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 需要更好的治疗遗传代谢疾病的方法。超过30多个天生的代谢错误是 预计会导致辅酶A（COA）的功能缺陷，包括大多数由 扩展的新生儿筛查。脂肪酸和氨基酸代谢的缺陷会产生高水平的有机物 酸会形成细胞内酰基COA酯，并导致COA的隔离或重新分布。二 现在也认识到COA生物合成的原发性前生错误。辅酶A对潜水员至关重要 细胞过程的范围，包括中间代谢，转录调控，信号转导， 和自噬。因此，不足的生物利用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长期发病率。 当前的治疗状态：管理这种潜水疾病群的主要诊断是早期的诊断， 预防分解代谢压力，并通过饮食修饰进行治疗，以降低前体的可用性和 输送小分子（肉碱和甘氨酸），以促进有毒代谢物的极端尿。同时 一般方法改善了急性毒性状态的生存，这些患者中很少有身体健康。 他们经常患有持续的异常代谢状态，而神经发达 残疾，心律失常，慢性肝病和其他并发症，预计会出现的问题 一部分来自COA的耗竭。 COA合成的原发性前生错误导致致命的小儿 当前没有治疗的神经退行性疾病。 为什么这项R21提案是创新的？在这里，我们提出了一种新颖的方法，不仅会阐明 选定的先天错误代谢的病理生理学 COA合成中的前体是复制COA水平的合理疗法。磷酸耐药，钥匙 最近发现COA合成中的中间体是快速COA的稳定前体 合成。使用代表四种不同COA部署障碍的动物模型（丙酸酸血症；谷氨酸 1型酸血症；非常长链酰基-COA脱氢酶缺乏；和泛素激酶相关 神经变性），我们建议1）证明这些突变动物比对照更敏感 选择性COA部署； 2）证明磷酸乙氨酸在改善疾病的效率 - 相关的生化和临床缺陷。这些R21探索性研究有可能 为对这些疾病的理解做出重要的知识，并促进 磷酸耐药及其衍生物用于进一步的人类研究。如果成功，这项工作从根本上可以 改变30多种人类疾病的管理管理，并显着改善成千上万人的生活 治疗选择差。