基因传递
脉络膜新生血管
腺相关病毒
遗传增强
黄斑变性
视网膜色素上皮
视网膜
衣壳
脉络膜
载体(分子生物学)
生物
转导(生物物理学)
病毒载体
眼科
视网膜变性
转基因
医学
视网膜
重组DNA
基因
病毒学
病毒
神经科学
遗传学
生物物理学
作者
Shuang Luo,Hao Jiang,Qingwei Li,Yingfei Qin,Shiping Yang,Jing Li,Lingli Xu,Yan Gou,Yafei Zhang,Fengjiang Liu,Xiao Ke,Qiang Zheng,Xun Sun
标识
DOI:10.1038/s41467-024-48221-4
摘要
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.
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