Gene Therapy Platform for Rare Diseases

从最初项目中吸取的经验教训为TRND提供了坚实的基础，为ncats领导的一项新倡议——平台载体基因治疗（PaVe-GT）试点项目做出贡献。PaVe-GT旨在通过对多种罕见病基因疗法使用相同的基因传递系统和制造方法，提高临床试验启动效率。这一跨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）和尤妮斯·肯尼迪·施莱佛国家儿童健康与人类发展研究所（NICHD）的合作伙伴。PaVe-GT将开发四种疾病的基因疗法：两种先天性肌无力综合征（Dok7缺乏症；ColQ缺乏症）和两种有机酸血症(丙酸血症（PA）；B型甲基丙二酸血症（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，以推进所有四种疗法在患者中的临床试验。

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 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 begun and toxicology studies to demonstrate safety are in the planning phase. The FDA has been engaged to gather early feedback on our development plan for PA, and an Orphan Drug Designation (ODD) has been received for the AAV9-hPCCA gene therapy product. Identification of the lead candidates, animal model natural history studies, and proof of concept studies are in progress for the other three disease indications under the Pave-GT umbrella. In addition, a new collaboration with the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) is being established for development of an open access platform for AAV production. Dissemination efforts include drafting a white paper to outline the regulatory process for obtaining an ODD. Additional dissemination activities are in progress and are geared towards creating a preclinical playbook outlining the gene therapy drug development process.