权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Phenylbutyrate therapy for maple syrup urine disease

丁酸苯酯治疗枫糖浆尿病

基本信息

批准号：
8286874
负责人：
Brendan Lee
金额：
$ 65.62万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8286874
关键词：
3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)Accounting Ammonia Animals Basic Science Beta Catenin Staining Method Biochemical Biological Branched-Chain Amino Acids Carboxy-Lyases Cell Culture Techniques Cell Cycle Inhibition Cell Line Cells Chemicals Clinical Clinical Research Clinical Treatment Clinical Trials Cohort Analysis Complex Coupled Cross-Over Studies Cystic Fibrosis Data Diabetes Mellitus Diagnosis Disease Double-Blind Method Essential Amino Acids Excretory function FDA approved Genetic Transcription Genotype Glutamine Goals Hemoglobinopathies Hepatic Hereditary Disease Histone deacetylase inhibition Human Hyperammonemia In Vitro Inborn Errors of Metabolism Isoenzymes Isoprenylation Inhibition Keto Acids Leucine Longitudinal Studies Maple Syrup Urine Disease Measures Mental Depression Molecular Chaperones Monitor Mouse Cell Line Multienzyme Complexes Mus Mutation Natural History Neonatal Screening Nitrogen Patients Pharmaceutical Preparations Pharmacological Treatment Pharmacotherapy Phenylacetates Phenylbutyrates Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Placebo Control Process Protein Dephosphorylation Proteins Recurrence Residual state Route Safety Sodium phenylbutyrate Spinal Muscular Atrophy Structure Testing Time Translating Variant Western Blotting base clinical phenotype efficacy testing enzyme activity in vitro Assay in vivo insight lymphoblast novel oxidation preclinical study research study response small molecule urea cycle urinary

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：本申请的目标是将基础科学发现转化为基于改变E1？支链酮酸脱羧酶复合物（BCKDC）的亚基。蛋白质磷酸化是参与所有疾病过程的关键调节机制。基于我们对FDA批准的药物苯丁酸钠（PB）治疗尿素循环障碍患者的纵向研究，我们观察到其在人体中使用对支链氨基酸的选择性抑制作用。使用人类，小鼠，细胞和生物化学研究的组合，我们发现PB直接调节BCKDC的E1a亚基的磷酸化，该亚基负责支链氨基酸和酮酸的氧化，从而解释了这种效应。基于我们的初步数据，我们提出回答三个问题，这将直接将我们的观察转化为通过靶向蛋白磷酸化治疗枫糖浆尿病（MSUD）：1）PB能否用于临床治疗支链酮酸脱羧酶复合物突变的枫糖浆尿病患者？2)我们能否开发出一种预测性的体外试验，以预测BCKDC对PB的反应，并与体内临床反应相关联？3)我们能否通过阐明特定MSUD突变亚类中PB应答的结构基础，基于基因型预测临床应答？通过结合临床试验，对患者细胞系和小鼠的临床前研究以及生化实验，我们希望将对PB的新机制活性的基本观察转化为治疗经典先天性代谢缺陷的更广泛方法，该方法目前没有可用的药理学治疗。