RDS mutations: Gene therapy for ADRP, macular degeneration and pattern dystrophy

RDS 突变：ADRP、黄斑变性和模式营养不良的基因治疗

基本信息

批准号：
7915378
负责人：
Alfred S Lewin
金额：
$ 57.12万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7915378
关键词：
Acute Affect Age Age related macular degeneration Blindness Catalytic RNA Cells Choroidal Neovascularization Cicatrix Dependovirus Developed Countries Disease Elderly Event Gene Targeting Genes Goals Inherited Knockout Mice Laboratories Lead Macular degeneration Maintenance Measures Mediating Messenger RNA Methods Modeling Morphogenesis Mus Mutation Pathologic Phase I Clinical Trials Photoreceptors Play Production Proteins RNA RNA replacement Reading Research Research Personnel Resistance Retina Retinal Cone Retinal Diseases Retinitis Pigmentosa Role Small Interfering RNA Structure Supplementation Technology Testing Vertebrate Photoreceptors Vision Work adeno-associated viral vector design gene replacement gene therapy genetic risk factor loss of function mutation macula mouse model mutant nonhuman primate null mutation pattern dystrophies peripherin programs promoter prospective research study retinal rods safety testing therapeutic gene

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this research is to generate a gene therapy for dominantly inherited forms of retinal disease which lead to blindness. The aims of this project are designed to develop a treatment for mutations in the RDS/peripherin gene which lead to pattern dystrophy, macular degeneration and autosomal dominant retinitis pigmentosa (ADRP). For this work we will employ mouse models that contain mutations in the RDS/peripherin gene, and we will use Adeno-associated virus to deliver potential therapeutic genes. Because mutations in the RDS/peripherin gene are frequently associated with degeneration of cone photoreceptor cells, we will target the expression of therapeutic genes to cones in addition to rod cells. We have four specific aims: (1) To develop an RNA replacement technology for RDS/peripherin in which levels of endogenous mRNA are reduced using a ribozyme or an siRNA, and a ribozyme- or siRNA-resistant version of the mRNA is supplied simultaneously. (2) To test the gene replacement method in the P216L mouse line that expresses a mutant version of RDS/peripherin leading to ADRP. (3) To develop an AAV- mediated gene targeting method for cone photoreceptor cells, the cells affected by peripherin/rd mutations in pattern dystrophy and macular degeneration. (4) To express the P216L mutation in the context of the NRL knockout mouse, which produces only cone photoreceptors, and to test RNA replacement in this model. Preliminary results from our laboratories and from those of other investigators suggest that these experiments will prove fruitful and will lead to a treatment for retinal diseases caused by RDS mutations. This project is relevant to age-related macular degeneration and retinitis pigmentosa. Age-related macular degeneration (AMD) is the major blinding disease affecting the elderly in developed countries. Some form of AMD affects as many as 1 in 3 people over the age of 70. It leads to scarring and degeneration of the cone-rich central retina, which is required for acute vision, including reading and face-recognition. Retinitis Pigmentosa (RP) affects fewer people, 60,000-100,000 in the US, but it robs them of useful vision at an earlier age. Since many of the mutant genes for RP are known, a gene therapy may be possible for many forms of the disease.

描述（由申请人提供）：这项研究的长期目标是为导致失明的显性遗传性视网膜疾病开发一种基因疗法。该项目的目的是开发一种针对 RDS/外周蛋白基因突变的治疗方法，这些突变会导致模式营养不良、黄斑变性和常染色体显性视网膜色素变性 (ADRP)。在这项工作中，我们将采用含有 RDS/外周蛋白基因突变的小鼠模型，并且我们将使用腺相关病毒来传递潜在的治疗基因。由于 RDS/外周蛋白基因的突变通常与视锥细胞感光细胞的变性相关，因此除了视杆细胞外，我们还将针对视锥细胞表达治疗基因。我们有四个具体目标：(1) 开发 RDS/外周蛋白的 RNA 替代技术，其中使用核酶或 siRNA 降低内源 mRNA 水平，并同时提供 mRNA 的核酶或 siRNA 抗性版本。 (2) 在表达导致 ADRP 的 RDS/外周蛋白突变版本的 P216L 小鼠系中测试基因替换方法。 (3) 开发一种针对视锥细胞的 AAV 介导的基因靶向方法，视锥细胞受外周蛋白/rd 突变影响，导致营养不良和黄斑变性。 (4) 在只产生视锥光感受器的 NRL 敲除小鼠中表达 P216L 突变，并在该模型中测试 RNA 替换。我们实验室和其他研究人员的初步结果表明，这些实验将取得丰硕成果，并将导致 RDS 突变引起的视网膜疾病的治疗。该项目与年龄相关性黄斑变性和色素性视网膜炎相关。年龄相关性黄斑变性（AMD）是影响发达国家老年人的主要致盲疾病。某种形式的 AMD 会影响 70 岁以上的三分之一的人。它会导致富含视锥细胞的中央视网膜出现疤痕和退化，而中央视网膜是敏锐视力（包括阅读和面部识别）所必需的。色素性视网膜炎 (RP) 影响的人数较少，在美国为 60,000-100,000 人，但它会在较早的时候剥夺他们的有用视力。由于许多 RP 突变基因是已知的，因此基因疗法可能适用于多种形式的疾病。