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.

项目总结 需要更好的方法来治疗遗传性代谢紊乱。30多种先天的新陈代谢错误 预计会导致辅酶A(CoA)功能缺陷，包括由 扩大新生儿筛查范围。脂肪酸和氨基酸代谢缺陷会产生高水平的有机 酸，它在细胞内形成酰基辅酶A酯，并导致辅酶A的固定或重新分布。二 CoA生物合成的主要先天错误现在也被认识到了。辅酶A对多种不同的 一系列的细胞过程，包括中间代谢，转录调控，信号转导， 和自噬。因此，缺乏生物可利用的CoA会扰乱无数的细胞过程，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：处理这一多样化疾病组的主要手段是早期诊断， 预防分解代谢应激，并通过改变饮食来减少前体的可获得性和 提供小分子(肉碱和甘氨酸)，以促进有毒代谢物的尿液排泄。虽然这件事 一般的治疗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。 他们经常遭受持续的代谢异常状态的困扰，并无法茁壮成长，神经发育 残疾、心律失常、慢性肝病和其他并发症，预计在 部分是由于CoA的耗尽。先天性辅酶A合成错误导致致死性儿童 目前尚无治疗方法的神经退行性疾病。 为什么这个R21方案是创新的？在这里，我们提出了一种新的方法，它不仅将阐明 选择的先天缺陷代谢的病理生理学，但也将提供一个“去-不去”的决定使用 辅酶A合成中的前体作为补充辅酶A水平的合理治疗方法。一把钥匙--磷酸丙氨酸 合成辅酶A的中间体，最近被发现作为快速辅酶A的稳定前体 综合。使用代表四种不同CoA耗竭障碍(丙酸血症；戊二酸)的动物模型 1型酸血症；超长链酰辅酶A脱氢酶缺乏症；泛酸酸激酶相关 神经变性)，我们建议1)证明这些突变动物比对照动物更敏感 选择性CoA耗竭；以及2)证明磷酸铁氨酸在改善疾病方面的有效性。 相关的生化和临床缺陷。这些R21探索性调查有可能 为了解这些疾病提供重要知识，并推动 用于进一步人体研究的磷酸茶碱及其衍生物。如果成功，这项工作可能从根本上 改变对30多种人类疾病的管理，显著改善数万人的生活 有糟糕的治疗选择。