rAAV-CNGB3 Gene Therapy for Achromatopsia: Translational Research Studies

描述（由申请人提供）：我们提出了一系列协调的活动，旨在将CNGB3型色盲的成功临床前基因治疗转化为临床试验。这种新型重组腺相关病毒（rAAV）基因递送试剂是一种“同类首创”的治疗剂，可解决CNGB3相关性色盲患者未满足的视力需求。为实现这一目标，我们提出了六个具体目标。目标1将通过系统地修改每个成分（启动子、内含子、cDNA和polyA）来优化rAAV-CNGB3载体，使载体不超过其最佳包装容量，能够靶向所有三种锥体亚类，并具有优化的密码子，以最小剂量实现最大功效。Aim 2将生产用于动物研究的raav -人CNGB3载体，以确定最佳载体结构，然后将生产用于GLP安全性研究和临床试验，使用我们开发的可扩展的、重组单纯疱疹病毒的生产方法，该方法符合GMP标准和FDA要求。目的3将评估另一种血清型衣壳和锥体启动子对CNGB3-/-色盲小鼠模型的疗效。这将完善初步结果，表明玻璃体内给药载体可能导致锥体光感受器的相关转导。表达人类CNGB3和眼部递送部位的最佳载体构建将用于非人灵长类动物的初步安全性研究。目的4将使用一系列最先进的方法来评估CNGB3色盲患者，以建立自然病史，适当的纳入/排除标准和适合临床试验的终点。Aim 5将使用Aim 2的最佳载体在大鼠和非人灵长类动物中进行glp兼容毒理学和生物分布研究。在启动这些研究之前，我们将与FDA进行IND前会议，以审查拟议的研究设计和制造/释放测试方法，以就满足IND要求的研究达成协议。基于这些数据，我们将在Aim 6中准备并向FDA提交IND。IND将包括1/2期临床试验的方案，其设计将以前五个特定目标的结果为指导。

DESCRIPTION (provided by applicant): We propose a set of coordinated activities aimed at enabling the translation of a successful preclinical gene therapy for the CNGB3 form of achromatopsia into a clinical trial. This novel recombinant adeno-associated virus (rAAV) gene delivery reagent is a "first in class" therapeutic agent to address the unmet vision needs of patients with CNGB3 related achromatopsia. To achieve this goal we propose six Specific Aims. Aim 1 will optimize the rAAV-CNGB3 vector by systematically modifying each of the components (promoter, intron, cDNA and polyA) so that the vector does not exceed its optimal packaging capacity, is able to target all three cone subclasses, and has optimized codons that enable maximal efficacy at a minimum dose. Aim 2 will produce rAAV-human CNGB3 vectors for use in animal studies in order to identify an optimal vector construct, which will then be produced for use in GLP safety studies and in clinical trials using a scalable, recombinant herpes simplex virus-based production method we developed that meets GMP standards and FDA requirements. Aim 3 will evaluate an alternative serotype capsids and cone promoters for efficacy in a CNGB3-/- mouse model of achromatopsia. This will refine preliminary results suggesting that intravitreal administration of vector may lead to relevant transduction of cone photoreceptors. The optimal vector construct expressing human CNGB3 and ocular site of delivery will then be used to perform preliminary safety studies in nonhuman primates. Aim 4 will evaluate CNGB3 achromatopsia patients using a battery of state-of-the-art methods to establish natural history, appropriate inclusion/exclusion criteria and endpoints appropriate for the clinica trial. Aim 5 will the use the optimal vector from Aim 2 to perform GLP-compliant toxicology and biodistribution studies in rats and nonhuman primates. Prior to initiating these studies, we will conduct a pre-IND meeting with the FDA to review the proposed study design and manufacturing/release testing methods, to reach agreement on the studies that will satisfy IND requirements. Based on these data, in Aim 6 we will prepare and submit an IND to the FDA. The IND will include a protocol for a Phase 1/2 clinical trial whose design will be guided by results from the previous five Specific Aims.