Department of Pharmacology, Institue of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India.
Department of Pharmacology, College of Pharmacy, Shri Venkateshwara University, Gajraula, Uttar Pradesh, India.
Ageing Res Rev. 2024 Jul;98:102321. doi: 10.1016/j.arr.2024.102321. Epub 2024 May 8.
Over the last three decades, neurodegenerative diseases (NDs) have increased in frequency. About 15% of the world's population suffers from NDs in some capacity, which causes cognitive and physical impairment. Neurodegenerative diseases, including Amyotrophic Lateral Sclerosis, Parkinson's disease, Alzheimer's disease, and others represent a significant and growing global health challenge. Neuroinflammation is recognized to be related to all NDs, even though NDs are caused by a complex mix of genetic, environmental, and lifestyle factors. Numerous genes and pathways such as NFκB, p38 MAPK, Akt/mTOR, caspase, nitric oxide, and COX are involved in triggering brain immune cells like astrocytes and microglia to secrete inflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1β, and IL-6. In AD, the binding of Aβ with CD36, TLR4, and TLR6 receptors results in activation of microglia which start to produce proinflammatory cytokines and chemokines. Consequently, the pro-inflammatory cytokines worsen and spread neuroinflammation, causing the deterioration of healthy neurons and the impairment of brain functions. Gene therapy has emerged as a promising therapeutic approach to modulate the inflammatory response in NDs, offering potential neuroprotective effects and disease-modifying benefits. This review article focuses on recent advances in gene therapy strategies targeting neuroinflammation pathways in NDs. We discussed the molecular pathways involved in neuroinflammation, highlighted key genes and proteins implicated in these processes, and reviewed the latest preclinical and clinical studies utilizing gene therapy to modulate neuroinflammatory responses. Additionally, this review addressed the prospects and challenges in translating gene therapy approaches into effective treatments for NDs.
在过去的三十年中，神经退行性疾病（NDs）的发病率有所增加。大约 15%的世界人口在某种程度上患有 NDs，这会导致认知和身体功能障碍。神经退行性疾病，包括肌萎缩侧索硬化症、帕金森病、阿尔茨海默病等，代表着一个重大且日益严重的全球健康挑战。尽管神经退行性疾病是由复杂的遗传、环境和生活方式因素共同引起的，但神经炎症被认为与所有 NDs 都有关。许多基因和途径，如 NFκB、p38 MAPK、Akt/mTOR、半胱天冬酶、一氧化氮和 COX，参与触发大脑免疫细胞如星形胶质细胞和小胶质细胞分泌炎症细胞因子，如肿瘤坏死因子-α、白细胞介素 (IL)-1β 和 IL-6。在 AD 中，Aβ 与 CD36、TLR4 和 TLR6 受体结合导致小胶质细胞被激活，从而开始产生促炎细胞因子和趋化因子。因此，促炎细胞因子会加重和扩散神经炎症，导致健康神经元的恶化和大脑功能的损伤。基因治疗已成为一种有前途的治疗方法，可以调节 NDs 中的炎症反应，提供潜在的神经保护作用和疾病修饰益处。本文综述了针对 NDs 中神经炎症途径的基因治疗策略的最新进展。我们讨论了涉及神经炎症的分子途径，强调了这些过程中涉及的关键基因和蛋白质，并回顾了利用基因治疗来调节神经炎症反应的最新临床前和临床研究。此外，本文还探讨了将基因治疗方法转化为 NDs 有效治疗方法的前景和挑战。
