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

Author:

Luo ShuangORCID,Jiang HaoORCID,Li Qingwei,Qin Yingfei,Yang Shiping,Li Jing,Xu Lingli,Gou Yan,Zhang Yafei,Liu FengjiangORCID,Ke XiaoORCID,Zheng QiangORCID,Sun XunORCID

Abstract

AbstractRecombinant 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.

Funder

the Fundamental Research Funds for the Central Universities

Publisher

Springer Science and Business Media LLC

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