Translational Research for Retinal Degeneration Therapies

视网膜变性治疗的转化研究

• 批准号: 8366544
• 负责人: GUSTAVO David AGUIRRE
• 金额: $ 81.86万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8366544
• 关键词: Accounting; Adverse effects; Animal Model; Animals; Area; Atrophic; Basic Science; Benchmarking; Biological Models; Blindness; Canis familiaris; Cells; Ciliary Neurotrophic Factor; Clinical Treatment; Clinical Trials; Collaborations; Complementary DNA; Degenerative Disorder; Dendrites; Development; Diagnosis; Disease; Disease model; Dose; Europe; Exons; Florida; Frameshift Mutation; Funding; GRB10 gene; Genes; Goals; Grant; Guanosine Triphosphate Phosphohydrolases; Health; Human; Image; Inherited; Investigational Therapies; Lead; Length; Link; Measures; Modeling; Molecular; Mutation; North America; Operative Surgical Procedures; Outcome Assessment; Outcome Measure; Patients; Pennsylvania; Phase; Phase I Clinical Trials; Phenotype; Photoreceptors; Positioning Attribute; RPE65 protein; Reagent; Regulator Genes; Relative (related person); Research; Research Infrastructure; Research Personnel; Resources; Retina; Retinal; Retinal Cone; Retinal Degeneration; Retinal Detachment; Retinal Diseases; Retinitis Pigmentosa; Route; Safety; Scientist; Severities; Staging; Structure; Testing; Therapeutic; Toxic effect; Translational Research; Translations; Trauma; Treatment Efficacy; Treatment outcome; Universities; Vertebrate Photoreceptors; Viral Vector; Vision; Work; base; clinical application; comparative efficacy; early onset; effective therapy; experience; fovea centralis; gene therapy; human RPGR protein; human disease; in vivo; macula; man; multidisciplinary; novel therapeutic intervention; photoreceptor degeneration; postnatal; prevent; promoter; research study; response; retinal rods; safety study; subretinal injection; success; therapeutic development; translational study; vector

DESCRIPTION (provided by applicant): A multi-investigator, multi-center research plan is proposed to finalize the development of gene-based retinal therapy in dog models of X-linked RP caused by mutations in RPGR prior to use in human patients. This uniformly severe, early onset human disease accounts for ~ 8-10% RP cases in North America, 15-20% in Europe, and 25% of simplex patients. The application builds on the success achieved during the current funding period which developed an AAV5-based viral vector that, together with the human IRBP promoter and human full-length RPGR cDNA, prevents the retina from degenerating in the 'slow' disease model (XLPRA1), or arrests the degeneration and maintains the photoreceptors at normal integrity in the 'fast' disease model (XLPRA2). This vector now serves as the benchmark therapeutic reagent for assessing treatment paradigms, and testing a novel therapeutic approach via the intravitreal route of delivery. The application will evaluate gene therapy in dogs having phenotypically distinct photoreceptor degenerations caused by stop or frameshift mutations in RPGRORF15, and is divided into 3 aims that will: 1-assess the long term efficacy of treatment and determine the dose-response range to establish efficacy vs toxicity dose~ 2- facilitate translational studies by targeting treatment to patient-relevant disease stage to assess treatment outcomes using criteria established during the current funding period~ 3- carry out comparative efficacy studies on modified vectors delivered via the intravitreal route that avoid secondary surgical trauma in compromised diseased photoreceptors. Four coordinated modules (M) are described that take advantage of the special expertise of each group to create a complementary and focused approach to the proposed translational studies. M1 (Large Animal experimental) will produce the dog models, and provide infrastructure resources for this work~ M2 (Large Animal Therapy) will carry out therapy studies in the canine models and develop ex vivo morphologic measures for outcome assessment~ M3 (Non-invasive Studies-Dog Models) will establish functional and structural disease features, and evaluate success of therapies using non-invasive outcome measures chosen appropriate for RPGR disease, and correlate the results with ex vivo morphologic studies~ M4 (Molecular Therapeutic Development) will provide therapeutic vectors for both subretinal and intravitreal delivery. The research studies described in this application represents a continuation of a longstanding collaboration between the module scientists that already has brought retinal gene therapy for RPE65-LCA patients to a Phase I clinical trial. The University of Pennsylvania leads this collaboration with the University of Florida. PUBLIC HEALTH RELEVANCE: X-linked retinitis pigmentosa (XLRP) caused by mutations in the RPGR gene is among the most severe and common causes of inherited retinal blindness in man. To finalize the development of gene therapy for use in human patients, we will exploit viral vectors already proven effective in preventing or arresting disease in two canine models, and optimize treatments at disease stages comparable to human patients using either subretinal or intravitreal delivery routes.

描述(由申请人提供)：一项多研究者、多中心的研究计划被提出，以完成在RPGR突变引起的X连锁RP犬模型中基于基因的视网膜治疗的发展，然后再用于人类患者。这种严重的、发病早的人类疾病占北美RP病例的8%-10%，欧洲的15%-20%，单纯性病例的25%。这项应用建立在当前资助期间取得的成功的基础上，该资助期间开发了一种基于AAV5的病毒载体，与人IRBP启动子和人全长RPGR基因一起，可以防止“慢”疾病模型(XLPRA1)中的视网膜退化，或阻止退化，并在“快”疾病模型(XLPRA2)中保持光感受器的正常完整性。该载体现在作为基准治疗试剂，用于评估治疗范例，并通过玻璃体内输送途径测试一种新的治疗方法。该应用程序将评估对因RPGRORF15的停止或移码突变而导致表型明显的光感受器变性的狗的基因治疗，并分为3个目标：1-评估治疗的长期疗效并确定剂量-反应范围，以确定有效性与毒性剂量~2-通过针对患者相关疾病阶段的治疗促进翻译研究，以使用当前资助期内建立的标准评估治疗结果~3-对通过玻璃体内途径输送的经玻璃体内传递的可避免受损疾病光感受器二次手术创伤的改良型载体进行疗效比较研究。文中描述了四个协调单元(M)，它们利用每个小组的专门知识，为拟议的翻译研究创造了一个补充和重点突出的办法。M1(大型动物实验)将制作狗模型，并为这项工作提供基础设施资源~M2(大型动物治疗)将在犬模型中开展治疗研究，并开发结果评估的体外形态指标~M3(非侵入性研究-狗模型)将建立功能和结构疾病特征，并使用适合RPGR疾病的非侵入性结果指标评估治疗的成功，并将结果与体外形态研究相关联~M4(分子治疗开发)将为视网膜下和玻璃体内输送提供治疗载体。本申请中描述的研究代表了模块科学家之间长期合作的延续，该模块科学家已经将RPE65-LCA患者的视网膜基因治疗带入I期临床试验。宾夕法尼亚大学领导着与佛罗里达大学的合作。 公共卫生相关性：由RPGR基因突变引起的X-连锁视网膜色素变性(XLRP)是人类遗传性视网膜失明最严重和最常见的原因之一。为了完成用于人类患者的基因治疗的开发，我们将在两个犬类模型中利用已被证明有效预防或阻止疾病的病毒载体，并使用视网膜下或玻璃体内给药途径优化与人类患者相当的疾病阶段的治疗。