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Therapies for inborn errors of metabolism (IEMTx)
Start date: Nov 1, 2012, End date: Oct 31, 2017 PROJECT  FINISHED 

We discovered that phenylbutyrate, prevents both in vitro and in vivo the inactivation by phosphorylation of the branched chain ketoacid dehydrogenase complex (BCKDC) and pyruvate dehydrogenase complex (PDHC). We show that phenylbutyrate is effective for treatment of maple syrup urine disease (MSUD) due to deficiency of branched chain ketoacid dehydrogenase complex (BCKDC), and has potential for therapy of deficiency of pyruvate dehydrogenase complex (PDHC). We propose to investigate phenylbutyrate for PDHC deficiency in a zebrafish model and in PDHC-deficient patients. We have recently developed a systems biology tool for prediction of drug mode of action starting from their gene expression profiles. This tool has a significant potential for drug discovery and repositioning. Through this approach, we found several FDA-approved drugs sharing with phenylbutyrate a similar mode of action. We propose to investigate the efficacy of these drugs for increasing the enzymatic activity of both BCKDC and PDHC and their therapeutic potential. While useful for proof-of-concept studies animal models are not suited to predict patient response to drugs which depends upon multiple factors including type of mutation and affected enzyme subunit. We propose to develop PDHC deficient neurons and MSUD hepatocytes from induced pluripotent stem cells (iPSCs) derived from patients’ fibroblasts. Drug response in these disease-relevant cell types will better predict clinical response of patients. Human iPSCs will be generated through a novel system based on high cloning capacity, non-integrating helper-dependent adenoviral (HDAd) vector expressing a combination of reprogramming factors. We will investigate altered metabolic pathways in PDHC deficient neurons and MSUD hepatocytes to search for effective drugs by an innovative systems biology approach. In summary, the results of the proposed study have the potential to provide novel and effective treatments for MSUD and PDHC deficiency.

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