The goal of this application is to translate a basic science discovery into new and better treatments for patients with MSUD based on the approach of modifying the phosphorylation status of the E1? subunit of Branched Chain Ketoacid Decarboxylase Complex (BCKDC). Protein phosphorylation is a critical regulatory mechanism involved in all disease processes. Based on our longitudinal study of an FDA approved medication sodium phenylbutyrate (PB) in urea cycle disorder patients, we observed selective depression of branched chain amino acids as an effect of its use in humans. Using a combination of human, mouse, cell, and biochemical studies, we discovered that PB directly regulates the phosphorylation of the E1a subunit of the BCKDC that is responsible for oxidation of branched chain amino and ketoacids, thereby explaining this effect. Based on our preliminary data, we propose to answer three questions which will directly translate our observation into the treatment of Maple Syrup Urine Disease (MSUD) by targeting protein phosphorylation: 1) Can PB be used in the clinical treatment of maple syrup urine disease patients who have mutations in the branched chain ketoacid decarboxylase complex? 2) Can we develop a predictive in vitro assay of BCKDC response to PB that would correlate with in vivo clinical response? 3) Can we predict clinical response based on genotype by elucidating the structural basis of this response to PB in specific subclasses of MSUD mutations? By combining a clinical trial, preclinical studies on patient cell lines and mice, and biochemical experiments, we hope to translate a basic observation on a novel mechanistic activity of PB into a broader approach for treating a classical inborn error of metabolism that has no currently available pharmacological treatment.

R01DK092921

2011-07-01

2017-05-31