Translational Research for Retinal Degeneration Therapies

提出了一项多研究者、多中心的计划，以开发基于基因的LCA视网膜疗法， 使用狗NPHP 5模型的纤毛病变。这些人类纤毛病的一个亚组显示出早发性， 由于感光细胞发育异常而导致的严重先天性视网膜和视觉功能障碍 (PR)然后退化该提案建立在本赠款期取得的成功的基础上， 将RPGR-XLRP转移到临床试验中，最近在NPHP 5模型中的研究表明scAAV 2/8- 基于病毒载体，与人GRK 1启动子和人全长NPHP 5 cDNA一起， ERG视杆细胞和视锥细胞功能以及视力至少持续1年，但PR继续退化，尽管在 慢得多的速度。该载体现在用作基准测试载体，以评估治疗范例， 优化PR靶向、感染性和治疗性转基因表达，这将导致永久性疾病 纠正一下该提案将评估基因治疗在狗有这种侵略性和严重的LCA- 睫状体病，并分为三个目标，将：1-建立基准剂量和疾病阶段 2-选择具有优化的前导载体假型和启动子 转导效率和靶向不同PR疾病阶段的功效; 3-促进翻译研究 通过定义犬和患者的疾病自然史，犬的治疗效果，以及 确定仍然适合治疗的PR/视网膜疾病的程度。虽然测试平台是 NPHP 5-LCA狗模型，所解决的治疗问题广泛适用于其他LCA纤毛病变。四 协调小组[又名：模块（M）]，描述了利用每个模块的特殊专长， 小组创建一个互补的和重点突出的方法，以拟议的翻译研究。M1（大） Animal Experimental）将制作犬模型，并为工作提供基础设施资源; M2 （大型动物治疗）将开展治疗研究，并制定结果评估措施; M3 （非侵入性患者和犬研究）将建立功能和结构性疾病的特点， 患者和模型，并使用非侵入性结局指标评估犬中治疗的成功率， 与离体形态学研究相关; M4（分子治疗开发）将提供治疗 向量。本提案中所述的研究是一项长期的 模块科学家之间的合作，已经带来了视网膜基因疗法的治疗， RPE 65-LCA（I期临床试验）、CNGB 3-色盲和RPGR-XLRP（均在 临床试验的最后准备）。宾夕法尼亚大学领导这项合作， 佛罗里达大学。

A multi-investigator, multi-center plan is proposed to develop gene-based retinal therapies for LCA- ciliopathies using the dog NPHP5 model. A subgroup of these human ciliopathies show early onset and profound congenital retinal and visual malfunction that results from abnormally developed photoreceptors (PR) that subsequently degenerate. The proposal builds on success achieved in the current grant period in moving RPGR-XLRP to a clinical trial, and recent studies in the NPHP5 model showing that a scAAV2/8- based viral vector, together with the human GRK1 promoter and human full-length NPHP5 cDNA, rescues ERG rod and cone function, and vision, for at least 1 year, but that PRs continue to degenerate, albeit at a much slower rate. This vector now serves as the benchmark test vector to assess treatment paradigms to optimize PR targeting, infectivity and therapeutic transgene expression that will result in permanent disease correction. The proposal will evaluate gene therapy in dogs having this aggressive and severe LCA- ciliopathy, and is divided into three aims that will: 1- establish the benchmark dose and disease stage treatment efficacy of the test vector; 2- select the lead vector pseudotype and promoter with optimized transduction efficiency, and efficacy in targeting different PR disease stages; 3- facilitate translational studies by defining the natural history of the disease in dogs and patients, the effect of treatment in dogs, and determining the degree of PR/retinal disease still amenable to treatment. While the test platform is the NPHP5-LCA dog model, the therapeutic questions addressed apply broadly to other LCA-ciliopathies. Four coordinated groups [a.k.a. 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 the work; M2 (Large Animal Therapy) will carry out therapy studies and develop measures for outcome assessment; M3 (Non-invasive Patient and Dog Studies) will establish functional and structural disease features in the patients and model, and evaluate success of therapies in dogs using non-invasive outcome measures that correlate with ex vivo morphologic studies; M4 (Molecular Therapeutic Development) will provide therapeutic vectors. The research studies described in this proposal represents a continuation of a longstanding collaboration between the module scientists that already has brought retinal gene therapy for the treatment of patients with RPE65-LCA (Phase I clinical trial), and CNGB3-achromatopsia and RPGR-XLRP (both in final preparations for clinical trials). The University of Pennsylvania leads this collaboration with the University of Florida.