Translational Research for Retinal Degeneration Therapies

视网膜变性治疗的转化研究

• 批准号: 7679418
• 负责人: GUSTAVO David AGUIRRE
• 金额: $ 85.07万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7679418
• 关键词: Accounting; Affect; Age; Animal Model; Animals; Applications Grants; Area; Basic Science; Blindness; Canis familiaris; Catalytic RNA; Cells; Clinic; Clinical; Clinical Research; Clinical Treatment; Clinical Trials; Cohort Studies; Collaborations; Complementary DNA; Computers; Consensus; Data; Development; Disease; Dose; Drug Compounding; Europe; Feedback; Florida; Frameshift Mutation; Functional Imaging; Functional disorder; Funding; Future; Genes; Goals; Histopathology; Hour; Human; Individual; Industry; Inherited; Investigational Drugs; Investigational New Drug Application; Investigational Therapies; Kinetics; Knowledge; Lead; Leber' s amaurosis; Link; Measures; Mediating; Metric; Modeling; Modification; Molecular; Mutation; Natural History; North America; Operative Surgical Procedures; Outcome; Outcome Assessment; Outcome Measure; Output; Patients; Pennsylvania; Phase I Clinical Trials; Phase II Clinical Trials; Philadelphia; Photoreceptors; Primates; Principal Investigator; Prospective Studies; RPE65 protein; Reagent; Research; Research Activity; Research Infrastructure; Research Personnel; Resources; Retina; Retinal; Retinal Cone; Retinal Degeneration; Retinal Diseases; Retinitis Pigmentosa; Rodent Model; Running; Safety; Schedule; Scientist; Site; Small Interfering RNA; Staging; Structure; Testing; Therapeutic; Time; Tissues; Toxic effect; Translating; Translational Research; Translations; Treatment Efficacy; Universities; Vertebrate Photoreceptors; Vision; Work; animal resource; base; comparative; design; disease phenotype; early onset; experience; functional restoration; gain of function; gene therapy; human disease; in vivo; interdisciplinary approach; loss of function; macula; man; meetings; member; mutant; novel; novel therapeutic intervention; organizational structure; photoreceptor degeneration; pre-clinical; pre-clinical therapy; preclinical safety; prevent; programs; promoter; research study; retinal rods; safety study; safety testing; symposium; therapeutic development; therapy development; therapy outcome; translational study; treatment strategy; vector

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.

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，以在狗模型中开发和测试基于基因的视网膜疗法，以转化为由 RPGR 突变引起的 X 连锁 RP 患者。在北美，这种严重的早发性疾病约占 RP 病例的 8-10%，在欧洲占 15-20%，在单纯性患者中占 25%。该提案分为 6 个目标，分别是：（目标 1、2）开发和验证载体、启动子、敲低构建体和替代 cDNA，用于治疗因 RPGR-ORF15 停止或移码突变而导致表型不同的光感受器变性的狗； （目标 3、5）使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，这些测量可以外推到患者身上； （目标 4）在 RPGR-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，并确定结果测量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部治疗。描述了六个协调模块（M），每个模块都有一组独特的具体目标，以独特但互补的方式为转化研究做出贡献。 M1（大型动物实验）将制作狗模型，并为此工作提供基础设施资源。 M2（大型动物治疗）将在犬类模型中进行治疗研究，并开发用于结果评估的形态学测量方法。 M3（分子治疗开发）将提供敲低（siRNA、核酶）试剂、硬化野生型 cDNA 靶标、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（M5）研究之间差距的研究。 M5（RPGR患者的转化研究）将建立动物模型和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查新兴治疗的可行性，设计疾病特异性结果测量，并确定视网膜变性的自然史。 M6（临床前安全性）将在 -05 年对候选治疗载体进行基于 GLP 的临床前安全性研究，作为 FDA 考虑未来 1 期临床试验 IND 的重要第一步。该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，该合作已经将针对 RPE65-LCA 患者的视网膜基因治疗引入 I 期临床试验。宾夕法尼亚大学牵头与康奈尔大学和佛罗里达大学合作。