Gene Therapy Platform for Rare Diseases

罕见病基因治疗平台

基本信息

批准号：
10910757
负责人：
Elizabeth Ottinger
金额：
$ 602.93万
依托单位：
NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10910757
关键词：
Address Animal Model Biotechnology Capsid Childhood Clinical Protocols Clinical Research Clinical Trials Cobalamin Collaborations Congenital Myasthenic Syndromes Dependovirus Development Development Plans Disease Engineering Feedback Foundations Gene Transduction Agent Genes Lead Learning Methods National Center for Advancing Translational Sciences National Human Genome Research Institute National Institute of Child Health and Human Development National Institute of Neurological Disorders and Stroke Natural History Orphan Drugs Paper Patients Pharmaceutical Preparations Phase Pilot Projects Preparation Process Production Rare Diseases Research Design Safety Scientist Speed Technology Therapeutic Therapeutics for Rare and Neglected Diseases Toxicology United States National Institutes of Health WASP protein assay development clinical center cost design gene delivery system gene therapy improved ketotic hyperglycinemia lead candidate manufacture manufacturing process meetings methylmalonic aciduria molecular pathology operation pre-Investigational New Drug meeting preclinical development preclinical study programs research clinical testing scale up vector

项目摘要

The learnings from the initial projects provided TRND with a robust foundation to contribute to a new NCATS-led initiative, the Platform Vector Gene Therapy (PaVe-GT) pilot project. PaVe-GT seeks to increase the efficiency of clinical trial startup by using the same gene delivery system and manufacturing methods for multiple rare disease gene therapies. This collaborative, trans-NIH initiative includes partners from NCATS, the National Human Genome Research Institute (NHGRI), the National Institute of Neurological Disorders and Stroke (NINDS) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). PaVe-GT will develop gene therapies for four diseases: two congenital myasthenic syndromes (Dok7 deficiency; ColQ deficiency) and two organic acidemias (propionic acidemia (PA); cobalamin type B methylmalonic acidemia (MMAB)). All will be based on the adeno-associated virus (AAV)-9 capsid. TRND scientists are conducting the preclinical development necessary to advance all four therapies to clinical testing in patients. To date, a lead AAV-9 gene therapy candidate has been identified for treating PCCA-related PA. Proof of concept studies have demonstrated efficacy of the lead candidate in PA animal models. Bioanalytic assay development is ongoing, and pilot batches of the lead candidate have been manufactured. Scale-up of the product manufacturing process has been completed with production of a feasibility lot. Engineering lot manufacturing is ongoing; efficacy, and toxicology studies to demonstrate safety are in the planning phase. Early regulatory feedback on the development plan for the first AAV9-hPPCA gene product was obtained through an INTERACT meeting with the FDA followed by a pre-IND meeting to gain feedback on the manufacturing process, planned IND-enabling studies, and clinical study design. In addition, Orphan Drug Designation (ODD) and Rare Pediatric Drug Designations (RPDD) have been received for the AAV9-hPCCA gene therapy product. Identification of the lead candidates, animal model natural history studies, proof of concept studies, and manufacturing of pilot batches are in progress for the other three disease indications under the PaVe-GT umbrella. Efforts for development of an open access platform for AAV production are in progress. The first dissemination milestone for PaVe-GT was achieved this year with release of the ODD and RPDD regulatory packages, templates and a white paper outlining how to successfully navigate this process. Finally, clinical trial activities, including clinical protocol preparations and operations for study implementation at the NIH Clinical Center have been initiated.

最初项目的经验教训为 TRND 奠定了坚实的基础，为 NCATS 主导的新举措——平台载体基因治疗 (PaVe-GT) 试点项目做出贡献。 PaVe-GT 寻求通过对多种罕见疾病基因疗法使用相同的基因传递系统和制造方法来提高临床试验启动的效率。这项跨 NIH 合作倡议包括来自 NCATS、国家人类基因组研究所 (NHGRI)、国家神经疾病和中风研究所 (NINDS) 以及尤尼斯·肯尼迪·施赖弗国家儿童健康和人类发展研究所 (NICHD) 的合作伙伴。 PaVe-GT将为四种疾病开发基因疗法：两种先天性肌无力综合征（Dok7缺陷；ColQ缺陷）和两种有机酸血症（丙酸血症（PA）；B型钴胺素甲基丙二酸血症（MMAB））。所有这些都将基于腺相关病毒 (AAV)-9 衣壳。 TRND 科学家正在进行必要的临床前开发，以将所有四种疗法推向患者临床测试。迄今为止，已确定一种主要的 AAV-9 基因疗法候选药物可用于治疗 PCCA 相关 PA。概念验证研究已证明主要候选药物在 PA 动物模型中的功效。生物分析检测的开发正在进行中，并且主要候选产品的中试批次已经生产。产品制造工艺的放大已经完成，并生产了可行性批次。工程批量制造正在进行中；证明安全性的功效和毒理学研究正处于规划阶段。第一个 AAV9-hPPCA 基因产品开发计划的早期监管反馈是通过与 FDA 举行的 INTERACT 会议获得的，随后召开了 IND 前会议，以获得有关制造过程、计划的 IND 支持研究和临床研究设计的反馈。此外，AAV9-hPCCA基因治疗产品还获得了孤儿药资格（ODD）和罕见儿科药物资格（RPDD）。 PaVe-GT 旗下其他三种疾病适应症的主要候选药物的鉴定、动物模型自然历史研究、概念验证研究和中试批次的生产正在进行中。用于 AAV 生产的开放获取平台的开发工作正在进行中。今年，随着 ODD 和 RPDD 监管包、模板以及概述如何成功引导这一流程的白皮书的发布，PaVe-GT 实现了第一个传播里程碑。最后，临床试验活动，包括临床方案准备和 NIH 临床中心研究实施的操作已经启动。