Translational Research for Retinal Degeneration Therapies

描述（由申请人提供）：提出了一项多研究者、多中心的研究计划，在狗模型中开发和测试基于基因的视网膜治疗方法，并将其转化为由RPGR突变引起的x连锁RP患者。这种严重的早发性疾病在北美约占8-10%的RP病例，在欧洲占15-20%，在单纯性患者中占25%。该提案分为6个目标：（目标1,2）开发和验证载体、启动子、低表达构建体和替代cdna，用于治疗由rgr - orf15停止或移码突变引起的具有明显不同表型的光感受器变性的狗；（目标3,5）利用形态学和非侵入性功能和成像，在模型中建立治疗结果测量，可以外推到患者；（目标4）在rgr - xlrp患者中进行前瞻性研究，以确定将临床前治疗转化为临床的可行性或设施，并确定结果措施，以适应针对更脆弱的中央视网膜中的视杆细胞和视锥细胞的局灶治疗。描述了六个协调模块(M)，每个模块都有一套独特的具体目标，以独特但互补的方式为翻译研究做出贡献。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）将在犬模型中进行治疗研究，并制定用于结果评估的形态学措施。M3 （Molecular Therapeutic Development）将提供敲低（siRNA、核酶）试剂、硬化野生型cDNA靶点、启动子和载体。M4（非侵入性研究-狗模型）将使用非侵入性措施评估M2进行的治疗，确定视网膜重塑的功能和结构后果，并将开展弥合动物和人类研究之间差距的研究（M5）。M5 （Translational Studies in RPGR patients）将建立动物模型与人类疾病表达之间的关系，通过研究视网膜结构和共定位功能来检验新兴治疗方法的可行性，设计疾病特异性结局指标，确定视网膜变性的自然历史。M6（临床前安全性）将在2005年开展一项基于glp的候选治疗载体的临床前安全性研究，作为FDA考虑未来i期临床试验IND的重要第一步。本提案中描述的研究代表了模块科学家之间长期合作的延续，该合作已经将RPE65-LCA患者的视网膜基因治疗带入了I期临床试验。宾夕法尼亚大学与康奈尔大学和佛罗里达大学领导了这项合作。

DESCRIPTION (provided by applicant): A multi-investigator, multi-center research plan is proposed to develop and test gene-based retinal therapy in dog models for translation to patients with X-linked RP caused by mutations in RPGR. This uniformly severe, early onset disease accounts for ~ 8-10% RP cases in North America, 15-20% in Europe, and 25% of simplex patients. The proposal has been divided into 6 aims that will: (aim 1, 2) develop and validate vectors, promoters, knockdown constructs and replacement cDNAs for therapy of dogs having phenotypically distinct photoreceptor degenerations caused by stop or frameshift mutations in RPGR-ORF15; (aims 3, 5) establish therapy outcome measures in the models using morphologic and non-invasive functional and imaging that can be extrapolated to patients; (aim 4) perform prospective studies in RPGR-XLRP patients to determine the feasibility or facility of translating pre-clinical therapy to the clinic, and defining outcome measures to accommodate a focal therapy targeting rods and cones in the more vulnerable central retina. Six coordinated modules (M) are described, each with a distinct set of specific aims that contributes in a unique but complementary way to the 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 morphologic measures for outcome assessment. M3 (Molecular Therapeutic Development) will provide knockdown (siRNA, ribozymes) reagents, hardened wild type cDNA targets, promoters and vectors. M4 (Non-invasive Studies-Dog Models) will evaluate therapies carried out by M2 using non-invasive measures, determine functional and structural consequences of retinal remodeling, and will carry out studies that bridge the gap between animal and human (M5) research. M5 (Translational Studies in RPGR patients) will establish the relationship between the animal models and human disease expression, examine the feasibility of emerging treatments by studying retinal structure and colocalized function, design disease-specific outcome measures, and determine the natural history of the retinal degeneration. M6 (Preclinical Safety) will carry out in -05 year a GLP-based preclinical safety study of the candidate therapeutic vector as the essential first step for FDA consideration of an IND for a future Phase 1 Clinical Trial. The research studies described in this proposal represent 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 Cornell University and University of Florida.