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.

Public Health Relevance

Maple Syrup Urine Disease (MSUD) is a genetic condition diagnosed via newborn screening with no drug treatment. We are testing whether an FDA approved drug, sodium phenylbutyrate, can be used to treat MSUD and whether we can develop tests to predict who might respond to this treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK092921-02
Application #
8286874
Study Section
Special Emphasis Panel (ZRG1-GGG-N (02))
Program Officer
Mckeon, Catherine T
Project Start
2011-07-01
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$656,180
Indirect Cost
$148,328
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Burrage, Lindsay C; Jain, Mahim; Gandolfo, Laura et al. (2014) Sodium phenylbutyrate decreases plasma branched-chain amino acids in patients with urea cycle disorders. Mol Genet Metab 113:131-5
Berry, Susan A; Lichter-Konecki, Uta; Diaz, George A et al. (2014) Glycerol phenylbutyrate treatment in children with urea cycle disorders: pooled analysis of short and long-term ammonia control and outcomes. Mol Genet Metab 112:17-24
Burrage, Lindsay C; Nagamani, Sandesh C S; Campeau, Philippe M et al. (2014) Branched-chain amino acid metabolism: from rare Mendelian diseases to more common disorders. Hum Mol Genet 23:R1-8
Tso, Shih-Chia; Gui, Wen-Jun; Wu, Cheng-Yang et al. (2014) Benzothiophene carboxylate derivatives as novel allosteric inhibitors of branched-chain ?-ketoacid dehydrogenase kinase. J Biol Chem 289:20583-93
Tso, Shih-Chia; Qi, Xiangbing; Gui, Wen-Jun et al. (2014) Structure-guided development of specific pyruvate dehydrogenase kinase inhibitors targeting the ATP-binding pocket. J Biol Chem 289:4432-43
Ferriero, Rosa; Manco, Giuseppe; Lamantea, Eleonora et al. (2013) Phenylbutyrate therapy for pyruvate dehydrogenase complex deficiency and lactic acidosis. Sci Transl Med 5:175ra31
Smith, Wendy; Diaz, George A; Lichter-Konecki, Uta et al. (2013) Ammonia control in children ages 2 months through 5 years with urea cycle disorders: comparison of sodium phenylbutyrate and glycerol phenylbutyrate. J Pediatr 162:1228-34, 1234.e1
Diaz, George A; Krivitzky, Lauren S; Mokhtarani, Masoud et al. (2013) Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate. Hepatology 57:2171-9
Tso, Shih-Chia; Qi, Xiangbing; Gui, Wen-Jun et al. (2013) Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain *-ketoacid dehydrogenase kinase. Proc Natl Acad Sci U S A 110:9728-33
Kennerson, Marina L; Yiu, Eppie M; Chuang, David T et al. (2013) A new locus for X-linked dominant Charcot-Marie-Tooth disease (CMTX6) is caused by mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. Hum Mol Genet 22:1404-16

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