黑猩猩腺病毒介导的针对年龄相关性黄斑变性的多基因疗法。
Chimpanzee adenovirus-mediated multiple gene therapy for age-related macular degeneration.
作者信息
Wei-Zhang Selena, Cui Bohao, Xing Man, Liu Jiaojiao, Guo Yingying, He Kai, Bai Tinghui, Dong Xue, Lei Yi, Zhou Wei, Zhou Hui, Liu Shengnan, Wang Xiaohong, Zhou Dongming, Yan Hua
机构信息
Department of Ophthalmology, Tianjin Key Laboratory of Ocular Trauma, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China.
Laboratory of Molecular Ophthalmology, Tianjin Medical University, Tianjin 300070, China.
出版信息
iScience. 2023 Sep 16;26(10):107939. doi: 10.1016/j.isci.2023.107939. eCollection 2023 Oct 20.
Neovascular age-related macular degeneration AMD (nAMD) is characterized by choroidal neovascularization (CNV) and could lead to irreversible blindness. However, anti-vascular endothelial growth factor (VEGF) therapy has limited efficacy. Therefore, we generated a chimpanzee adenoviral vector (AdC68-PFC) containing three genes, pigment endothelial-derived factor (PEDF), soluble fms-like tyrosine kinase-1 (sFlt-1), and soluble forms of CD59 (sCD59), to treat nAMD. The results showed that AdC68-PFC mediated a strong onset of PEDF, sFlt-1, and sCD59 expression both and . AdC68-PFC showed preventive and therapeutic effects following intravitreal (IVT) injection in the laser-induced CNV model and very low-density lipoprotein receptor-deficient () mouse model. assessment indicated that AdC68-PFC had a strong inhibitory effect on endothelial cells. Importantly, the safety test showed no evidence of toxicity of adenovirus in murine eyes. Our findings suggest that AdC68-PFC may be a long-acting and safe gene therapy vector for future nAMD treatments.
新生血管性年龄相关性黄斑变性（AMD，nAMD）的特征是脉络膜新生血管形成（CNV），可导致不可逆性失明。然而，抗血管内皮生长因子（VEGF）疗法的疗效有限。因此，我们构建了一种包含色素内皮衍生因子（PEDF）、可溶性fms样酪氨酸激酶-1（sFlt-1）和可溶性CD59（sCD59）三种基因的黑猩猩腺病毒载体（AdC68-PFC），用于治疗nAMD。结果表明，AdC68-PFC在体内和体外均介导了PEDF、sFlt-1和sCD59的强烈表达起始。在激光诱导的CNV模型和极低密度脂蛋白受体缺陷（）小鼠模型中，玻璃体内（IVT）注射AdC68-PFC后显示出预防和治疗作用。评估表明，AdC68-PFC对内皮细胞有强烈的抑制作用。重要的是，安全性测试显示在鼠眼中没有腺病毒毒性的证据。我们的研究结果表明，AdC68-PFC可能是未来nAMD治疗的一种长效且安全的基因治疗载体。
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