Critically ill COVID-19 associated trait genetics reveals CDK6 inhibitors as potential treatment

Klinger, J. E.; Ravarani, C. N. J.; Bannard, C.; Lamparter, M. R. J.; Schwinges, A. R. E. C.; Cope, J. L.; Baukmann, H. A.; Schmidt, M. F.

Despite the recent development of vaccines and monoclonal antibodies preventing SARS-CoV-2 infection, treating critically ill COVID-19 patients still remains a top goal. In principle, drug repurposing, the use of an already existing drug for a new indication, could provide a shortcut to a treatment. However, drug repurposing is often very speculative due to the lack of clinical evidence. We here report on a methodology to find and test gene drug target candidates for drug repurposing. We matched critically ill COVID-19 cases from the UK Biobank with healthy controls and screened for significant differences in 33 blood cell types, 30 blood biochemistries, and body mass index in cases and controls. Significant differences in traits that have previously been associated with critically ill COVID-19 status, such as alanine aminotransferase, body mass index, C-reactive protein, and neutrophil cell count were further investigated. In-depth statistical analysis of COVID-19 associated traits and their genetics using regression modeling and propensity score stratification identified cyclin-dependent kinase 6 (CDK6) as a more promising drug target to selectively treat critically ill COVID-19 patients than the previously reported interleukin 6. Four existing CDK6 inhibitors abemaciclib, ribociclib, trilaciclib, and palbociclib have been approved for breast cancer. Clinical evidence for CDK6 inhibitors in treating critically ill COVID-19 has been reported. Further clinical investigations are ongoing.