Gene Therapy Platform for Rare Diseases

TRND计划启动了与生物技术和学术团体的一些合作，这些团体被选为试点项目。总体目标是使TRND能够帮助应对临床前开发中的挑战，包括基因载体设计和制造。推进这些技术，以及实现基因治疗监管批准的最佳实践，将有助于协调临床前研究和方法，旨在提高开发速度，降低基因治疗的总体成本。试点项目包括杜氏肌营养不良症、芳香族L氨基酸脱羧酶缺乏症和庞贝病的临床前治疗方法的开发。TRND的支持使我们能够在庞培病患者(NCT03533673)中启动I期试验，并使我们的合作者能够继续为AADC缺陷提交生物制品许可申请(BLA)。 我们在Duchenne肌营养不良症(DMD)方面的持续合作包括开发新的制造方法，以扩大AAV的生产，以治疗肌肉骨骼疾病。转导足够的骨骼肌细胞需要每个患者非常多的载体基因组。目前的生产方法无法生产出所有DMD患者所需的产品数量。我们正在试验小分子增强剂、悬浮细胞、昆虫细胞和生产细胞系，以解决整个系统的生产问题。该合作还探索了DMD的大型动物模型，这种模型被普遍认为更容易转化为人类疾病。我们正在试验CRISPR技术，作为治疗DMD的潜在治疗方法，以及预测安全参数的方法，特别是与AAV和Cas9在患者中诱导的先天性和获得性免疫反应相关的安全参数。 从个别基因治疗项目中学到的经验为TRND提供了一个坚实的基础，为NCATS领导的一个新的倡议--平台载体基因治疗(Pave-GT)试点项目做出贡献。Pave-GT寻求通过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，用于多种罕见疾病的基因治疗。这项跨NIH的合作倡议包括来自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)和尤尼斯·肯尼迪·施莱弗国家儿童健康和人类发育研究所(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缺乏症；ColQ缺乏症)和两种有机酸血症(丙酸血症；钴胺B型甲基丙二酸血症)。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进到患者的临床测试中。

The TRND Program initiated a number of collaborations with biotech and academic groups that were selected to serve as pilot projects. The overall goal is to enable TRND to help address challenges in preclinical development, including gene vector design and manufacturing. Advancing these technologies, along with best practices to achieve regulatory approval of gene therapies, will help harmonize preclinical studies and approaches, aiming to improve the speed of development and reduce costs for gene therapy in general. The pilot projects included preclinical development of therapies for Duchenne muscular dystrophy, aromatic L-amino acid decarboxylase (AADC) deficiency and Pompe disease. TRND support enabled the initiation of a phase I trial in Pompe disease patients (NCT03533673) and positioned our collaborators to proceed to filing a Biologics Licensing Application (BLA) for AADC deficiency. Our continuing collaboration on Duchenne muscular dystrophy (DMD) involves developing novel manufacturing methods to scale up AAV production to treat a musculoskeletal condition. Transducing enough skeletal muscle cells requires a very high number of vector genomes per patient. Current production methods cannot produce the amount of product needed for all DMD patients. We are experimenting with small molecule potentiators, suspension cells, insect cells, and producer cell lines to address this systemwide production problem. The collaboration also explores large animal models of DMD, which are generally accepted as more translatable to the human disease condition. We are experimenting with CRISPR technology as a potential curative approach to DMD, as well as ways to predict safety parameters, particularly related to AAV- and Cas9-induced innate and adaptive immune responses in patients. The learnings from the individual gene therapy 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; cobalamin type B methylmalonic acidemia). 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.