Novel drug treatments for pyruvate dehydrogenase complex deficiency

? DESCRIPTION (provided by applicant): Glucose serves as the primary oxidizable fuel for energy production in the brain during development and adulthood, and hence an impairment in glucose metabolism can have severe consequences on brain development and function. Genetic defects of the pyruvate dehydrogenase (PDH) complex (PDC) are associated with severe neurological malformations and impaired cerebral function. In the large majority of cases of PDC deficiency is due to defects in the PDHA1 gene located on chromosome X, and hence affected males and females manifest severity of the disease quite variably. We have developed a murine model that carries a mutation in the X-linked Pdha1 gene. Our findings show that PDC deficiency in the developing mouse brain results in many of the same structural defects that have been reported in affected children. The standard treatments such as ketogenic diet and supplementation of vitamins, have proven to be less effective in PDC- deficient patients. Our mouse model presents an opportunity to explore the efficacy of other compounds to increase acetyl-CoA formation by either activation of residual inactive phosphorylated PDC activity using phenylbutyrate, a potent inhibitor of PDH kinases, or by enhacing amino acid catabolism via mitochondrial metabolism using rapamycin, an inhibitor of mTOR, in the immediate postnatal life. Our two specific aims are to: (i) Investigate the potential beneficial effects of an early postnatal treatment with phenylbutyrate, an inhibitor of PDK kinases, aiming to enhance glucose oxidation at the level of residual active PDC activity to improve cerebellar development, and (ii) investigate beneficial effects of rapamycin administration during the suckling period to increase amino acid oxidation and to reduce mitochondrial dysfunction to minimize abnormal cerebellar development in PDC-deficient mice. We will investigate the efficacy for beneficial effects of these two drugs using the following three parameters: (i) histological and immuno-histological analyses and semi- quantitative morphometric analysis of cerebellar cortex, (ii) BrdU labeling and immunostaining to monitor differentiation, migration and proliferation of cells in the postnata period, and (iii) behavioral evaluation of the cerebellar function in the postweaning period. This comprehensive set of studies promises to provide insight into novel therapeutic treaments for a clinically important inherited metabolic disorder such as PDC deficiency which limits glucose metabolism by the brain. Testing of phenylbutyrate and rapamycin for improvement in PDC deficiency outcomes are novel pre-translational approaches. These compounds have a high potential to provide new therapeutic approaches for treating PDC deficient patients and could improve quality of life, save lives, and reduce health care costs.