Combined pharmacologic and AAV gene therapy of pyruvate dehydrogenase deficiency

The National Institute of Child Health and Human Development awarded the University of Florida $419,375 on June 2, 2026, under the Child Health and Human Development Extramural Research program (CFDA 93.865) to develop a combined pharmacological and gene therapy approach for pyruvate dehydrogenase complex deficiency in children.

The research combines dichloroacetate (DCA), an oral medication that stimulates residual pyruvate dehydrogenase complex activity, with next-generation adeno-associated viral (AAV) vectors designed to deliver a functional E1A subunit gene (PDHA1) to restore enzyme activity in affected patients. A completed Phase 3 trial demonstrated that DCA monotherapy in 34 children with the disease was safe, significantly improved muscle function, caused sustained reductions in plasma lactate, and significantly increased survival; the FDA is expected to approve DCA as the first pharmacological treatment for the condition in May 2025. The proposed work leverages capsid- and genome-modified next-generation AAV vectors capable of high-efficiency transduction of the central nervous system and muscles, the primary pathological targets of pyruvate dehydrogenase complex deficiency.

Performance occurs in Gainesville, Florida, with a completion date of May 31, 2028. The award is a project grant, the assistance type supporting investigator-initiated research at academic institutions.

Abstract

Our ultimate goal is to develop a combined pharmacological and gene therapy approach for children with congenital deficiency of the mitochondrial pyruvate dehydrogenase complex (PDC), a vital energy homeostat in all eukaryotic cells. PDC deficiency (pdcd) is a rare, but devastating and ultimately fatal, disease devoid of any FDA-approved therapy. We have developed dichloroacetate (DCA) as a safe oral medication to stimulate residual PDC activity in pdcd-affected children. In addition, we have a productive history using first-generation recombinant adeno-associated viral (AAV) vectors to successfully deliver a functional E1Α subunit gene (PDHA1) of the PDC (mutations of which account for ~90% of all molecular genetic causes of pdcd), solely or in combination with DCA, as a means of restoring enzyme activity in pdcd patient cells. Two recent developments have provided the impetus for this application. First, we recently completed a federally-funded, multicenter phase 3 trial of chronic, oral DCA in children with pdcd. In this trial, DCA as single therapy in 34 children with pdcd was found to be safe, significantly improved muscle function and caused a significant, sustained fall in plasma lactate. IT also significantly increased survival. Accordingly, the FDA has accepted a new drug application and we anticipate its approval in may, 2025 of DCA as the first pharmacological treatment for pdcd. Second, we have helped lead the development of capsid- and genome-modified next generation (nextgen) adeno-associated virus (AAV) vectors, with which high-efficiency transduction of target cells and tissues can be achieved, including the central nervous system (CNS) and muscles - the primary pathological targets of pdcd. Thus, we are poised to combine our knowledge of DCA pharmacology and AAV vectorology toward developing a combined pharmacological and gene therapy approach for pdcd by accomplishing the following specific aims: specific aim 1: develop liver DE-targeted capsid- and genome-modified nextgen AAV vectors for high- efficiency transduction of skeletal muscles (AAVRH74) and CNS (AAV9) and demonstrate enhanced transgene expression from AAV-PDHA1 vectors. Specific aim 2: conduct proof-of-concept studies of combined DCA and AAV vector-mediated gene therapy to evaluate safety and efficacy of nextgen AAVRH74- and AAV9-PDHA1 vectors in a mouse model of pdcd. Successful completion of these aims is likely to lead to novel strategies toward the potential DCA+AAV gene therapy of pdcd in humans.