Gene Therapy for Alzheimer's Disease

项目总结/摘要 氧化损伤和炎症随着年龄的增长而积累，是许多疾病的重要组成部分。 遗传和年龄相关疾病。阿尔茨海默病（AD）和许多其他神经退行性疾病， 在疾病进展的早期表现出氧化损伤和炎症的迹象。很可能 β-淀粉样蛋白前体蛋白及其裂解产物的蛋白质积累刺激氧化， AD中的炎症，超出了生物体适当调节正常保护性反应的能力。Nrf2， 一种转录因子，是生物体激活对异常蛋白质反应的正常机制的一部分。 它调节超过100个基因，可以保护氧化，炎症，异生物质应激和自噬。 然而，在AD中，似乎Nrf 2的活性不响应于疾病过程而上调。一 因此，一种新的方法是通过使用病毒基因疗法递送Nrf 2基因来增强身体的自然反应。 这种方法已经成功地延长了神经变性和急性视网膜病变动物模型的视力。 神经损伤 我们建议测试Nrf 2减少两种神经元死亡和行为症状的能力。 AD小鼠模型。将用于直接输送到大脑的病毒载体AAV正在测试中 因为该载体正在成为临床应用的可行候选物。两种AD小鼠模型， 将对AD的不同遗传原因进行测试，以确定该策略是否适用于所有疾病 江西篇章此外，将使用几种不同的测定来测试不同类型的反应，作为 功效如果有效的话，AAV-Nrf 2可能被证明在延长神经元健康和功能方面是有用的，而不仅仅是在神经元中。 AD，但可能在其他神经退行性疾病，也表现出炎症和氧化。

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.