Metabolism and Mitochondrial Energetics Therapy for Septic Shock

PROJECT SUMMARY / ABSTRACT Metabolic reprogramming plays a critical role in immune cell activation, differentiation, and function in response to severe sepsis. Broad defects in leukocyte bioenergetics underlie the immunometabolic paralysis in sepsis. Dichloroacetate (DCA) is an investigational drug and the prototypic inhibitor of pyruvate dehydrogenase kinase (PDK) that inhibits the mitochondrial pyruvate dehydrogenase complex (PDC) by reversible phosphorylation. PDC catalyzes the rate-limiting step in aerobic glucose oxidation in mitochondria. Our Central Hypothesis is that DCA represents a novel, mechanism-based therapy that targets the underlying mitochondrial bioenergetic failure responsible for sepsis. Accordingly, to evaluate DCA’s safety and therapeutic potential more rigorously in septic shock, Medosome Biotec, in collaboration with the University of Florida, Wake Forest University, and Northwestern University, will evaluate various DCA intravenous dosages for the treatment of sepsis in pigs as a large animal model of sepsis. The Specific Aims (SA) of this STTR Phase I/Phase II Fast-track grant proposal focus on conducting pharmacokinetic, safety and efficacy experiments and establishing Chemistry, Manufacturing and Controls (CMC) information. Following a Pre-IND meeting with the Center for Drug Evaluation and Research (CDER), we will complete all IND-enabling studies (GLP, toxicity studies, etc.) required for the IND application and, upon approval, apply to initiate future clinical trials evaluating DCA as a treatment for sepsis.