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视网膜基因治疗中的腺相关病毒载体:挑战、创新与未来方向

Adeno-Associated Virus Vectors in Retinal Gene Therapy: Challenges, Innovations, and Future Directions.

作者信息

Huang Jiayu, Li Jiajun, Xu Xiangzhong, Li Keran

机构信息

Department of Ophthalmology, The Affiliated Eye Hospital of Nanjing Medical University, 138 Hanzhong Road, Nanjing 210029, China.

The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China.

出版信息

Biomolecules. 2025 Jun 28;15(7):940. doi: 10.3390/biom15070940.

Abstract

Adeno-associated virus (AAV) vectors have emerged as the leading platform for retinal gene therapy due to their favorable safety profile, low immunogenicity, and ability to mediate long-term transgene expression within the immune-privileged ocular environment. By integrating diverse strategies such as gene augmentation and gene editing, AAV-based therapies have demonstrated considerable promise in treating both inherited and acquired retinal disorders. However, their clinical translation remains limited by several key challenges, including restricted packaging capacity, suboptimal transduction efficiency, the risk of gene therapy-associated uveitis, and broader societal concerns such as disease burden and ethical oversight. This review summarizes recent advances aimed at overcoming these barriers, with a particular focus on delivery route-specific disease applicability, multi-vector systems, and capsid engineering approaches to enhance payload capacity, targeting specificity, and biosafety. By synthesizing these developments, we propose a conceptual and technical framework for a more efficient, safer, and broadly applicable AAV platform to accelerate clinical adoption in retinal gene therapy.

摘要

腺相关病毒(AAV)载体因其良好的安全性、低免疫原性以及在免疫赦免的眼部环境中介导长期转基因表达的能力,已成为视网膜基因治疗的主要平台。通过整合基因增强和基因编辑等多种策略,基于AAV的疗法在治疗遗传性和获得性视网膜疾病方面已显示出巨大的前景。然而,它们的临床转化仍受到几个关键挑战的限制,包括包装容量受限、转导效率欠佳、基因治疗相关葡萄膜炎的风险,以及诸如疾病负担和伦理监督等更广泛的社会问题。本综述总结了旨在克服这些障碍的最新进展,特别关注特定递送途径的疾病适用性、多载体系统以及衣壳工程方法,以提高有效载荷容量、靶向特异性和生物安全性。通过综合这些进展,我们提出了一个概念和技术框架,以构建一个更高效、更安全且广泛适用的AAV平台,从而加速视网膜基因治疗的临床应用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8471/12292589/7ae1610d70f7/biomolecules-15-00940-g001.jpg

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