Phenylbutyrate therapy for maple syrup urine disease

描述（由申请人提供）：本申请的目标是基于修改E1磷酸化状态的方法，将基础科学发现转化为MSUD患者新的更好的治疗方法。支链酮酸脱羧酶复合物（BCKDC）的亚基。蛋白磷酸化是参与所有疾病过程的关键调控机制。基于我们对FDA批准的药物苯丁酸钠（PB）在尿素循环障碍患者中的纵向研究，我们观察到在人类中使用它会选择性地抑制支链氨基酸。通过人、小鼠、细胞和生化研究的结合，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，从而解释了这种作用。根据我们的初步数据，我们提出回答三个问题，这些问题将直接将我们的观察转化为针对蛋白磷酸化治疗枫糖浆尿病（MSUD）： 1) PB是否可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)我们能否开发一种与体内临床反应相关的BCKDC对PB反应的预测性体外试验？3)通过阐明特定MSUD突变亚类对PB反应的结构基础，能否预测基于基因型的临床反应？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新机制活性的基本观察转化为更广泛的方法，以治疗目前尚无药物治疗的经典先天性代谢错误。

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.