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AAV2-ASPA-Based Metabolic Intervention for Alzheimer's Disease

基于 AAV2-ASPA 的阿尔茨海默病代谢干预

基本信息

批准号：
8644061
负责人：
Scott William John McPhee
金额：
$ 27万
依托单位：
ASKLEPIOS BIOPHARMACEUTICAL, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-15 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8644061
关键词：
ATP Synthesis Pathway Acetates Acetyl Coenzyme A Acetylcholine Achievement Acids Address Adolescent Age-Months Age-associated memory impairment Alzheimer&apos s Disease Alzheimer&apos s disease model Amino Acids Amyloid Animal Model Aspartate Aspartic Acid Aspartoacylase Biochemical Biodistribution Biological Models Brain Caring Catabolism Cell Count Cell Respiration Cell Survival Cells Citric Acid Cycle Clinical Clinical Trials Cognitive Data Deacetylation Dementia Development Disease Dose Engineered Gene Enzymes Fatty Acids Foundations Functional disorder Gene Transfer Genes Glutathione Disulfide Hippocampus (Brain)Human Impaired cognition Injury International Intervention Measures Mediating Memory Metabolic Metabolism Modeling Mus N-acetylaspartate Nerve Degeneration Neurodegenerative Disorders Neuroglia Neuronal Dysfunction Neurons Oligodendroglia Outcome Oxidative Stress Pathology Patients Performance Phase Phenotype Prevalence Process Production Prosencephalon Reaction Relative (related person)Reporting Resistance Safety Short-Term Memory Technology Testing Therapeutic Effect Therapeutic Intervention Time Toxic effect Toxicology Transgenic Mice World Health Organization acetylcholine transporter adeno-associated viral vector basal forebrain cholinergic neurons base cholinergic cognitive function combat density familial Alzheimer disease gene delivery system gene therapy human disease improved indexing mouse model myelination neuroprotection novel overexpression pre-clinical prevent programs public health relevance research study therapeutic target treatment strategy vector

项目摘要

Abstract We propose to initiate preclinical development of a gene therapeutic targeted to Alzheimer's Disease. The World Health Organization's and Alzheimer's Disease International's report on Dementia (2012) recognizes that the global burden of Alzheimer Disease is forecast to worsen significantly with prevalence predicted to double every 20 years. Interventions that could provide a modest delay in progression would provide a significant reduction in the high level care required later in the disease. This Phase I proposal describes an Adeno-associated viral vector-based metabolic intervention strategy to combat age-related cognitive decline in the 5xFAD model of familial Alzheimer's disease. A broad range of neurodegenerative disorders manifest abnormalities in the metabolism of the abundant amino acid derivative N-acetyl-L-aspartic acid (NAA). Fluctuations in NAA concentration within the brain are generally accepted as an index of oxidative metabolic integrity in neurons. NAA synthesis and catabolism are prominent in developmental myelination, where the deacetylation of NAA in glial cells is thought to support fatty acid synthesis. Our collaborators on this proposal have recently demonstrated the importance of the deacetylation of NAA to not only fatty acid synthesis, but to the production of ATP during myelination also. These preliminary data indicate that the catabolism of acetylated aspartate leads to the synthesis of ATP by the tricarboxylic acid (TCA) cycle in myelinating glia. Preliminary studies have demonstrated that the overexpression of the NAA deacetylating enzyme, aspartoacylase (ASPA) promotes ATP synthesis, thereby providing a means of support during periods of oxidative stress and promotion of cell survival following anoxic injury. In Phase I we will quantify the therapeutic effect in an animal model of neurodegenerative disease. Using our technology platform we will express a gene encoding an oligodendrocyte-localized catabolic enzyme in neurons to enable the liberation of free acetate from the abundant amino acid derivative N- acetylaspartate. Assessment will be made of biochemical, histopathological and cognitive outcomes. In summary, the experiments described herein will address the potential of using adeno- associated viral vectors to provide a means by which metabolic intermediates of oxidative metabolism are made available to cholinergic basal forebrain neurons of transgenic mice that model -amyloid induced neurodegeneration and cognitive decline. This novel yet simple strategy may promote metabolic integrity and improved cognitive performance in a model of familial Alzheimer's disease using an established gene delivery system with proven clinical safety. If the treatment provides a significant magnitude of benefit in the established models of AD it will be advanced into Phase II testing involving dose ranging, toxicity and biodistribution studies.

摘要我们建议启动针对阿尔茨海默氏症的基因治疗的临床前开发疾病世界卫生组织和阿尔茨海默病国际组织的报告痴呆症（2012年）认识到，阿尔茨海默病的全球负担预计将恶化预计每20年发病率将翻一番。的救命的药剂适度延迟进展将显著降低高水平疾病后期需要的护理。本I期提案描述了一种腺相关病毒基于矢量的代谢干预策略，以对抗年龄相关的认知下降，家族性阿尔茨海默病的5xFAD模型。广泛的神经退行性疾病表现为神经元代谢异常，富含氨基酸衍生物N-乙酰-L-天冬氨酸（NAA）。NAA的波动脑内的浓度通常被认为是氧化代谢完整性的指标在神经元中。NAA的合成和catalysts是突出的发展髓鞘，其中神经胶质细胞中NAA的脱乙酰化被认为支持脂肪酸合成。我们该建议的合作者最近证明了脱乙酰化的重要性， NAA不仅对脂肪酸的合成有促进作用，而且对髓鞘形成过程中ATP的产生也有促进作用。这些初步数据表明，乙酰化天冬氨酸的催化作用导致在髓鞘形成的神经胶质中通过三羧酸（TCA）循环合成ATP。初步研究已经证明过表达的NAA脱乙酰酶，乙酰化酶，（ASPA）促进ATP合成，从而在妊娠期间提供支持手段。氧化应激和促进缺氧损伤后的细胞存活。在第一阶段，我们将量化在神经变性疾病的动物模型中的治疗效果。使用我们的技术在这个平台上，我们将表达一种编码少突胶质细胞定位的分解代谢酶的基因，神经元，以使游离乙酸从丰富的氨基酸衍生物N- 乙酰天冬氨酸。将对生化、组织病理学和认知功能进行评估。结果。总之，本文所述的实验将解决使用腺病毒载体的潜力。相关的病毒载体，以提供氧化代谢中间体使代谢可用于转基因小鼠的胆碱能基底前脑神经元，模型-淀粉样蛋白诱导的神经变性和认知能力下降。这部小说还很简单策略可以促进代谢的完整性和改善的认知能力，使用已建立的基因递送系统治疗家族性阿尔茨海默病，安全为代价的如果治疗在已建立的模型中提供了显著的益处， AD将进入第二阶段测试，包括剂量范围，毒性和生物分布问题研究