Translational Gene Therapy for CNGB1 Retinitis Pigmentosa

目前还没有治疗常染色体隐性遗传性视网膜色素变性(Arrp)的方法，这是由于rod基因突变引起的。 感光基因。这一多研究者、多中心的研究项目将通过优化 重组腺相关病毒载体基因增强治疗环核苷酸门控 通道Beta 1(CNGB1)链接的RP。优化后的向量将经过所需的阶段 正在研究的新药(IND)提交，为未来的I/II期临床试验做准备。协作 团队在rAAV载体的开发和生产、视网膜的临床前和临床试验方面拥有专业知识 营养不良，ARRP患者的临床评估和招募，CNG通道生理学和小和 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来填充 这种未得到满足的需求。首先，CNGB1突变会导致视杆功能丧失，但只会缓慢丧失视杆，这意味着 在仍有剩余的燃料棒的情况下，干预的机会很大。第二，有以下几种 具有良好特征的CNGB1-RP小(鼠)和大(狗)动物模型概括了人类 表型。第三，在两种CNGB1-RP模型中，rAAV基因增强治疗都能有效地(1)挽救 (2)延缓视杆细胞的退变。该项目有四个目标：目标1是开发一个 针对非人类灵长类动物的杆状光感受器进行高效和特异靶向的优化载体。我们要开始了 带有新的短视紫红质启动子的有效载体已经在CNGB1-RP中显示出有效性 动物模型。最终的rAAV-CNGB1载体将用于启动良好制造规范(GMP) 流程开发。这个最终的向量将被用来研究在小鼠和 犬CNGB1-RP模型的建立，同时也回答了一个重要的问题 结构的退化能得到挽救和保存吗？目标2将包括招募以下人员 临床试验的候选患者。一系列临床测试方法将在三年内使用 精确描述RP表型并为将来的临床试验确定最佳结果指标的时期。 测试还将确定两只眼睛之间是否有类似的疾病进展，这将使 第二只眼用作非治疗对照。目标3将包括动物毒理学和 IND提交所需的药代动力学和疗效研究。我们提出了一个标准的普洛斯 大鼠的毒理学/生物分布研究与CNGB1-RP犬的混合疗效/安全性研究相结合 模特。IND前与FDA的会议将审查研究设计并确保其符合监管规定 要求。然后将完成GMP载体的生产。最后，在目标4中，我们将准备并提交一份 IND应用程序。该项目实现了FOA的目标，即开发一种治疗方法，然后可以在 一项临床试验。“

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.”