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Canavan Disease: Pathogenesis and Treatment

卡纳万病：发病机制和治疗

基本信息

批准号：
7415290
负责人：
ARYAN Mangalam NAMBOODIRI
金额：
$ 30.78万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-12-01 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7415290
关键词：
ATP Citrate (pro-S)-Lyase Acetate-CoA Ligase Acetates Acetyl Coenzyme A Affect Age Amino Acids Animals Aspartoacylase Astrocytes Biochemical Brain Canavan Disease Cells Characteristics Child Chronic Classification Code Coenzyme A Condition Daily Data Deacetylation Defect Development Dietary Supplementation Disease Dose Edema Electron Microscopy Ensure Enzymes Equilibrium Experimental Designs Extracellular Space Fatty Acids Follow-Up Studies Funding Gene Targeting Genes Goals Histopathology Hour In Vitro Indium Injection of therapeutic agent Kinetics Knock-out Knockout Mice Knowledge Label Lead Light Link Lipids Liver Localized Metabolic Pathway Metabolism Methods Mitochondria Modeling Morphology Motor Mus Mutation Myelin N-acetylaspartate N-terminal Nature Nervous system structure Neurodegenerative Disorders Neurologic Neurology Neurons New York Numbers Oligodendroglia Optic Nerve Oral Administration Pathogenesis Pathology Pathway interactions Patients Pattern Peptide antibodies Peripheral Play Positioning Attribute Principal Investigator Prion Diseases Progress Reports Rate Rattus Reporting Research Research Personnel Role Sampling Schwann Cells Seizures Source Supplementation Swelling System Testing Therapeutic Therapeutic Effect Thinking Time Tissues Toxic effect Universities Vacuole Water Week Work base behavior test calcium acetate comparative cost day expectation experience extracellular follow-up gene therapy innovation insight interest knockout animal leukodystrophy lipid biosynthesis medical schools myelination neurodevelopment null mutation postnatal preclinical study prevent programs research study size success uptake

项目摘要

Canavan disease (CD) is an autosom al-recessive neurodegenerative disorder caused by mutations in the gene coding for the enzyme aspartoacylase (ASPA). ASPA catalyzes deacetylation of N-acetylaspartate (NAA), an abundant (~ 10 mM) and nervous system-specific amino acid derivative. CD is characterized by spongiform degeneration of the brain resulting in severe psychomotor retardation, with most affected children dying before the age of 10. The precise pathogenesis of CD remains unclear. The central hypothesis is that ASPA activity is required for myelin synthesis via liberating the NAA-derived acetate for the synthesis of acetyl CoA, which is used in the synthesis of the lipid portion of myelin. In this hypothesis, CD is thought to result from defective myelin synthesis caused by a deficiency in the supply of the NAA- derived acetate. A number of studies, including our recent demonstration of the selective localization of ASPA in oligodendrocytes in the CNS, are consistent with the acetate deficiency hypothesis of CD. Furthermore, we have recently tested the acetate deficiency hypothesis in the murine model of CD (ASPA -/- ) directly by 1) determining acetate levels in the brain and 2) studying the myelin-associated lipid synthesis. The results showed that in CD mice brain acetate levels decreased by about 80% and synthesis of a number of myelin related lipids also decreased significantly. These results provided the first direct evidence in support of this hypothesis. A major implication of these findings is that acetate supplementation is likely to provide a simple and inexpensive therapeutic approach for CD. Toward this goal, we have made progress by finding that oral administration of glyceryl triacetate (Triacetin), an acetate precursor, caused acetate levels in the brain to increase by about 10- fold in 1-2 hours, and efforts to test whether or not acetate supplementation using glyceryl triacetate is effective as a treatment of CD is in progress. The Central hypothesis of this competitive renewal application remains the same as that of the previous application. This application involves additional specific aims focused on continuing our efforts toward acetate supplementation therapy for CD and testing additional aspects of CD pathogenesis as a follow up to the current findings. The immediate goals are 1) to continue our ongoing efforts to correct the acetate deficiency of CD using chronic GT A administration and to test its effect on the development of CD, 2) to characterize the acetate pathway of myelin lipid synthesis to further understand the functional roles of NAA and 3) to determine the CNS tissue compartments in which NAA is increased in CD as a first step to understand the role of increased NAA in CD pathology. These studies are likely to lead to a simple and inexpensive method for the treatment of CD and also advance our knowledge on the functional roles of NAA and the relationship of increased NAA to CD pathology.

Canavan病（CD）是一种常染色体隐性遗传的神经退行性疾病，由编码β-淀粉酰化酶（ASPA）的基因突变引起。ASPA催化N-乙酰天冬氨酸（NAA）的脱乙酰化，NAA是一种丰富的（约10 mM）神经系统特异性氨基酸衍生物。CD的特征是大脑的海绵状变性，导致严重的精神发育迟滞，大多数受影响的儿童在10岁之前死亡。CD的确切发病机制尚不清楚。中心假设是ASPA活性是髓鞘合成所需的，其通过释放用于合成乙酰辅酶A的NAA衍生的乙酸酯来进行，乙酰辅酶A用于合成髓鞘的脂质部分。在这一假说中，CD被认为是由缺乏NAA衍生的乙酸盐引起的髓鞘合成缺陷引起的。一些研究，包括我们最近证明的选择性定位的ASPA在少突胶质细胞在中枢神经系统中，是一致的醋酸缺乏假说的CD。此外，我们最近在CD（ASPA -/-）鼠模型中直接通过1）测定脑中的乙酸盐水平和2）研究髓鞘相关脂质合成来测试乙酸盐缺乏假说。结果表明，CD小鼠脑内乙酸水平下降约80%，许多髓鞘相关脂质的合成也显着减少。这些结果为支持这一假设提供了第一个直接证据。这些发现的一个主要含义是，醋酸补充剂可能为CD提供一种简单而廉价的治疗方法。为了实现这一目标，我们已经取得了进展，发现口服三乙酸甘油酯（三醋精），一种乙酸酯前体，导致大脑中的乙酸酯水平在1-2小时内增加约10倍，并且正在努力测试使用三乙酸甘油酯补充乙酸酯是否有效作为CD的治疗。该竞争性续期申请的中心假设与先前申请的中心假设相同。本申请涉及额外的具体目标，重点是继续我们对CD的醋酸盐补充治疗的努力，并测试CD发病机制的其他方面，作为对当前发现的后续研究。近期目标是1）继续我们正在进行的努力，以使用长期给予GT A来纠正CD的乙酸盐缺乏，并测试其对CD发展的影响，2）表征髓鞘脂质合成的乙酸途径，以进一步理解NAA的功能作用，以及3）确定CD中NAA增加的CNS组织区室，作为理解增加的NAA在CD病理学中的作用的第一步。这些研究可能会导致一个简单和廉价的方法来治疗CD，也推进我们的知识的功能作用的NAA和增加NAA CD病理的关系。