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

• 批准号: 7679416
• 负责人: Alfred S Lewin
• 金额: $ 56.75万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7679416
• 关键词: Acute; Affect; Age; Age related macular degeneration; Blindness; Catalytic RNA; Cells; Choroidal Neovascularization; Cicatrix; Dependovirus; Developed Countries; Developing 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

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视网膜疾病的主要遗传形式产生一种基因治疗。该项目的目的旨在开发用于RDS/外周基因突变的治疗方法，该突变导致型格营养不良，黄斑变性和常染色体显性视网膜炎色素（ADRP）。对于这项工作，我们将采用含有RDS/外围蛋白基因突变的小鼠模型，我们将使用与腺相关的病毒传递潜在的治疗基因。由于RDS/外周基因中的突变经常与锥形光感受器细胞的变性有关，因此除了杆细胞外，我们还将针对锥体的治疗基因的表达。我们有四个具体的目的：（1）为RDS/外围蛋白开发RNA替代技术，其中使用核酶或siRNA降低内源mRNA的水平，并同时提供抗核酶或耐siRNA的mRNA。 （2）在P216L小鼠系中测试基因置换方法，该方法表达了导致ADRP的RDS/外周的突变版本。 （3）为锥形感光细胞开发一种辅助介导的基因靶向方法，在模式营养不良和黄斑变性中受外周/RD突变影响的细胞。 （4）在NRL基因敲除小鼠的背景下表达P216L突变，该小鼠仅产生锥形感受器，并在该模型中测试RNA替代。我们实验室和其他研究人员的初步结果表明，这些实验将证明是富有成果的，并将导致对RDS突变引起的视网膜疾病的治疗。 该项目与年龄相关的黄斑变性和色素性视网膜炎有关。与年龄相关的黄斑变性（AMD）是影响发达国家老年人的主要盲目疾病。某种形式的AMD影响了70岁以上的三分之一的人。这导致锥形丰富的中央视网膜的疤痕和退化，这是急性视觉所必需的，包括阅读和面部识别。色素性视网膜炎（RP）在美国影响较少的人，60,000-100,000人，但在更早的时候就剥夺了他们有用的视力。由于许多RP的突变基因是已知的，因此许多形式的疾病可能可以使用基因疗法。