AAV-mediated gene therapy for GM2-gangliodoses

泰-萨克斯病(TSD)和桑德霍夫病(SD)是与溶酶体储存密切相关的疾病 由于Ys-N-乙酰氨基己糖苷酶(Hex)活性不足所致。集体归类为 这些遗传性神经退行性疾病于1881年首次被描述为GM2神经节苷脂增多症，至今仍存在 到目前为止总是致命的。AAV基因治疗GM2神经节苷脂增多症小鼠模型的初步结果 非常鼓舞人心，用颅内注射媒介治疗的小鼠存活时间是 未经处理的小鼠。这个翻译项目的目标是为人类准备一个有前途的aav载体系统。 通过在小鼠和猫疾病模型上进行所有必要的临床前实验进行临床试验 目标1和2)，制备用于GLP毒性和生物分布研究的GMP级载体(特定目标3)和 获得所有必要监管机构对启动试验的批准(具体目标4)。这个项目将是 由泰-萨克斯基因治疗联盟(www.tsgtconortium.com)的成员进行，一组 在神经节苷脂疾病和基因治疗方面有可靠记录的科学家来自4个机构：马萨诸塞州。一般信息 医院，大学。英国剑桥大学、波士顿学院和奥本大学。对GM2小鼠的研究将证明 首先，双侧丘脑和深部注射新的AAV载体制剂的生物等效性 小脑核团，随后进行长期疗效和安全性研究，直到20个月龄。在GM2猫身上，我们 将首先测试双侧脑内注射新的AAV载体制剂的治疗效果的稳定性 4周龄时的相同结构，并验证临床相关工具以评估治疗。最后我们会 评估AAV载体制剂在GM2猫存活到 2岁。一旦这一阶段完成，Genzyme Corporation将生产GMP级载体 大学的GLP毒性和生物分布研究。佛罗里达州鲍威尔基因治疗中心的。监管 在今年最后一年，我们会在有经验的监管顾问的协助下获得批准。 项目。从这个项目中获得的经验和方法将立即可供应用 40种溶酶体贮积性疾病，其中大多数与大脑有关

Tay-Sachs Disease (TSD) and Sandhoff Disease (SD) are closely-related lysosomal storage diseases resulting from deficient activity of the enzyme yS-N-acetlyhexosaminidase (Hex). Collectively categorized as 'GM2 gangliosidoses,' these inherited neurodegenerative diseases were first described in 1881 yet remain invariably fatal to date. Initial results with AAV gene therapy in a mouse model of GM2 gangliosidosis have been extremely encouraging, with mice treated by intracranial injection of vector living >3 times longer than untreated mice. The goal of this translational project is to ready the promising AAV vector system for human clinical trials by performing all necessary preclinical experiments in mouse and cat disease models (Specific Aims 1 and 2), preparing GMP-grade vector for GLP toxicity and biodistribution studies (Specific Aim 3) and obtaining approval for trial initiation from all necessary regulatory bodies (Specific Aim 4). This project will be conducted by members of the Tay-Sachs Gene Therapy Consortium (www.tsgtconsortium.com), a group of scientists with proven track record in gangliosidoses and gene therapy from 4 institutions: Mass. General Hospital, Univ. of Cambridge (UK), Boston College and Auburn Univ. Studies in GM2 mice will demonstrate first the bioequivalence of a new AAV vector formulation injected bilaterally into the thalamus and deep cerebellar nuclei, followed by long-term efficacy and safety studies out to 20 months of age. In GM2 cats, we will first test the stability of the therapeutic effect of the new AAV vector formulation injected bilaterally into the same structures at 4 weeks of age, and validate clinically relevant tools to assess therapy. Finally we will evaluate the long-term safety and efficacy of the AAV vector formulation in GM2 cats allowed to survive up to 2 years of age. Once this phase is completed, Genzyme Corporation will produce GMP-grade vectors for GLP toxicity and biodistribution studies at the Univ. of Florida Powell Gene Therapy Center. Regulatory approval will be obtained with the assistance of an experienced regulatory consultant in the final year of this project. The experience and methodology gained from this project will be available for immediate application to the >40 lysosomal storage diseases, most of which have brain involvemen