Therapeutic Inhibition of MIF in Type 1 Diabetes

DESCRIPTION provided by applicant The long term product goal of this project is a small molecule therapeutic to prevent or treat Type diabetes T D Our objective is to reduce the inflammatory response triggered by the pro inflammatory cytokine macrophage migration inhibitory factor MIF Under physiological conditions MIF is secreted by cells and regulates their function but during immunoinflammatory events the pancreatic islets secrete high amounts of MIF that mediate islet apoptosis Immunoneutralization or genetic deletion of MIF in mouse models of T D has correlated with halting the progression of T D or completely preventing the disease Since MIF is an upstream regulator of the inflammatory cascade small molecule therapeutics targeting MIF activity are expected to provide effective treatment for T D which currently afflicts million people in the US alone and for which there is no curative therapy To this end we have identified novel small molecule MIF inhibitors Our lead proprietary small molecules F and A block MIF driven cellular activation pathways that are associated with the immunopathology of T D including apoptosis and production of proinflammatory mediators F and A are minimally cytotoxic and are structurally unique possessing functional groups that have not been previously associated with MIF inhibitory activity The immediate objectives of the Phase I is to demonstrate the therapeutic efficacy of L andapos s proprietary F and A small molecules to reverse or prevent T D in the well established T D non obese diabetic NOD mouse model NOD mice which are the mainstay of preclinical diabetes research as they share similarities with human T D will be treated with our lead compounds and controls in a time and dose dependent manner Therapeutic efficacy will be monitored by measuring blood glucose levels and cell death by our recently developed novel droplet digital PCR In addition we will perform cellular assays measuring Th Th and T regulatory cytokine levels as well as apoptosis to determine the effects of the F and A on MIF driven inflammatory process All of these efforts are expected to yield a lead compound suitable for further development towards a small molecule therapeutic for T D PUBLIC HEALTH RELEVANCE Type diabetes is characterized by an autoimmune destruction of cells of the pancreas The long term goal of this project is to develop a novel type diabetes therapeutic drug that blocks the action of the pro inflammatory cytokine macrophage migration inhibitory factor