GENE THERAPY FOR TREATMENT OF RETINAL DEGENERATION

治疗视网膜变性的基因疗法

• 批准号: 6342594
• 负责人: Horst A. von Recum
• 金额: $ 4.02万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-17 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6342594
• 关键词: gene expression; gene targeting; gene therapy; laboratory rat; method development; retina degeneration; retinal pigment epithelium; tissue /cell culture; tissue engineering; visual photoreceptor

The delivery of cytokines into the subretinal space may play an important role in the treatment of retinal degenerative diseases such as age related macular degeneration and certain forms of retinitis pigmentosa. These diseases, which constitute the leading cause of adult onset blindness spring from a variety of genetic sources, and have few available treatment options. Transplantation of retinal cells, as well as delivery of genes to restore lost function are currently being investigated both in the laboratory and clinical setting as possible treatments. This proposal combines elements of both procedures with the goal of long-term drug delivery into the subretinal space. Preliminary research has shown that single dose injection of cytokines into the eye show short-term prevention of photoreceptor degeneration in rat disease models. In order to achieve long-term delivery and prevention we propose the use of genetically modified cells which can overexpress the desired cytokines upon external pharmacological signaling. The method of action of these primarily neurotrophic cytokines could be simultaneously in the photoreceptor and the retinal pigmented epithelium (RPE). We propose that these biomolecules cause upregulation in photoreceptor metabolism, maintaining viable pre-dystrophic levels of gene expression. In the RPE upregulation prevents dedifferentiation into a wound-healing phenotype allowing maintenance of the immunoisolating blood-retina barrier. We intend to use the genetically altered transplant model to investigate these two hypotheses, following photoreceptor rescue and cellular metabolism. The long term goal of this project is to provide tissue engineering therapy which can be applicable to retinal dystrophies with differing etiology.

将细胞因子递送至视网膜下间隙可能发挥重要作用 在视网膜退行性疾病的治疗中发挥着重要作用 如年龄相关性黄斑变性和某些形式的视网膜炎 色素变性。 这些疾病是成人发病的主要原因 发病性失明有多种遗传来源，并且很少有 可用的治疗方案。视网膜细胞移植 目前正在运送基因以恢复失去的功能 尽可能在实验室和临床环境中进行研究 治疗。 该提案结合了这两个程序的要素 将药物长期输送到视网膜下腔的目标。 初步的 研究表明，单剂量注射细胞因子到眼睛 显示短期预防大鼠疾病中的光感受器变性 模型。 为了实现长期交付和预防我们 提议使用可以过度表达的转基因细胞 根据外部药理信号传导所需的细胞因子。 方法 这些主要神经营养细胞因子的作用可能是 同时在光感受器和视网膜色素上皮中 （RPE）。 我们认为这些生物分子导致上调 光感受器代谢，维持营养不良前的可行水平 基因表达。 在 RPE 中上调可防止去分化 进入伤口愈合表型，允许维持 免疫隔离血视网膜屏障。 我们打算利用基因 改变移植模型来研究这两个假设，如下 光感受器救援和细胞代谢。 长期目标是 该项目旨在提供组织工程疗法 适用于不同病因的视网膜营养不良。