阿尔茨海默病的AAV基因治疗研究进展

摘要/Abstract

摘要： 阿尔茨海默病（Alzheimer′s disease， AD）是导致痴呆最主要的疾病。据估计，2020年全球AD及相关痴呆患者有约5427万，其中超过1/4患者在我国。随着全球人口老龄化加快，AD患者数目快速增加，AD在给患者带来沉重疾病痛苦的同时，也将给家庭和社会带来沉重经济压力。当前，治疗AD的药物还只是着眼于缓解症状，并不影响疾病的进程。虽然最近临床试验数据表明，多个β-淀粉样蛋白（amyloid-beta，Aβ）抗体药物可以改善病理和减缓疾病进程，但其临床价值一直饱受争议。所以，研发出新的有效的AD治疗药物迫在眉睫。传统AD药物的研发失败率高达99.6%，使得科学家们不得不积极探寻新的AD疗法。腺相关病毒（adeno-associated virus， AAV ）基因治疗是一种新兴的、强有力的治疗手段，在治疗其他神经退行性相关疾病上已取得较大成功，提示其在AD的治疗上极有可能取得突破。本研究在梳理当前国内外AD发病现状和风险因素的基础上，明确提出目前亟待新的AD治疗药物和治疗方法；通过介绍AAV基因治疗AD的优势和潜能，并基于Aβ级联反应假说、tau蛋白假说、神经营养因子假说、APOE假说、神经炎症假说，自噬-溶酶体障碍假说、线粒体功能障碍假说等各种假说机制，综述了AD的AAV基因治疗临床前和临床研究进展，并提出AAV基因治疗虽尚处早期阶段，其发展充满挑战，但终将可能为AD的治疗带来新希望和新突破。

关键词: font-size:medium, ">阿尔茨海默病；β-淀粉样蛋白；神经退行性疾病；基因治疗；腺相关病毒

Abstract: Alzheimer′s disease (AD) is the leading cause of dementia. It is estimated that there were approximately 54.27 million AD and related dementia patients worldwide in 2020， while the situation is even more severe in China， with approximately 16.25 million patients. With the accelerated aging of the global population， the number of AD patients will also rapidly increase. Therefore， AD just only brings huge pain to patients but also brings huge economic pressure to families and society. Currently， drugs for AD just focus on alleviating symptoms and do not affect the progression of the disease. Although clinical trial data from the past one or two years indicate that multiple amyloid-beta (Aβ) antibody drugs can improve pathology and slow disease progression， their clinical value has always been controversial. Therefore， it is urgent to develop new and effective AD drugs. The failure rate of traditional AD drug development is as high as 99.6%， forcing scientists to actively explore new AD therapies. Adeno-associated virus (AAV) gene therapy is a new and powerful treatment method， which has achieved great success in treating other neurodegenerative-related diseases， indicating that it will make a breakthrough in the treatment of AD. Based on an extensive review of the current situation and risk factors of AD both domestically and internationally， this study proposes the urgent need for new treatment drugs and methods for AD. By introducing the advantages and potential of AAV gene therapy for AD， and based on the Aβ cascade hypothesis， tau protein hypothesis， neurotrophic hypothesis， APOE hypothesis， neuroinflammation hypothesis， autophagy-lysosome disorder hypothesis， mitochondrial disorder hypothesis， and others， this study reviewed the preclinical and clinical research progress of AAV gene therapy for AD and proposed that although still in its early stage and its development will be full of challenges， AAV gene therapy will eventually bring new hope and breakthroughs for the treatment of AD.

Key words: font-size:medium, ">Alzheimer′s disease； Aβ； Neurodegenerative disease； Gene therapy；AAV

中图分类号:

戴中华, 张丽娜, 章嫣, 吴小兵. 阿尔茨海默病的AAV基因治疗研究进展[J]. 中国医药导刊, 2023, 25(7): 677-686.

DAI Zhonghua, ZHANG Lina, ZHANG Yan, WU Xiaobing. Research Progess on AAV Based Gene Therapy in Alzheimer′s Disease[J]. CHINESE JOURNAL OF MEDICINAL GUIDE, 2023, 25(7): 677-686.

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