rAAV-CNGB3 Gene Therapy for Achromatopsia: Translational Research Studies

rAAV-CNGB3 基因治疗全色盲：转化研究

• 批准号: 8893994
• 负责人: WILLIAM W HAUSWIRTH
• 金额: $ 129.82万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8893994
• 关键词: Address; Agreement; Animals; Biodistribution; Canis familiaris; Capsid; Clinic; Clinical Trials; Codon Nucleotides; Color; Complementary DNA; Cone; Cyclic GMP; Data; Discrimination; Disease; Dose; Exclusion Criteria; Funding; Future; Gene Delivery; Genes; Goals; Health; Human; Inherited; Introns; Investigational New Drug Application; Lead; Medical; Methods; Mutation; Natural History; Patients; Phase; Photophobia; Plasmids; Preparation; Production; Protocols documentation; Rattus; Reagent; Recombinant adeno-associated virus (rAAV); Recombinants; Reporter Genes; Research; Research Design; Research Proposals; Retinal Cone; Retinal Diseases; Route; Series; Serotyping; Simplexvirus; Site; Testing; Therapeutic Agents; Toxicology; Transfection; Translational Research; Translations; United States Food and Drug Administration; Vision; Visual Acuity; achromatopsia; adeno-associated viral vector; base; cohort; cyclic-nucleotide gated ion channels; design; efficacy testing; experience; fovea centralis; gene therapy; inclusion criteria; meetings; mouse model; mutant; nonhuman primate; novel; pre-clinical; promoter; research study; safety study; tool; vector

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.

描述（由申请人提供）：我们提出了一系列协调活动，旨在将针对 CNGB3 形式色盲的成功临床前基因疗法转化为临床试验。这种新型重组腺相关病毒 (rAAV) 基因递送试剂是“同类首创”治疗剂，可解决 CNGB3 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。目标 1 将通过系统地修改每个组件（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，能够靶向所有三个视锥细胞亚类，并具有优化的密码子能够以最小剂量发挥最大功效。目标 2 将生产用于动物研究的 rAAV-人 CNGB3 载体，以确定最佳载体构建体，然后使用基于可扩展的重组单纯疱疹病毒的生产方法生产该载体用于 GLP 安全性研究和临床试验我们开发的产品符合 GMP 标准和 FDA 要求。目标 3 将评估替代血清型衣壳和视锥启动子在 CNGB3-/- 色盲小鼠模型中的功效。这将完善初步结果，表明载体的玻璃体内施用可能导致视锥光感受器的相关转导。然后，表达人 CNGB3 和眼部递送位点的最佳载体构建体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来评估 CNGB3 色盲患者，以确定自然史、适当的纳入/排除标准和适合临床试验的终点。目标 5 将使用目标 2 中的最佳载体在大鼠和非人类灵长类动物中进行符合 GLP 的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，审查拟议的研究设计和制造/发布测试方法，以便就满足 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 1/2 期临床试验的方案，其设计将以之前五个具体目标的结果为指导。