Neutrophils cause critical illness in COVID-19 and reveal CDK6 inhibitors as potential treatment

Abstract

BackgroundDespite recent development of vaccines and monoclonal antibodies to prevent SARS-CoV-2 infection, treatment of critically ill COVID-19 patients remains an important goal. In principle, genome-wide association studies (GWAS) could shortcut the clinical evidence needed to repurpose drugs - the use of an existing drug for a new indication. However, it has been shown that the genes found in GWA studies usually do not encode an established drug target and the causal role for disease, a key requirement for drug efficacy, is unclear. We report here an alternative method for finding and testing causal target candidates for drug repurposing. MethodsRather than focusing on the genetics of the disease, we looked for disease-causing traits by searching for significant differences in 33 blood cell types, 30 blood biochemistries, and body mass index between an infectious disease phenotype and healthy controls. We then matched critically ill COVID-19 cases with controls that exhibited mild or no symptoms after SARS-CoV-2 infection in order to identify disease-causing traits by applying causal inference methods. ResultsWe found high neutrophil cell count as a causal trait for the immune overreaction in critical illness due to COVID-19. Based on these findings, we identified the enzyme CDK6 as a potential drug target to prevent the immune overreaction in critical illness due to COVID-19. ConclusionsThe genetics of disease-causing traits turns out to be a rich reservoir for the identification of known drug targets. This is due to the usually larger datasets of traits, as they also cover healthy ones. A clinical trial testing CDK6 inhibitor palbociclib in critically ill COVID-19 patients is currently ongoing (ClinicalTrials.gov Identifier: NCT05371275).