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能够帮助应对基因载体设计和制造方面的挑战。这些技术，以及实现基因治疗监管批准的最佳实践，将有助于提高基因治疗的开发速度，并总体上降低成本。试点项目包括治疗Duchenne肌营养不良症、庞贝病和芳香族L氨基酸脱羧酶缺乏症的临床前开发。 庞贝病：在与TRND合作期间，腺相关病毒(AAV)基因治疗技术获得了Asklepios生物制药公司的许可。AskBio成立了一家衍生公司Actus Treeutics，以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(Dwight Koeberl博士)能够在庞培病患者(NCT03533673)中启动I期试验。TRND通过与国家关节炎、肌肉骨骼和皮肤病研究所(NIAMS)达成合作协议，共同资助这项临床试验。 AADC不足：该团队完成了与美国食品和药物管理局(FDA)的第二阶段结束会议，讨论从在台湾进行的AGIL-AADC试验获得的临床数据，以及PTC Treeutics是否可以继续寻求美国市场的批准，而不需要在美国进行额外的桥梁试验。临床包，加上由TRND开发的关键临床前安全性、生物分布和化学、制造和控制数据，导致FDA同意PTC Treateutics可以继续在美国提交生物制品许可申请(BLA)以供上市批准。AGIL-AADC已在美国获得孤儿药物和罕见儿科疾病称号，以及在欧洲获得孤儿药物产品地位。孤儿药物指定提供了进入FDA快速优先审查途径的途径。TRND正在进行的研究包括从3000个随机选择和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。 Duchenne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多的载体基因组。目前的生产方法不能实际满足所有DMD患者的需求。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。

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.