Introduction
COVID-19 can present with complex multiorgan pathologies that can trigger long-term sequela. Given that inflammasome products, play a role in COVID-19, we investigated caspases across the spectrum of COVID-19 disease.
Methods
We assessed transcriptional states of multiple caspases and using flow cytometry, the expression of active caspase-1 in blood cells from COVID-19 patients in acute and convalescent stages of disease. We also conducted a 1:1 randomized, double blind, placebo-controlled Phase 1 study to assess safety of a pan-caspase inhibitor, emricasan, given for 14 days in mild-symptomatic COVID-19.
Results
Single-cell RNA-seq data of immune cells from COVID-19 patients showed a distinct caspase expression pattern in immune cells. Caspase-1 was upregulated in CD4+ T-cells from hospitalized COVID-19 patients compared with unexposed controls. Post-COVID-19 patients with lingering symptoms also showed upregulated caspase-1activity in CD4+ T-cells that ex vivo was attenuated with a select pan-caspase inhibitor. A total of 13 subjects consented for the Phase 1 study. As the primary endpoint, overall fewer adverse events with emricasan compared to placebo. In secondary endpoints, patients receiving emricasan had complete and much earlier resolution of COVID-19 symptoms and improvement (Figure) in the 8-point ordinal scale compared to placebo that was statistically significant compared to placebo.
Conclusion
Our preliminary results suggest an exuberant caspase response in COVID-19. Further clinical correlations of caspase expression in different stages of COVID-19 will be needed. Pan-caspase inhibition could emerge as a therapeutic strategy to ameliorate or prevent severe COVID-19.
Figure 1. Time to complete recovery of disease symptoms based on FDA-recommended 14-item patient reported outcome questionaire for COVID-19.