rAAV-CNGB3 Gene Therapy for Achromatopsia: Translational Research Studies

描述（由申请人提供）：我们提出了一组协调活动，旨在将CNGB 3形式的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“一流的”治疗剂，可解决CNGB 3相关色盲患者未满足的视力需求。为了实现这一目标，我们提出了六个具体目标。目的1将通过系统地修饰每个组分（启动子、内含子、cDNA和polyA）来优化rAAV-CNGB 3载体，使得载体不超过其最佳包装容量，能够靶向所有三种视锥细胞亚类，并且具有能够以最小剂量实现最大功效的优化密码子。目的2将生产用于动物研究的rAAV-人CNGB 3载体，以确定最佳载体构建体，然后使用我们开发的符合GMP标准和FDA要求的可扩展的基于重组单纯疱疹病毒的生产方法生产该载体构建体用于GLP安全性研究和临床试验。目的3将评估替代血清型衣壳和锥启动子在色盲CNGB 3-/-小鼠模型中的功效。这将细化初步结果，表明玻璃体内给予载体可能导致视锥光感受器的相关转导。表达人CNGB 3和眼部递送位点的最佳载体构建体随后将用于在非人灵长类动物中进行初步安全性研究。目标4将使用一系列最先进的方法评估CNGB 3色盲患者，以建立自然病史、适当的入选/排除标准和适用于临床试验的终点。目标5将使用目标2中的最佳载体在大鼠和非人灵长类动物中进行GLP合规性毒理学和生物分布研究。在启动这些研究之前，我们将与FDA举行IND前会议，以审查拟定的研究设计和生产/放行检测方法，并就满足IND要求的研究达成一致。根据这些数据，在目标6中，我们将准备并向FDA提交IND。IND将包括一项1/2期临床试验方案，其设计将以前五个特定目的的结果为指导。

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.