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.
