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

• 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
• 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' -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

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.

项目摘要 需要更好的方法来治疗遗传代谢紊乱。超过30种先天性代谢缺陷， 预测会导致辅酶A（CoA）的功能缺陷，包括大多数条件检测 扩大新生儿筛查。脂肪酸和氨基酸代谢的缺陷会产生高水平的有机 酸，其形成细胞内酰基辅酶A酯并导致辅酶A的螯合或再分布。两 CoA生物合成的主要先天性缺陷现在也被认识到。辅酶A是一种重要的 一系列细胞过程，包括中间代谢，转录调节，信号转导， 和自噬。因此，缺乏生物可利用的CoA会破坏无数的细胞过程，并有助于 受这些疾病影响的人的慢性发病率。 目前的治疗状况：管理这一多样化疾病的主要手段是早期诊断， 预防分解代谢应激，并通过饮食调整进行治疗，减少前体的可用性， 提供小分子（肉毒碱和甘氨酸），以促进有毒代谢物的尿液排泄。虽然这 一般的方法已经改善了急性中毒状态的存活率，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，通常无法茁壮成长，神经发育， 残疾，节律失调，慢性肝病和其他并发症，预计在 部分来自CoA的消耗。CoA合成的原发性先天性错误导致致命的儿科疾病 神经退行性疾病，目前没有治疗方法。 为什么R21提案具有创新性？在这里，我们提出了一种新的方法，不仅将阐明 选择的先天性代谢缺陷的病理生理学，但也将提供一个“去-不去”的决定， 辅酶A合成中的前体作为补充辅酶A水平的合理治疗。磷酸泛酰巯基乙胺，一个关键 辅酶A合成的中间体，最近被发现作为快速辅酶A的稳定前体 合成.使用代表四种不同CoA耗竭疾病（丙酸血症;谷氨酰胺血症）的动物模型 1型酸血症;极长链酰基辅酶A脱氢酶缺乏症;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耗竭;和2）证明磷酸泛酰巯基乙胺在改善疾病中的功效- 相关的生化和临床缺陷。这些R21探索性研究有可能 为了解这些疾病提供重要知识，并促进 磷酸泛酰巯基乙胺及其衍生物用于进一步的人体研究。如果成功，这项工作将从根本上 改变30多种人类疾病的管理，显著改善数万人的生活 治疗方案不佳