Department of Physiology, Anatomy and Genetics, Sherrington Building, University of Oxford, Oxford, UK.
Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
J Alzheimers Dis. 2021;84(2):491-504. doi: 10.3233/JAD-215145.
Effective, disease modifying therapies for Alzheimer's disease (AD) remain a quandary, following a panoply of expensive failures in human clinical trials. Given the stagnation in therapeutics, alternative approaches are needed. Recent successes of genetic therapies in other neurodegenerative diseases may highlight the way forward. This scoping review explores suggested targets of genetic therapy in AD, with a focus on vector-based approaches in pre-clinical and clinical trials. Putative targets of genetic therapies tested in pre-clinical trials include amyloid pathway intermediates and enzymes modulation, tau protein downregulation, APOE4 downregulation and APOE2 upregulation, neurotrophin expression (nerve growth factor (NGF) and brain-derived neurotrophic factor), and inflammatory cytokine alteration, among several other approaches. There have been three completed human clinical trials for genetic therapy in AD patients, all of which upregulated NGF in AD patients, showing some mixed evidence of benefit. Several impediments remain to be surpassed before genetic therapies can be successfully applied to AD, including the challenge of delivering monogenic genetic therapies for complex polygenic disorders, risks in the dominant delivery method (intracranial injection), stability of genetic therapies in vivo, poor translatability of pre-clinical AD models, and the expense of genetic therapy production. Genetic therapies represent an exciting opportunity within the world of AD therapeutics, but clinical applications likely remain a long term, rather than short term, possibility.
在一系列昂贵的人类临床试验失败后，针对阿尔茨海默病（AD）的有效、可改变疾病进程的治疗方法仍然是一个难题。鉴于治疗方法的停滞不前，需要寻找替代方法。其他神经退行性疾病中基因治疗的最近成功可能为前进的道路指明了方向。本范围界定综述探讨了 AD 基因治疗的建议靶点，重点关注临床前和临床试验中的基于载体的方法。在临床前试验中测试的基因治疗的推定靶点包括淀粉样蛋白途径中间产物和酶调节、tau 蛋白下调、APOE4 下调和 APOE2 上调、神经生长因子（NGF）和脑源性神经营养因子等神经营养因子的表达，以及炎症细胞因子的改变等几种方法。已经有三项针对 AD 患者的基因治疗的人类临床试验完成，所有这些试验都上调了 AD 患者的 NGF，显示出一些有益的混合证据。在基因治疗能够成功应用于 AD 之前，仍然存在几个需要克服的障碍，包括为复杂的多基因疾病提供单基因基因治疗的挑战、主要传递方法（颅内注射）的风险、体内基因治疗的稳定性、临床前 AD 模型的较差可转化性，以及基因治疗生产的费用。基因治疗代表了 AD 治疗领域令人兴奋的机会，但临床应用可能仍然是一个长期的、而非短期的可能性。
