Translational Gene Therapy for CNGB1 Retinitis Pigmentosa

CNGB1 色素性视网膜炎的转化基因治疗

• 批准号: 10333786
• 负责人: WILLIAM W HAUSWIRTH
• 金额: $ 36.36万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10333786
• 关键词: Animal Model; Animals; Biodistribution; Canis familiaris; Clinical Trials; Clinical assessments; Coupled; Development; Disease Progression; Drug Kinetics; Ensure; Eye; Future; Genes; Goals; Human; Hybrids; Intervention; Investigational Drugs; Investigational New Drug Application; Link; Methods; Modeling; Mus; Mutation; Outcome Measure; Patients; Phase I/II Clinical Trial; Phenotype; Physiology; Preparation; Process; Production; Public Health; Rattus; Recombinant adeno-associated virus (rAAV); Research; Research Design; Research Personnel; Research Project Grants; Retinal Dystrophy; Retinitis Pigmentosa; Rhodopsin; Rod; Structure; Testing; Therapeutic; Toxicology; adeno-associated viral vector; cyclic-nucleotide gated ion channels; efficacy study; gene augmentation therapy; gene therapy; meetings; nonhuman primate; preclinical trial; preservation; promoter; recruit; research clinical testing; retinal rods; safety study; vector

Currently there is no treatment for autosomal recessive retinitis pigmentosa (arRP) due to mutations in rod photoreceptor genes. This multi-investigator, multi-center research project will fill this gap by optimizing recombinant adeno-associated virus (rAAV) vector gene augmentation therapy for cyclic nucleotide-gated channel beta 1 (CNGB1) linked RP. The optimized vector will be taken through the stages needed for an investigational new drug (IND) submission in preparation for a future phase I/II clinical trial. The collaborative team has expertise in rAAV vector development and production, preclinical and clinical trials for retinal dystrophies, clinical assessment and recruitment of arRP patients, CNG channel physiology and small and large animal proof-of-concept gene therapy studies. There are compelling reasons to select CNGB1-RP to fill this unmet need. First, CNGB1 mutations cause a loss of rod function, but only a slow loss of rods, meaning there is a wide window of opportunity for intervention while there are still remaining rods. Second, there are well characterized small (mouse) and large (dog) animal models of CNGB1-RP that recapitulate the human phenotype. Third, in both CNGB1-RP models rAAV gene augmentation therapy can efficiently (1) rescue the function and (2) delay the degeneration of rods. There are four aims to the project: Aim 1 is development of an optimized vector that efficiently and specifically targets rod photoreceptors in nonhuman primates. We will start with an efficient vector with a new short rhodopsin promoter that has already shown efficacy in CNGB1-RP animal models. The final rAAV-CNGB1 vector will be used to start the Good Manufacturing Practice (GMP) process development. This final vector will be used to investigate duration of rescue achievable in mouse and dog CNGB1-RP models and also answer the important question of "how late in the process of rod degeneration can rescue and preservation of structure be obtained?” Aim 2 will consist of recruitment of candidate patients for the clinical trial. A barrage of clinical testing methods will be used over a three year period to precisely describe the RP phenotype and identify optimal outcome measures for a future clinical trial. The testing will also ascertain if there is similar disease progression between the two eyes which would allow the second eye to be used as a non treatment control. Aim 3 will consist of the animal toxicology and pharmacokinetic and efficacy studies needed for IND submission. We propose a standard GLP toxicology/biodistribution study in rats coupled with a hybrid efficacy/safety study using the CNGB1-RP dog model. A pre-IND meeting with the FDA will review the study design and ensure that it meets regulatory requirements. GMP vector production will then be completed. Finally, in Aim 4 we will prepare and submit an IND application. This project fulfills the FOA goal of “development of a therapeutic, which can then be tested in a clinical trial.”

目前尚无治疗因视杆细胞突变导致的常染色体隐性色素性视网膜炎 (arRP) 的方法 这个多研究者、多中心的研究项目将通过优化来填补这一空白。 用于环核苷酸门控的重组腺相关病毒（rAAV）载体基因增强疗法 通道 beta 1 (CNGB1) 连接的 RP 将经过优化的向量。 提交研究性新药 (IND)，为未来的 I/II 期临床试验做准备。 团队拥有 rAAV 载体开发和生产、视网膜临床前和临床试验方面的专业知识 营养不良、arRP 患者的临床评估和招募、CNG 通道生理学以及小型和小型 大型动物概念验证基因治疗研究有令人信服的理由选择 CNGB1-RP 来填补。 首先，CNGB1 突变会导致视杆细胞功能丧失，但只是缓慢地丧失视杆细胞。 在仍有剩余棒的情况下，存在很大的干预机会。 CNGB1-RP 的小型（小鼠）和大型（狗）动物模型具有良好的特征，可再现人类 第三，在两种 CNGB1-RP 模型中，rAAV 基因增强疗法可以有效地 (1) 挽救。 功能和（2）延缓视杆细胞的退化 该项目有四个目标： 目标 1 是开发一种 我们将开始高效、特异性地针对非人类灵长类动物的杆状光感受器的优化载体。 带有新的短视紫红质启动子的高效载体，该启动子已在 CNGB1-RP 中显示出功效 最终的 rAAV-CNGB1 载体将用于启动良好生产规范 (GMP)。 该最终载体将用于研究小鼠和小鼠中可实现的救援持续时间。 狗 CNGB1-RP 模型，并回答了“杆过程中晚到什么程度”的重要问题 退化可以得到拯救和保存结构吗？”目标2将包括招募 临床试验的候选患者将在三年内使用一系列临床测试方法。 精确描述 RP 表型并确定未来临床试验的最佳结果指标。 该测试还将确定两只眼睛之间是否存在类似的疾病进展，这将允许 用作非治疗对照的第二只眼睛将包括动物毒理学和 IND 提交所需的药代动力学和功效研究我们提出了标准 GLP。 大鼠毒理学/生物分布研究以及使用 CNGB1-RP 狗的混合功效/安全性研究 与 FDA 举行的 IND 前会议将审查研究设计并确保其符合监管要求。 最后，在目标 4 中，我们将准备并提交一份 GMP 载体生产。 该项目实现了 IND 申请“开发一种治疗方法，然后进行测试”的目标。 临床试验。”