《生命科学》 2026, 38(4): 677-688
跨越血脑屏障：AAV 基因疗法在中枢神经系统疾病中的进展与前沿
摘 要：
腺相关病毒（adeno-associated virus，AAV）凭借安全性高、持久表达与多样的血清型组合，已成为治疗中枢神经系统（central nervous system，CNS）疾病的核心载体。本文系统综述AAV基因疗法的生物学基础、装载与表达策略、给药途径与免疫学问题；总结其在阿尔茨海默病、帕金森病等常见神经退行性疾病，及以Rett综合征、黏多糖贮积症、亨廷顿舞蹈症等为代表的罕见神经发育与遗传性脑病中的最新临床与转化进展；重点讨论“面向CNS的AAV衣壳筛选如何确定与最新进展”，以及“靶向全脑 vs 特定脑区，面向特定神经细胞类型精准递送”的最新策略，包括跨物种选择、受体靶向的理性设计、增强子/启动子与miRNA调控、聚焦超声辅助递送等；最后，评述AAV递送碱基与引导编辑工具在脑内的应用态势、脱靶与安全性挑战，并提出面向临床的未来方向。本文力求以规范的引文与最新证据为依据，为CNS疾病基因治疗临床研究与产业化提供参考。
通讯作者：仇子龙 , Email:qiuzilong@shsmu.edu.cn
Abstract:
Adeno-associated virus (AAV) vectors have emerged as a leading platform for gene therapy targeting central nervous system (CNS) disorders; however, efficient, safe, and scalable delivery across the blood-brain barrier (BBB) remains a central challenge for clinical translation. This review provides a comprehensive and forward-looking synthesis of recent advances in AAV-based CNS gene therapy, focusing on delivery strategies, disease applications, and genome editing technologies, while highlighting key translational factors influencing clinical outcomes. We first outline the biological properties of AAV vectors, including capsid diversity, genome packaging constraints, and regulatory elements that govern transgene expression and durability. We then compare major routes of administration—direct intracranial delivery, cerebrospinal fluid (CSF)-mediated approaches, and systemic intravenous injection—highlighting their advantages and limitations in achieving brain-wide versus region-specific transduction. In addition, we discuss key parameters affecting in vivo performance, including dose, distribution, and tissue tropism. Special emphasis is placed on recent advances in capsid engineering, including in vivo directed evolution, receptor-guided rational design, and cross-species validation strategies that aim to bridge long-standing translational gaps between rodent models and nonhuman primates or humans. We next summarize therapeutic progress across major CNS disorders, including neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, as well as monogenic neurodevelopmental and lysosomal storage disorders exemplified by Rett syndrome and mucopolysaccharidosis, together with emerging clinical insights from ongoing trials. In parallel, we describe the integration of AAV delivery with genome editing modalities—particularly base and prime editing—which offer precise and potentially safer alternatives to conventional gene replacement strategies, especially for diseases driven by defined genetic variants. Finally, we outline key translational bottlenecks, including host immune responses, dose-dependent toxicity, limited packaging capacity, and the need for improved cell-type specificity and regulatory control. We propose a framework for nextgeneration CNS gene therapy centered on “human receptor-guided capsid design, multi-layered transcriptional regulation, and precision genome editing”. Together with advances in scalable manufacturing, quality control, and regulatory standardization, these developments are expected to improve safety, enhance delivery efficiency, and support more durable therapeutic outcomes. This review provides an integrated perspective to guide future research and facilitate clinical translation of AAV-based therapeutics for CNS disorders.
Communication Author：QIU Zi-Long , Email:qiuzilong@shsmu.edu.cn
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