Phenylbutyrate therapy for maple syrup urine disease

描述(申请人提供)：这项申请的目标是将一项基础科学发现转化为针对MSUD患者的新的、更好的治疗方法，该方法是基于改变E1？支链酮酸脱羧酶复合体的亚单位(BCKDC)。蛋白质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，我们观察到支链氨基酸的选择性抑制作为其在人类中的使用效果。利用人、鼠、细胞和生化研究的组合，我们发现PB直接调节BCKDC E1A亚单位的磷酸化，该亚单位负责支链氨基酸和酮酸的氧化，从而解释了这一效应。根据我们的初步数据，我们建议回答三个问题，这些问题将直接将我们的观察转化为靶向蛋白磷酸化治疗枫糖浆尿病(MSUD)：1)PB能否用于支链酮酸脱羧酶复合体突变的枫糖浆尿病患者的临床治疗？2)我们能否建立体外预测PB对BCKDC的反应与体内临床反应相关的方法？3)我们能否通过阐明在MSUD突变的特定亚类中对PB的反应的结构基础来预测基于基因的临床反应？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一种新的机制活动的基本观察转化为一种更广泛的方法来治疗一种目前尚无可用的药物治疗的经典先天代谢错误。

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.