AAV-mediated gene therapy for GM2-gangliodoses

描述(申请人提供)：泰-萨克斯病(TSD)和桑德霍夫病(SD)是由Ys-N-乙酰氨基己糖苷酶(Hex)活性不足引起的溶酶体储存性疾病。这些遗传性神经退行性疾病于1881年首次被描述，统称为GM2神经节苷脂增多症，但到目前为止仍然是致命的。AAV基因治疗GM2神经节苷脂中毒小鼠模型的初步结果非常令人鼓舞，脑内注射载体Living-gt；的小鼠的治疗时间是未治疗小鼠的3倍。该翻译项目的目标是通过在小鼠和猫疾病模型上进行所有必要的临床前实验(特定目标1和2)，为GLP毒性和生物分布研究准备GMP级载体(特定目标3)，并获得所有必要监管机构的批准启动试验(特定目标4)，为人类临床试验准备有前景的AAV载体系统。这个项目将由泰-萨克斯基因治疗联盟(www.tsgtconortium.com)的成员进行，该联盟是一群科学家，他们在神经节苷脂和基因治疗方面有良好的记录，来自4个机构：麻省理工学院。总医院，大学。英国剑桥大学、波士顿学院和奥本大学。在GM2小鼠身上的研究将首先证明双侧丘脑和小脑深部核注射新的AAV载体制剂的生物等效性，然后进行长达20个月的长期疗效和安全性研究。在GM2猫身上，我们将首先测试新的AAV载体配方在4周龄时双侧注射到相同结构中的治疗效果的稳定性，并验证临床相关工具来评估治疗。最后，我们将评估AAV载体制剂在存活到2岁的GM2猫中的长期安全性和有效性。一旦这一阶段完成，Genzyme公司将生产GMP级载体，用于大学的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。在该项目的最后一年，将在一名经验丰富的监管顾问的协助下获得监管批准。从这个项目中获得的经验和方法将立即应用于40种溶酶体储存疾病，其中大多数涉及大脑。 公共卫生相关性：一种在GM2小鼠身上被证明非常有效的AAV基因治疗系统将被优化用于泰-萨克斯和桑德霍夫病的人类临床试验。该项目将执行准备AAV系统用于人类所需的所有实验、毒性/生物分布和监管程序。从这个项目中获得的经验和方法将直接适用于许多其他神经退行性疾病。

DESCRIPTION (provided by applicant): 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 involvement. PUBLIC HEALTH RELEVANCE: An AAV gene therapy system proven very effective in GM2 mice will be optimized for human clinical trials of Tay-Sachs and Sandhoff Disease. This project will perform all experimental, toxicity/biodistribution and regulatory procedures needed to prepare the AAV system for use in humans. Experience and methodology gained from this project will be directly applicable to many other neurodegenerative diseases.