The rapid spread of SARS-CoV2 presents an unprecedented challenge to urgently control disease morbidity, mortality, and spread. Antiviral drugs including remdesivir, favipiravir, and EIDD-2801 have emerged as front-line treatments. However, there are toxicity concerns for these drugs, especially as they are most effective when given at high doses early in disease progression. The ability to administer these antivirals more safely, particularly in less severely affected individuals, will allow for earlier treatment. In this project, we combine experimental genomic approaches and genetic association studies 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 toxicity of SARS-CoV-2 antiviral drugs in liver and intestinal cell lines.
In Aim 2, we will examine genetic associations of remdesivir efficacy and toxicity from ongoing clinical trials.
In Aim 3, we will combine this information to test approved pharmaceuticals or nutrients which are known to target or interact with genes we identify to determine if any mitigate drug cytotoxicity. We will also determine whether there are 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-2 antiviral drugs.
Antiviral drugs have shown promise in treating patients infected with SARS-CoV2, the virus that causes COVID- 19. Because the SARS-CoV2 outbreak has accelerated the timelines for clinical testing and widespread administration of such antiviral drugs, every effort must be made to conduct the typically methodical drug vetting process in real-time to ensure that these drugs are used most safely and effectively. We will establish new approaches to assess the risks of SARS-CoV2 antiviral drug toxicity, seeking to identify ways to mitigate these risks to permit safer and more effective treatment of patients with these drugs.
