Urgent Supplement: Correcting genetic disorders using predictable CRISPR/Cas9-induced exon skipping

Project Summary: The rapid spread of SARS-CoV2 presents an unprecedented challenge to urgently control diseasemorbidity, mortality, and spread. Antiviral drugs including remdesivir, favipiravir, and EIDD-2801 haveemerged as front-line treatments. However, there are toxicity concerns for these drugs, especially asthey are most effective when given at high doses early in disease progression. The ability to administerthese antivirals more safely, particularly in less severely affected individuals, will allow for earliertreatment. In this project, we combine experimental genomic approaches and genetic associationstudies to understand and mitigate toxicity of SARS-CoV-2 antiviral drugs.In Aim 1, we will use state-of-the-art genomic screening to identify human genes that mediate toxicityof SARS-CoV-2 antiviral drugs in liver and intestinal cell lines. In Aim 2, we will examine geneticassociations of remdesivir efficacy and toxicity from ongoing clinical trials. In Aim 3, we will combinethis information to test approved pharmaceuticals or nutrients which are known to target or interact withgenes we identify to determine if any mitigate drug cytotoxicity. We will also determine whether thereare any common genetic or disease conditions for which antiviral dosing may be inadvisable.Altogether, we aim to provide rapid and actionable insight on the toxicity of front-line SARS-CoV-2antiviral drugs.