MANUFACTURING OF PLASMID AND VECTOR AND GLP DOSE-ESCALATION TOXICOLOGY STUDIES IN NORMAL RATS AND NORMAL NHPS

目前，国家神经疾病和中风研究所(NINDS)通过其紧急网络， 正在资助一项制造AAV9/AGA载体、质粒和GLP的合作协议 剂量递增研究作为严重和进行性遗传性神经疾病的潜在治疗方法， 天冬氨酸氨基葡萄糖尿症(AGU)。紧急合作协议的目标是制造 AAV9/AGA载体、含有AGA基因的ITR载体和包装/辅助质粒 PAAV9和pALD-X80(它们提供AAV和腺病毒载体所需的AAV和腺病毒辅助功能 分别在哺乳动物细胞培养中生产)。对于AAV9/AGA矢量制造， 紧急网络将使用类似于所使用的制造工艺来制造载体 翻译基因治疗核心，产生具有类似质量属性的AAV9/AGA。 具体流程将在基本任务中描述的技术转让过程中公布。最终产品 资格和特性测试将包括无菌、内毒素、纯度、身份、 活性/效力、载体基因组滴度、衣壳颗粒滴度、外观和基因组结构。vt.在.的基础上 载体的建立，以及最优的特性，这个项目将向IND使能率迈进 和NHP毒理学研究，以支持IND。

Currently, the National Institute of Neurological Disorders and Stroke (NINDS), via its URGenT network, is funding a cooperative agreement for the manufacturing of an AAV9/AGA vector, plasmids, and GLP dose-escalating studies as a potential therapy the severe and progressive genetic neurological disorder, Aspartylglucosaminuria (AGU). The goals of the URGenT cooperative agreement are to manufacture the AAV9/AGA vector, the vector ITR plasmid containing the AGA gene, and the packaging/helper plasmids pAAV9 and pALD-X80 (which provide the AAV and Adenoviral helper functions needed for AAV vector production in mammalian cell culture, respectively). For the AAV9/AGA vector manufacturing, the URGenT network will manufacture the vector using a manufacturing process similar to that utilized by the Translational Gene Therapy Core that produces AAV9/AGA with comparable quality attributes. Specifics of the process will come during the tech transfer described in the base task. The final product qualification and characterization testing will include assays of sterility, endotoxin, purity, identity, activity/potency, vector genome titer, capsid particle titer, appearance, and genomic structure. Upon establishment of the vectors, and optimal characterization, this project will progress to IND-enabling rat and NHP toxicology studies to support the IND.