Gene Therapy Platform for Rare Diseases

从最初的项目中获得的经验为TRND提供了一个坚实的基础，以促进NCATS领导的新倡议，平台载体基因治疗（PaVe-GT）试点项目。PaVe-GT旨在通过使用相同的基因递送系统和制造方法来提高临床试验启动的效率。这项跨NIH的合作计划包括来自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）和尤妮斯·肯尼迪·施莱佛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（Dok 7缺乏症; ColQ缺乏症）和两种有机酸血症（丙酸血症（PA）;钴胺素B型甲基丙二酸血症（MMA B））。所有这些都将基于腺相关病毒（AAV）-9衣壳。TRND的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的临床测试。 迄今为止，已经确定了用于治疗PCCA相关PA的主要AAV-9基因治疗候选物。概念验证研究已经证明了先导候选药物在PA动物模型中的有效性。生物分析测定法的开发正在进行中，并已生产了先导候选药物的中试批次。产品生产工艺的规模扩大已完成，生产了可行性批次。工程批次生产正在进行中;用于证明安全性的疗效和毒理学研究处于计划阶段。通过与FDA的INTERACT会议以及IND前会议获得了对第一个AAV 9-hPPCA基因产品开发计划的早期监管反馈，以获得对制造工艺、计划的IND支持研究和临床研究设计的反馈。 此外，AAV 9-hPCCA基因治疗产品还获得了孤儿药认定（ODD）和罕见儿科药认定（RPDD）。在PaVe-GT保护伞下，其他三种疾病适应症的主要候选药物的鉴定、动物模型自然史研究、概念验证研究和中试批次的生产正在进行中。正在努力开发用于AAV生产的开放获取平台。 PaVe-GT的第一个传播里程碑是在今年实现的，发布了ODD和RPDD监管包、模板和一份白色文件，概述了如何成功地驾驭这一过程。最后，临床试验活动，包括临床方案准备和在NIH临床中心实施研究的操作已经开始。

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.