Coenzyme A replenishment as a therapeutic strategy for inborn errors of metabolism

补充辅酶 A 作为先天性代谢缺陷的治疗策略

基本信息

批准号：
9243829
负责人：
SUSAN J HAYFLICK
金额：
$ 23.1万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-16 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9243829
关键词：
4&apos -phosphopantetheine Acetyl Coenzyme A Acute Acyl Coenzyme A Advanced Development Affect Amino Acids Anabolism Animal Model Animals Autophagocytosis Bioavailable Biochemical Brain Carbohydrates Carnitine Cell model Cell physiology Cells Chemicals Childhood Chronic Clinical Coenzyme A DNA Defect Diet Modification Disease Early Diagnosis Energy-Generating Resources Esters Excretory function Failure to Thrive Fasting Fatty Acids Functional disorder Genetic Genetic Transcription Glycine Goals Growth and Development function Hallervorden-Spatz Syndrome Health Histologic Histone Acetylation Human Inborn Errors of Metabolism Inborn Genetic Diseases Investigation Knowledge Lead Long-Chain-Acyl-CoA Dehydrogenase Mammalian Cell Measures Metabolic Metabolic Diseases Metabolism Modeling Molecular Morbidity - disease rate Neonatal Screening Neurodegenerative Disorders Neurodevelopmental Disability Pantothenate kinase Patients Positioning Attribute Prevention Regulation Sentinel Signal Transduction Stress Testing Testis Therapeutic Toxic effect Transcriptional Regulation Translating Work acyl group amino acid metabolism base chronic liver disease cofactor dietary restriction disease phenotype fatty acid metabolism glutaric acidemia human disease improved improved outcome in vivo innovation ketotic hyperglycinemia mouse model mutant novel strategies organic acid small molecule success translation to humans urinary

项目摘要

PROJECT SUMMARY Better ways to treat genetic metabolic disorders are needed. More than 30 inborn errors of metabolism are predicted to lead to a functional deficiency of coenzyme A (CoA), including most conditions detected by expanded neonatal screening. Defects of fatty acid and amino acid metabolism generate high levels of organic acids, which form intracellular acyl CoA esters and lead to the sequestration or redistribution of CoA. Two primary inborn errors of CoA biosynthesis are now recognized, as well. Coenzyme A is critical to a diverse range of cellular processes, including intermediary metabolism, transcriptional regulation, signal transduction, and autophagy. Therefore deficient bioavailable CoA would disrupt myriad cellular processes and contribute to chronic morbidity in people affected by these diseases. Current state of treatment: The mainstay for managing this diverse group of disorders is early diagnosis, prevention of catabolic stress, and treatment with dietary modifications that decrease precursor availability and deliver small molecules (carnitine and glycine) to facilitate urinary excretion of toxic metabolites. While this general approach has improved survival of the acute toxic states, few of these patients are in good health. They suffer from a persistent abnormal metabolic state often with failure to thrive, neurodevelopmental disabilities, dysrhythmias, chronic liver disease and other complications, problems that are predicted to arise in part from depletion of CoA. The primary inborn errors of CoA synthesis cause lethal pediatric neurodegenerative disorders for which there are currently no treatments. Why is this R21 proposal innovative? Here, we propose a novel approach that will not only elucidate the pathophysiology of selected inborn errors metabolism but will also provide a “go-no go” decision for use of a precursor in CoA synthesis as a rational therapeutic to replenish CoA levels. Phosphopantetheine, a key intermediate in the synthesis of CoA, was recently discovered to serve as the stable precursor for rapid CoA synthesis. Using animal models representing four distinct CoA depletion disorders (propionic acidemia; glutaric acidemia type 1; very long-chain acyl-CoA dehydrogenase deficiency; and pantothenate kinase-associated neurodegeneration), we propose to 1) demonstrate that these mutant animals are more sensitive than controls to selective CoA depletion; and 2) demonstrate the efficacy of phosphopantetheine in ameliorating disease- associated biochemical and clinical defects. These R21 exploratory investigations have the potential to contribute important knowledge to the understanding of these diseases and to advance development of phosphopantetheine and its derivatives for further human studies. If successful, the work could fundamentally change management of 30+ human diseases and significantly improve the lives of tens of thousands of people with poor therapeutic options.

项目概要需要更好的方法来治疗遗传代谢紊乱 30 多种先天性代谢缺陷。预计会导致辅酶 A (CoA) 功能缺陷，包括由扩大新生儿筛查的脂肪酸和氨基酸代谢缺陷会产生高水平的有机物。酸，形成细胞内酰基 CoA 酯并导致 CoA 2 的隔离或重新分配。现在人们认识到辅酶 A 生物合成的原发性先天性缺陷对于多样性也至关重要。一系列细胞过程，包括中间代谢、转录调节、信号转导、因此，生物可利用的 CoA 不足会破坏无数的细胞过程并导致细胞自噬。受这些疾病影响的人的慢性发病率。目前的治疗状况：治疗这一类不同疾病的支柱是早期诊断，预防分解代谢应激，并通过饮食改变进行治疗，以减少前体的可用性和输送小分子（肉碱和甘氨酸）以促进有毒代谢物的尿液排泄。一般方法提高了急性中毒状态的生存率，但这些患者中很少有健康状况良好的。他们患有持续的异常代谢状态，常常无法茁壮成长，神经发育障碍残疾、心律失常、慢性肝病和其他并发症以及预计会出现的问题部分来自 CoA 的消耗 CoA 合成的主要先天性错误会导致致命的儿科疾病。目前尚无治疗方法的神经退行性疾病。为什么这个 R21 提案具有创新性？在这里，我们提出了一种新颖的方法，它不仅能够阐明选定的先天性代谢缺陷的病理生理学，但也将为使用 CoA 合成的前体作为补充 CoA 水平的合理治疗方法。 CoA 合成的中间体，最近被发现可作为快速 CoA 的稳定前体使用代表四种不同 CoA 耗竭疾病（丙酸血症；戊二酸血症）的动物模型。 1 型酸血症；极长链酰基辅酶 A 脱氢酶缺乏；和泛酸激酶相关；神经变性），我们建议 1）证明这些突变动物比对照组更敏感选择性 CoA 消耗；以及 2) 证明磷酸泛硫氨酸在改善疾病方面的功效- 这些 R21 探索性研究有可能解决相关的生化和临床缺陷。为了解这些疾病并促进疾病的发展提供重要的知识如果成功的话，这项工作将从根本上进行。改变30多种人类疾病的管理并显着改善数万人的生活治疗选择不佳。