Coenzyme A replenishment as a therapeutic strategy for inborn errors of metabolism

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PROJECT SUMMARY Better ways to treat genetic metabolic disorders are needed. More than 30 inborn errors of metabolism are predicted to lead to a functional deficiency of coenzyme A (CoA), including most conditions detected by expanded neonatal screening. Defects of fatty acid and amino acid metabolism generate high levels of organic acids, which form intracellular acyl CoA esters and lead to the sequestration or redistribution of CoA. Two primary inborn errors of CoA biosynthesis are now recognized, as well. Coenzyme A is critical to a diverse range of cellular processes, including intermediary metabolism, transcriptional regulation, signal transduction, and autophagy. Therefore deficient bioavailable CoA would disrupt myriad cellular processes and contribute to chronic morbidity in people affected by these diseases. Current state of treatment: The mainstay for managing this diverse group of disorders is early diagnosis, prevention of catabolic stress, and treatment with dietary modifications that decrease precursor availability and deliver small molecules (carnitine and glycine) to facilitate urinary excretion of toxic metabolites. While this general approach has improved survival of the acute toxic states, few of these patients are in good health. They suffer from a persistent abnormal metabolic state often with failure to thrive, neurodevelopmental disabilities, dysrhythmias, chronic liver disease and other complications, problems that are predicted to arise in part from depletion of CoA. The primary inborn errors of CoA synthesis cause lethal pediatric neurodegenerative disorders for which there are currently no treatments. Why is this R21 proposal innovative? Here, we propose a novel approach that will not only elucidate the pathophysiology of selected inborn errors metabolism but will also provide a “go-no go” decision for use of a precursor in CoA synthesis as a rational therapeutic to replenish CoA levels. Phosphopantetheine, a key intermediate in the synthesis of CoA, was recently discovered to serve as the stable precursor for rapid CoA synthesis. Using animal models representing four distinct CoA depletion disorders (propionic acidemia; glutaric acidemia type 1; very long-chain acyl-CoA dehydrogenase deficiency; and pantothenate kinase-associated neurodegeneration), we propose to 1) demonstrate that these mutant animals are more sensitive than controls to selective CoA depletion; and 2) demonstrate the efficacy of phosphopantetheine in ameliorating disease- associated biochemical and clinical defects. These R21 exploratory investigations have the potential to contribute important knowledge to the understanding of these diseases and to advance development of phosphopantetheine and its derivatives for further human studies. If successful, the work could fundamentally change management of 30+ human diseases and significantly improve the lives of tens of thousands of people with poor therapeutic options.