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

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

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Transcriptional regulation of N-acetylaspartate metabolism in the 5xFAD model of Alzheimer's disease: evidence for neuron-glia communication during energetic crisis.
在阿尔茨海默氏病的5xFAD模型中,N-乙酰天冬氨酸代谢的转录调节:在能量危机期间神经元 - 胶体通信的证据。
  • DOI:
    10.1016/j.mcn.2015.03.009
  • 发表时间:
    2015-03
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Zaroff S;Leone P;Markov V;Francis JS
  • 通讯作者:
    Francis JS
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Scott William John McPhee其他文献

Scott William John McPhee的其他文献

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{{ truncateString('Scott William John McPhee', 18)}}的其他基金

Self-Complementary AAV2 Factor IX for Hemophilia B
用于治疗 B 型血友病的自我互补 AAV2 因子 IX
  • 批准号:
    7928438
  • 财政年份:
    2010
  • 资助金额:
    $ 27万
  • 项目类别:
Preclinical Studies Supporting Phase Ib Study of Minidystrophin Gene in AAV Vecto
支持 AAV Vecto 中微型肌营养不良蛋白基因的 Ib 期研究的临床前研究
  • 批准号:
    7692195
  • 财政年份:
    2008
  • 资助金额:
    $ 27万
  • 项目类别:
Preclinical Studies Supporting Phase Ib Study of Minidystrophin Gene in AAV Vecto
支持 AAV Vecto 中微型肌营养不良蛋白基因的 Ib 期研究的临床前研究
  • 批准号:
    7540342
  • 财政年份:
    2008
  • 资助金额:
    $ 27万
  • 项目类别:
Preclinical Development of AAV-Galanin for Epilepsy
AAV-甘丙肽治疗癫痫的临床前开发
  • 批准号:
    7540498
  • 财政年份:
    2008
  • 资助金额:
    $ 27万
  • 项目类别:

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钯催化的硅烷化乙酸烯丙酯新型有机转化的开发
  • 批准号:
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