Systems medicine analysis of sarcoidosis by targeting mTOR in a co-clinical trial in patients and mice

Sarcoidosis is a chronic disease of unknown etiology affecting multiple organs lacking targeted therapies. We have recently identified mTOR activation in macrophages as a reversible cause of progressive sarcoidosis in mice, raising the exciting prospect of using clinically available mTOR inhibitors in the treatment of sarcoidosis. The proposed project will employ an integrative systems approach to dissect the pathomechanisms of sarcoidosis and the effect of mTOR inhibition in an unprecedented parallel study of mice and patients undergoing the same treatment regimen. We set up a human clinical trial that investigates the efficacy of mTOR inhibition in progressive sarcoidosis patients, in which each patient is sequentially exposed to different treatment regimens with the mTOR inhibitor sirolimus. This study will be replicated in a co-clinical trial using our sarcoidosis mouse model. Time series samples will be profiled using single-cell sequencing technology. Cross-patient and cross-species bioinformatic analysis will elucidate the pathophysiology of sarcoidosis and mechanisms of action of mTOR inhibition. Key results will be functionally validated in our mouse model and inducible pluripotent stem cells. By combining a clinical trial and a unique mouse model with single-cell technology, this proposal connects mechanism-based and high-throughput research to patient needs for an underserved disease to establish a new therapy and validate targets for future clinical studies