Gene Therapy for Alzheimer's Disease

阿尔茨海默病的基因治疗

• 批准号: 9761945
• 负责人: CONSTANCE L CEPKO
• 金额: $ 18.12万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761945
• 关键词: Acute; Age; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Antioxidants; Area; Autophagocytosis; Behavioral; Behavioral Symptoms; Biological Assay; Brain; Cell Nucleus; Cytoplasm; Disease; Disease Progression; Exhibits; Free Radicals; Frequencies; Future; Gene Proteins; Genes; Genetic; Health; Hippocampus (Brain); Inflammation; Knockout Mice; Lead; Learning; Location; Memory; Messenger RNA; Modality; Mus; Nerve; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Organism; Pathology; Patients; Performance; Play; Population; Process; Proteins; Reporting; Retinal Degeneration; Role; Signal Transduction; Stress; Subfamily lentivirinae; Suggestion; Testing; Therapeutic; Therapeutic Effect; Tissues; Vasodilation; Viral Genes; Viral Vector; Vision; Xenobiotics; adeno-associated viral vector; age related; behavior test; clinical application; clinical candidate; combat; dietary supplements; fighting; gene therapy; human model; mouse model; neuron loss; neuronal survival; oxidation; oxidative damage; protein B; reduce symptoms; response; side effect; targeted treatment; transcription factor; vector

PROJECT SUMMARY / ABSTRACT Oxidative damage and inflammation accumulate as we age and are prominent components of many genetic and age-related diseases. Alzheimer’s Disease (AD), and many other neurodegenerative diseases, show signs of oxidative damage and inflammation early in the disease progression. It is likely that the accumulation of a protein, the β-amyloid precursor protein and its cleavage products, stimulates oxidation and inflammation in AD, beyond an organism’s ability to properly regulate the normally protective responses. Nrf2, a transcription factor, is part of an organism’s normal mechanism to activate a response to abnormal proteins. It regulates >100 genes that can be protective of oxidation, inflammation, xenobiotic stress, and autophagy. However, in AD, it appears that the activity of Nrf2 is not upregulated in response to the disease process. One approach is thus to augment the body’s natural response by delivering the Nrf2 gene using viral gene therapy. This approach has been successful in prolonging vision in animal models of neurodegeneration and acute nerve damage. We propose to test the ability of Nrf2 to reduce the neuronal death and behavioral symptoms in two mouse models of AD. The viral vector, AAV, that will be used for delivery directly to the brain, is being tested as this vector is emerging as a viable candidate for clinical applications. Two mouse models of AD with different genetic causes of AD will be tested to determine if the strategy is applicable across the disease spectrum. In addition, several different assays will be used to test different types of responses as indicators of efficacy. If effective, AAV-Nrf2 may prove to be useful in extending neuronal health and function, not only in AD, but perhaps in other neurodegenerative diseases that also exhibit inflammation and oxidaiton.

项目摘要 /摘要 随着年龄的增长，氧化损伤和炎症会累积，并且是许多人的重要组成部分 遗传和与年龄有关的疾病。阿尔茨海默氏病（AD）和许多其他神经退行性疾病， 在疾病进展的早期显示氧化损伤和炎症的迹象。很可能 蛋白质的积累，β-淀粉样蛋白前体蛋白及其裂解产物的积累，刺激氧化和 AD的炎症，超出了生物体正确调节正常受保护反应的能力。 NRF2， 转录因子是生物体激活异常蛋白质反应的正常机制的一部分。 它调节> 100个基因，可以保护不受氧化，注射，异种胁迫和自噬的影响。 但是，在AD中，似乎没有根据疾病过程更新NRF2的活性。一 因此，方法是通过使用病毒基因治疗传递NRF2基因来增强人体的自然反应。 这种方法在延长神经退行性和急性动物模型的视力方面已经成功 神经损伤。 我们建议测试NRF2减少两种神经元死亡和行为症状的能力 AD的鼠标模型。正在测试将用于直接传递到大脑的病毒矢量AAV 随着该矢量成为临床应用的可行候选者。两种鼠标AD模型 将测试不同的AD遗传原因，以确定该策略是否适用于整个疾病 光谱。此外，将使用几种不同的分析来测试不同类型的响应作为指标 有效的。如果有效，则AAV-NRF2可能被证明可用于扩展神经元健康和功能，不仅在 AD，但也许在其他表现出注射和氧化的神经退行性疾病中。