Gene Delivery in Retinal Diseases

视网膜疾病中的基因传递

• 批准号: 7198012
• 负责人: John M Nickerson
• 金额: $ 33.43万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7198012
• 关键词: 11 cis Retinal; Adverse effects; Animal Model; Animals; Arts; Biological Models; Blindness; Cells; Characteristics; Charge; Complementary DNA; Condition; DNA; DNA delivery; Data; Defect; Diffusion; Disease; Disease model; Dose; Drug Formulations; Electrophoresis; Electroporation; Esters; Eye; Future; Gene Delivery; Genes; Glaucoma; Goals; Guanylate Cyclase; Human; In Vitro; Inherited; Invasive; Iontophoresis; Knock-out; Knowledge; Lead; Learning; Leber' s amaurosis; Lesion; Life; Macular degeneration; Measures; Methods; Mus; Mutate; Mutation; Natural regeneration; Night Blindness; Nucleic Acids; Operative Surgical Procedures; Outcome Measure; Pharmaceutical Preparations; Point Mutation; Property; Proteins; RNA; RPE65 protein; Research; Research Project Grants; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Rhodopsin; Safety; Sclera; Series; Staging; Structure of retinal pigment epithelium; System; Testing; Therapeutic; Thick; Time; Tissues; Transgenic Mice; Viral; Vision; Work; base; dosage; electric field; electrical property; expression vector; gene therapy; improved; in vivo; mouse model; novel; prevent; research study; size; theories

DESCRIPTION (provided by applicant): Delivery of genes and drugs to the cells of the retina is a significant challenge in the treatment of retinal and other disorders. We have developed a non-invasive method that exploits electrical fields applied trans- sclerally to efficiently deliver larger amounts of RNA or DNA to the retinal pigmented epithelium (RPE). This noninvasive approach will avoid side effects that can occur with surgical subretinal viral delivery, and repeated dosing should be easy and practical. In the future, once developed in the present simple model system, these results will guide us in adapting gene therapy to ophthalmic practice to treat diseases including glaucoma and retinal and macular degenerations. The disease and gene defect selected for this study is known to be treatable in animal models, and prior work serves as guidance and as a baseline for efficacy comparisons with our delivery approach. Our DNA delivery systems are established and meet the priority function of trans-scleral DNA delivery in vitro already. The electrical fields will be refined to aid and establish starting parameters for in vivo studies. Safety studies are planned to help achieve high delivery without damage to eye tissues or the animal. Iterative improvements are made based on optimization experiments, and outcome measures are collected both in vitro and in vivo. In the latter stages of the study, efficacy data are obtained. We plan to learn when and how to prevent severe night blindness and retinal degeneration in LCA caused by mutations in RPE65 in this project. This research project has two goals. The first goal is to optimize the amounts of nucleic acids that can be driven into the RPE trans-sclerally. The second goal is to evaluate the safety and efficacy of RPE65 gene delivery and expression in vivo in mice with lesions in this gene.

描述（由申请人提供）：将基因和药物递送到视网膜细胞是视网膜和其他疾病治疗的重大挑战。我们已经开发了一种非侵入性方法，该方法利用了跨紧身巩膜的电场，以有效地向视网膜色素上皮（RPE）提供大量的RNA或DNA。这种无创方法将避免手术下病毒传递可能会发生的副作用，并且重复给药应该容易且实用。将来，一旦在当前的简单模型系统中开发，这些结果将指导我们将基因治疗适应眼科实践，以治疗包括青光眼，视网膜和黄斑变性在内的疾病。 已知为这项研究选择的疾病和基因缺陷在动物模型中是可以治疗的，并且先前的工作是指导和基准与我们的递送方法的疗效比较。 我们的DNA递送系统已建立，并符合体外跨委托DNA递送的优先函数。电场将被改进，以帮助并建立体内研究的起始参数。计划进行安全研究以帮助实现高递送，而不会损害眼组织或动物。基于优化实验进行迭代改进，并在体外和体内收集结果指标。在研究的后期，获得了疗效数据。 我们计划学习何时以及如何预防由RPE65突变引起的LCA严重的夜失明和视网膜变性。该研究项目有两个目标。第一个目标是优化可以将可以驱动到RPE反式统计的核酸的量。第二个目标是评估该基因病变的小鼠中RPE65基因递送和体内表达的安全性和功效。