Gene Therapy Platform for Rare Diseases

罕见病基因治疗平台

• 批准号: 10259364
• 负责人: Donald Lo
• 金额: $ 516.43万
• 依托单位: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
• 依托单位国家: 美国
• 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/10259364
• 关键词: Address; Amino Acids; Animal Model; Biological; Biotechnology; CRISPR/Cas technology; Capsid; Carboxy-Lyases; Cell Line; Cells; Clinical Trials; Cobalamin; Collaborations; Congenital Myasthenic Syndromes; Deficiency Diseases; Dependovirus; Development; Disease; Duchenne muscular dystrophy; Foundations; Gene Transduction Agent; Genes; Glycogen storage disease type II; Goals; Individual; Insecta; Learning; Licensing; Methods; Muscle Fibers; Musculoskeletal; National Human Genome Research Institute; National Institute of Child Health and Human Development; National Institute of Neurological Disorders and Stroke; Patients; Pilot Projects; Positioning Attribute; Production; Rare Diseases; Safety; Scientist; Speed; Suspensions; Technology; Therapeutic; Therapeutics for Rare and Neglected Diseases; United States National Institutes of Health; adaptive immune response; aromatic L-amino acid decarboxylase deficiency; base; cost; design; experimental study; gene delivery system; gene therapy; human disease; improved; ketotic hyperglycinemia; methylmalonic aciduria; molecular pathology; novel; phase I trial; preclinical development; preclinical study; programs; research clinical testing; scale up; small molecule; therapy development; vector; vector genome

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.

TRND计划发起了一系列与生物技术和学术团体的合作，这些团体被选为试点项目。总体目标是使TRND能够帮助解决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，沿着最佳实践以实现基因疗法的监管批准，将有助于协调临床前研究和方法，旨在提高开发速度并降低基因疗法的总体成本。试点项目包括临床前开发杜氏肌营养不良症、芳香族L-氨基酸脱羧酶（AADC）缺乏症和庞贝氏症的治疗方法。TRND的支持使庞贝氏症患者的I期试验（NCT 03533673）得以启动，并使我们的合作者能够继续提交AADC缺陷的生物制品许可申请（BLA）。 我们在杜氏肌营养不良症（DMD）方面的持续合作涉及开发新的制造方法，以扩大AAV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高数量的载体基因组。目前的生产方法无法生产所有DMD患者所需的产品量。我们正在用小分子增效剂、悬浮细胞、昆虫细胞和生产细胞系进行实验，以解决这个系统范围的生产问题。该合作还探索了DMD的大型动物模型，这些模型通常被认为更适合人类疾病。我们正在试验CRISPR技术作为DMD的潜在治疗方法，以及预测安全性参数的方法，特别是与患者中AAV和Cas9诱导的先天性和适应性免疫反应相关的方法。 从各个基因治疗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（Dok 7缺乏症; ColQ缺乏症）和两种有机酸血症（丙酸血症;钴胺素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向患者的临床测试。