Genome-wide CRISPR screens for drug target identification and inhibition of SARS-CoV-2 replication – CRISPR-TARGET-CoV

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the current coronavirus disease 2019 (COVID-19) pandemic. This virus emerged in China at the end of 2019 and has, since then, dramatically spread across the world. As of today (18th of June 2020), SARS-CoV-2 has caused more than 445,000 deaths worldwide, general lockdowns in many countries across the globe and an unprecedented global economic crisis. SARS-CoV-2 is the seventh coronavirus identified as capable of infecting humans and is closely related to the highly pathogenic SARS-CoV (or SARS-CoV-1), isolated in 2002. Similarly to SARS-CoV disease, COVID-19 is characterized by fever, breathing difficulty, acute respiratory distress syndrome and death in the most severe cases. There is currently no treatment or vaccine available. Strategies for vaccine development are being developed with several ongoing clinical trials in phase II and III, but even if some of these strategies prove to be efficient, a large-scale vaccine will take months to produce. There is therefore a dire need to better understand the requirements for SARS-CoV-2 replication at the cellular level in order to identify potential drug targets and rapidly help developing treatments.
Genetic screens with CRISPR (clustered regularly interspaced short palindromic repeats) technology are powerful approaches to identify genes and pathways involved in various biological processes, such as viral infections. With the CRISPR-TARGET-CoV project, we propose to rapidly perform genome-scale CRISPR screens to identify both cellular dependency factors and inhibitors of SARS-CoV-2 in close collaboration with Dr. John Doench, a world leader in the CRISPR field. This work will establish a map of new possible drug targets for COVID-19. We will then screen selected drugs of interest, which will be relevant with respect to the identified cellular factors. We will focus on approved molecules, that could be used in a repositioning strategy in order to rapidly identify new potential therapeutic avenues for COVID-19. The effect of the drugs will be validated ex vivo, in primary human airway epithelial cells, one of the best models for analysis of SARS-CoV-2 replication.