Gene Therapy Platform for Rare Diseases

罕见病基因治疗平台

• 批准号: 10004998
• 负责人: Na Yang
• 金额: $ 322.87万
• 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/10004998
• 关键词: Address; Amino Acids; Animal Model; Biodistribution; Biological; Biological Products; Biotechnology; Blood specimen; CRISPR/Cas technology; Carboxy-Lyases; Cell Line; Cells; Chemistry; Childhood; Clinical; Clinical Data; Clinical Trials; Collaborations; Data; Dependovirus; Development; Disease; Duchenne muscular dystrophy; Europe; Funding; Genes; Glycogen storage disease type II; Goals; Insecta; Lead; Licensing; Marketing; Methods; Muscle Fibers; Musculoskeletal; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Newborn Infant; Orphan; Orphan Drugs; Pathway interactions; Patients; Phase; Pilot Projects; Production; Rare Diseases; Research; Safety; Speed; Suspensions; System; Taiwan; Technology; Therapeutic; Therapeutics for Rare and Neglected Diseases; U-Series Cooperative Agreements; United States Food and Drug Administration; adaptive immune response; aromatic L-amino acid decarboxylase deficiency; clinical development; commercialization; cost; design; experimental study; gene therapy; human disease; improved; meetings; molecular pathology; novel; phase I trial; pre-clinical; preclinical development; preclinical safety; programs; scale up; screening panel; 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 gene vector design and manufacturing. These technologies, along with best practices to achieve regulatory approval of gene therapy, will help improve the speed of development and reduce costs for gene therapy in general. The pilot projects include preclinical development of therapies for Duchenne muscular dystrophy, Pompe disease, and aromatic L-amino acid decarboxylase (AADC) deficiency. Pompe disease: During the collaboration with TRND, the adeno-associated virus (AAV) gene therapy technology was licensed by Asklepios BioPharmaceutical, Inc. AskBio formed a spin-out company, Actus Therapeutics, to continue clinical development and commercialization. The key preclinical support provided by TRND enabled the lead collaborator (Dr. Dwight Koeberl) to initiate a phase I trial in Pompe disease patients (NCT03533673). TRND is co-funding the clinical trial through a cooperative agreement with the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). AADC deficiency: The team completed an end-of-phase 2 meeting with the U.S. Food and Drug Administration (FDA), to discuss the clinical data obtained from trials of AGIL-AADC conducted in Taiwan, and whether PTC Therapeutics could proceed to seeking U.S. market approval without requiring additional bridging trials in the U.S. The clinical package, plus key preclinical safety, biodistribution, and chemistry, manufacturing and controls data developed by TRND, led FDA to agree that PTC Therapeutics could proceed to file a Biologics Licensing Application (BLA) for marketing approval in the U.S. AGIL-AADC has received Orphan Drug and Rare Pediatric Disease designations in the U.S., as well as Orphan Medicinal Product status in Europe. The Orphan Drug designation provides access to the expedited Priority Review pathway at FDA. Ongoing research at TRND includes an effort to obtain DDC gene sequences from 3,000 randomly selected and deidentified newborn blood samples, with the potential to support an application to include the DDC gene in the recommended uniform screening panel. Duchenne muscular dystrophy: This collaboration involves developing novel manufacturing methods to scale up AAV production to treat a musculoskeletal condition. Transducing a sufficient number of skeletal muscle cells requires a very high number of vector genomes per patient. Current production methods cannot physically meet the needs for all DMD patients. We are experimenting with small molecule potentiators, suspension cells, insect cells, and producer cell lines to address this system-wide 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.

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能够帮助解决基因载体设计和制造方面的挑战。这些技术，沿着最佳实践，以实现基因治疗的监管批准，将有助于提高发展速度和降低成本的基因治疗一般。试点项目包括杜氏肌营养不良症、庞贝氏症和芳香族L-氨基酸脱羧酶（AADC）缺乏症的临床前治疗开发。 庞贝氏症：在与TRND合作期间，腺相关病毒（AAV）基因治疗技术获得了Asklepios BioPharmaceutical，Inc.的许可。AskBio成立了一家分拆公司Actus Therapeutics，继续进行临床开发和商业化。TRND提供的关键临床前支持使主要合作者（德怀特Koeberl博士）能够在庞贝氏症患者中启动I期试验（NCT 03533673）。TRND通过与国家关节炎、肌肉骨骼和皮肤疾病研究所（NIAMS）的合作协议共同资助了这项临床试验。 AADC缺陷：该团队完成了与美国食品药品监督管理局（FDA）的第二阶段结束会议，讨论了在台湾进行的AGIL-AADC试验中获得的临床数据，以及PTC Therapeutics是否可以在不需要在美国进行额外桥接试验的情况下继续寻求美国市场批准。TRND开发的生产和控制数据，导致FDA同意PTC Therapeutics可以继续提交生物制品许可申请（BLA）以在美国获得上市批准。AGIL-AADC已在美国获得孤儿药和罕见儿科疾病名称，以及欧洲的孤儿药地位。孤儿药认定提供了进入FDA加速优先审评途径的途径。TRND正在进行的研究包括努力从3,000个随机选择和去识别的新生儿血液样本中获得DDC基因序列，有可能支持将DDC基因纳入推荐的统一筛查小组的申请。 杜氏肌营养不良症：这项合作涉及开发新的制造方法，以扩大AAV的生产，以治疗肌肉骨骼疾病。转导足够数量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满足所有DMD患者的实际需求。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。