Gene Therapy for Retinal Degeneration using Home-grown Gene Transfer Vectors-Aim for Clinical Trial-

1. 基因治疗视网膜变性动物模型的疗效评价1)新的基因治疗技术的发展我们开发了携带hFGF-2或hPEDF和hFGF-2的新的SIV（猴免疫缺陷病毒）载体（SIV- fgf -2或SIV-dual）。此外，我们以临床试验为目标，开发了SIV-hPEDF的大规模生产系统。2) SIV-hPEDF和SIV-hFGF-2对两种视网膜变性动物模型（RCS大鼠和rds小鼠）的协同治疗效果。神经祖细胞基因治疗新策略的建立1)睫状体神经祖细胞培养分离方法的建立我们发现了睫状体源性细胞通过球体形成神经分化的新机制（重编程系统）。来自纤毛体的巢蛋白阴性上皮样细胞开始表达巢蛋白。2)通过SIV载体将基因有效地转移到眼睫状体的神经祖细胞中。我们评估了第三代SIV载体将基因转移到非人灵长类动物视网膜的能力。2)我们提出了VEGF-C和VEGF-D在RPE中的表达可能改变眼部血管生成，如年龄相关性黄斑变性（AMD）作为血管生成刺激剂。

1. The assessment of the efficacy of gene therapy for the animal models of retinal degeneration1) Development of new gene therapy technologyWe developed the new SIV (simian immunodeficiency virus) vectors carrying hFGF-2 or both hPEDF and hFGF-2 (SIV-FGF-2 or SIV-dual). Moreover, we developed the system for large-scale production of SIV-hPEDF with the aim of the clinical trail.2) We showed the synergistic therapeutic effect using SIV-hPEDF and SIV-hFGF-2 for two animal models of retinal degeneration (RCS rats and rds mice)2. The establishment of new gene therapy strategy by use of neural progenitor cells1) Development of the culture method to isolate neural progenitor cells from ciliary body of the eyeWe identified a new and divergent mechanism (a reprogramming system) underlying the neural differentiation of ciliary body-derived cells via sphere formation. The nestin-negative epithelial-like cells from ciliary body came to express nestin.2) We demonstrated the efficient gene transfer to neural progenitor cells from ciliary body of the eye via SIV vector3. Remains1) We evaluated the ability of our 3rd generation SIV vectors to transfer genes into nonhuman primate retinas.2) We suggested the possibility that VEGF-C and VEGF-D expression in RPE modify the ocular angiogenesis, such as age-related macular degeneration (AMD) as angiogenic stimulators.