AAV-mediated gene therapy for GM2-gangliodoses

描述（由申请人提供）：Tay-Sachs病（TSD）和Sandhoff病（SD）是密切相关的溶酶体贮积病，由ys - n -乙酰己糖苷酶（Hex）活性不足引起。这些遗传性神经退行性疾病被统称为“GM2神经节脂质剂量”，于1881年首次被描述，但迄今为止仍然是致命的。AAV基因治疗GM2神经节脂质病小鼠模型的初步结果非常令人鼓舞，经颅内注射载体治疗的小鼠比未治疗的小鼠存活时间长3倍。该转化项目的目标是通过在小鼠和猫疾病模型中进行所有必要的临床前实验（具体目标1和2），为GLP毒性和生物分布研究准备gmp级载体（具体目标3），并获得所有必要监管机构的试验启动批准（具体目标4），为有前途的AAV载体系统做好准备。该项目将由Tay-Sachs基因治疗联盟（www.tsgtconsortium.com）的成员进行，该联盟由来自4个机构的科学家组成，他们在神经节苷剂和基因治疗方面有着良好的记录：在GM2小鼠中进行的研究将首先证明一种新的AAV载体制剂在双侧注射到丘脑和小脑深部核中的生物等效性，然后进行20个月大的长期疗效和安全性研究。在GM2猫中，我们将首先测试在4周龄时双侧注射新的AAV载体制剂到相同结构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载体制剂在允许存活至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公司将在佛罗里达大学鲍威尔基因治疗中心生产用于GLP毒性和生物分布研究的gmp级载体。在项目的最后一年，将在经验丰富的监管顾问的协助下获得监管部门的批准。从这个项目中获得的经验和方法将可立即应用于bbbb40溶酶体贮积病，其中大多数与大脑有关。

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.