugs have been reported to significantly reduce the severity of COVID-19 in humans and are in use as part of clinical management (reviewed in ref. 118). In a study by Domínguez-Bendala et al.120, the treatment of SARS-CoV-2 infection in BALB/c mice with the angiotensin-converting enzyme inhibitor (ACEI) ramipril significantly reduced viral load compared to vehicle-treated controls, highlighting the utility of mouse kidney organoids as a model of SARS-CoV-2 pathogenesis, drug screening, and human-mouse chimera assessment. To date, several investigations have sought to identify a specific drug acting as a SARS-CoV-2 prophylaxis or treatment. The investigators of ref. 97 screened a library of 843 FDA-approved drugs for in vitro inhibition of SARS-CoV-2 replication in VeroE6 cells (resulting in reduced CPE compared to untreated control cultures). A subset of 20 compounds reduced viral replication by over 90%, including the clinically-used drugs lopinavir and ritonavir, the latter of which was additionally shown to reduce virus load in patient blood samples. Additional drug screening of the library was performed in the context of organoid cultures derived from separate protocols, though precluded by the limited supply of high quality kidney organoids of various ages, showing a similar reduction in viral replication compared to untreated controls. Recently, a single-blind, randomized, placebo-controlled trial of 37 patients in Wuhan, China examined the effect of the anti-inflammatory drug lopinavir as a SARS-CoV-2 treatment, finding that virus load was not significantly reduced in any individuals in the treatment arm compared to placebo104. However, as this study was underpowered to detect a treatment effect, these findings need to be interpreted with caution and controlled clinical studies remain necessary. Differences in SARS-CoV-2 replication levels between in vitro and in vivo remain unclear and the full range of in vitro conditions (e.g. access to vascular endothelium, oxygen tension) may not recapitulate the in vivo situation and consequently efficacy in humans. In these regards, organoids provide an in vivo-mimicking, human-relevant alternative to in vitro cell culture-based studies.
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