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: 8414960
• 负责人: WILLIAM W HAUSWIRTH
• 金额: $ 164.65万
• 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 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8414960
• 关键词: Address; Agreement; Animals; Biodistribution; Canis familiaris; Capsid; Clinic; Clinical Trials; Codon Nucleotides; Color; Complementary DNA; Cyclic GMP; Data; Discrimination; Disease; Dose; Exclusion Criteria; Funding; Future; Gene Delivery; Genes; Goals; 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; public health relevance; 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）：我们提出了一组协调的活动，旨在使CNGB3的Achromatopsia的成功临床前基因治疗转化为临床试验。这种新型的重组腺相关病毒（RAAV）基因递送试剂是一种“第一类”治疗剂，可满足CNGB3相关的Achromomopsia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。 AIM 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，从而使矢量不超过其最佳包装能力，能够靶向所有三个锥形子类，并且具有优化的代码子，可在最低剂量下启用最大效率。 AIM 2将生产Raav-Human CNGB3载体用于动物研究，以识别最佳矢量构建体，然后使用可扩展的，基于单纯疱疹病毒的生产方法在GLP安全研究和临床试验中生产，我们开发了满足GMP标准和FDA要求。 AIM 3将评估替代血清型衣壳和锥启动子在Achromomatia的CNGB3 - / - 小鼠模型中的功效。这将完善初步结果，表明玻璃体内载体的给药可能导致锥形感光体的相关转导。然后，表达人CNGB3和眼部传递部位的最佳矢量构建体将用于在非人类灵长类动物中进行初步的安全研究。 AIM 4将使用一系列最先进的方法来评估CNGB3 Achromomatia患者，以建立自然历史，适当的包含/排除标准以及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进行预先开会，以审查拟议的研究设计和制造/释放测试方法，以达成满足IND要求的研究的一致性。基于这些数据，在AIM 6中，我们将为FDA准备并提交IND。 IND将包括1/2期临床试验的方案，该方案将以前五个特定目标的结果为指导。