An adeno-associated virus variant enabling efficient ocular-directed gene delivery across species

Shuang Luo, Hao Jiang, Qingwei Li, Yingfei Qin, Shiping Yang, Jing Li, Lingli Xu, Yan Gou, Yafei Zhang, Fengjiang Liu, Xiao Ke (), Qiang Zheng () and Xun Sun ()
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Shuang Luo: Chengdu Origen Biotechnology Co. Ltd
Hao Jiang: Chengdu Origen Biotechnology Co. Ltd
Qingwei Li: Chengdu Origen Biotechnology Co. Ltd
Yingfei Qin: Chengdu Origen Biotechnology Co. Ltd
Shiping Yang: Chengdu Origen Biotechnology Co. Ltd
Jing Li: Chengdu Origen Biotechnology Co. Ltd
Lingli Xu: Chengdu Origen Biotechnology Co. Ltd
Yan Gou: Chengdu Origen Biotechnology Co. Ltd
Yafei Zhang: Chengdu Origen Biotechnology Co. Ltd
Fengjiang Liu: Guangzhou Laboratory
Xiao Ke: Chengdu Origen Biotechnology Co. Ltd
Qiang Zheng: Chengdu Origen Biotechnology Co. Ltd
Xun Sun: Sichuan University

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Recombinant adeno-associated viruses (rAAVs) have emerged as promising gene therapy vectors due to their proven efficacy and safety in clinical applications. In non-human primates (NHPs), rAAVs are administered via suprachoroidal injection at a higher dose. However, high doses of rAAVs tend to increase additional safety risks. Here, we present a novel AAV capsid (AAVv128), which exhibits significantly enhanced transduction efficiency for photoreceptors and retinal pigment epithelial (RPE) cells, along with a broader distribution across the layers of retinal tissues in different animal models (mice, rabbits, and NHPs) following intraocular injection. Notably, the suprachoroidal delivery of AAVv128-anti-VEGF vector completely suppresses the Grade IV lesions in a laser-induced choroidal neovascularization (CNV) NHP model for neovascular age-related macular degeneration (nAMD). Furthermore, cryo-EM analysis at 2.1 Å resolution reveals that the critical residues of AAVv128 exhibit a more robust advantage in AAV binding, the nuclear uptake and endosome escaping. Collectively, our findings highlight the potential of AAVv128 as a next generation ocular gene therapy vector, particularly using the suprachoroidal delivery route.

Date: 2024
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DOI: 10.1038/s41467-024-48221-4

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