Calpain Therapeutics to Inhibit Myofibroblast Generation in Fibrosis

Organ fibrosis and subsequent organ failure are estimated to account for at least one third of deaths worldwidePulmonary fibrosis is a relatively rare form of fibrosis but there are presently no effective treatmentsmean survival rates following diagnosis aretoyearsIn fibrosis of the lungas in other organsthe primary cell type that drives disease is the myofibroblastThis cell type is derived by direct conversion of other cell types in response to cell signaling factors such as TGFCalpaina cysteine proteasehas been implicated in the development of fibrosis but its role has not been fully exploredIn genetic studiesmice that lack calpain activity do not develop pulmonary fibrosis when exposed to the toxinbleomycinWe extended these results by demonstrating that fibroblasts isolated from these miceunlike their wild type counterpartsdo not form myofibroblasts in response to TGFtreatmentPhelix Therapeutics has developed a series of potent calpain inhibitors that show promising results in initial attempts to block myofibroblast generation in a cell based modelWe propose to further develop this model by employing quantitative measures of myofibroblast formationWe will use this model to evaluate the ability of calpain inhibitors to prevent myofibroblast formation from a variety of lung cell typesFinallyour best inhibitors will be tested in pharmacokinetic and ADME studies and optimized to improve their properties in vivo for subsequent use in efficacy studies in a mouse model of pulmonary fibrosis !Fibrosis is the process by which cells called myofibroblasts deposit matrix proteins in an organeventually leading to organ failureIn the lungpulmonary fibrosis lacks effective treatment options and has a mean survival rate oftoyearsWe have developed a promising class of compounds to block the formation of myofibroblastspotentially yielding the first anti fibrotic drugs!