Journal
EMBO MOLECULAR MEDICINE
Volume 13, Issue 1, Pages -Publisher
WILEY
DOI: 10.15252/emmm.202013426
Keywords
clinical trial; combination therapy; COVID-19; treatment
Categories
Funding
- Innovative Medicines Initiative 2 Joint Undertaking (JU) [101005026]
- European Union
- EFPIA
- Canada 150 Research Chair program
- von Zastrow foundation
- COVID-19 grants from CIHR
- Austrian WWTF
- CIHR [440347, FDN143285, OV3-170344]
- European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program [StG-2014-640525_REGMAMKID]
- Swedish research council [2018-05766]
- Instituto de Salud Carlos III (ACE2ORG)
- Spanish Ministry of Economy and Competitiveness/FEDER [SAF2017-89782-R]
- Generalitat de Catalunya
- CERCA Programme [2017 SGR 1306]
- Asociacion Espanola contra el Cancer [LABAE16006]
- Marie Skodowska-Curie Individual Fellowships (IF) grant [796590]
- EFSD/Boehringer Ingelheim European Research Programme in Microvascular Complications of Diabetes
- Marie Curie Actions (MSCA) [796590] Funding Source: Marie Curie Actions (MSCA)
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The combination therapy of remdesivir with recombinant soluble ACE2 shows significant therapeutic effects against SARS-CoV-2 in both cell and kidney organoid models. By targeting two different modalities of the virus's life cycle, this approach improves therapeutic windows. The study lays the groundwork for investigating combinatorial regimens in future COVID-19 clinical trials.
There is a critical need for safe and effective drugs for COVID-19. Only remdesivir has received authorization for COVID-19 and has been shown to improve outcomes but not decrease mortality. However, the dose of remdesivir is limited by hepatic and kidney toxicity. ACE2 is the critical cell surface receptor for SARS-CoV-2. Here, we investigated additive effect of combination therapy using remdesivir with recombinant soluble ACE2 (high/low dose) on Vero E6 and kidney organoids, targeting two different modalities of SARS-CoV-2 life cycle: cell entry via its receptor ACE2 and intracellular viral RNA replication. This combination treatment markedly improved their therapeutic windows against SARS-CoV-2 in both models. By using single amino-acid resolution screening in haploid ES cells, we report a singular critical pathway required for remdesivir toxicity, namely, Adenylate Kinase 2. The data provided here demonstrate that combining two therapeutic modalities with different targets, common strategy in HIV treatment, exhibit strong additive effects at sub-toxic concentrations. Our data lay the groundwork for the study of combinatorial regimens in future COVID-19 clinical trials.
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