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

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

Jiayu Huang  1   2 , Jiajun Li  1   2 , Xiangzhong Xu  1 , Keran Li  1   2
Affiliations
Review

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

Jiayu Huang et al. Biomolecules. .

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.

Keywords: adeno-associated virus (AAV); capsid engineering; gene therapy-associated uveitis; large-gene delivery; retinal gene therapy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Comparison of Lentivirus, Adenovirus, and Adeno-Associated Virus. Created with BioRender (http://app.biorender.com), accessed on 22 April 2025.
Figure 2
Figure 2
Schematic of the general process of AAV infection in target cells. Created with BioRender (http://app.biorender.com), accessed on 22 April 2025.
Figure 3
Figure 3
Application of AAV-mediated gene therapy in hereditary retinal diseases. Created with BioRender (http://app.biorender.com), accessed on 22 April 2025. Color-coded arrows indicate: Red arrows: Gene augmentation therapy; Purple arrows: Gene editing therapy; Yellow arrows: RNA interference (RNAi) therapy; Brown arrows: Optogenetic therapy.
Figure 4
Figure 4
Application of AAV-mediated gene therapy in acquired retinal diseases. Created with BioRender (http://app.biorender.com), accessed on 22 April 2025.
See this image and copyright information in PMC

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