AAV-mediated gene therapy for GM2-gangliodoses

AAV 介导的 GM2 神经节剂量基因治疗

• 批准号: 7917374
• 负责人: MIGUEL S ESTEVES
• 金额: $ 85.6万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7917374
• 关键词: 2 year old; Achievement; Age; Age-Months; Bilateral; Biodistribution; Boston; Brain; Cat Diseases; Cerebellar Nuclei; Cerebellum; Charge; Clinical; Clinical Protocols; Clinical Trials; Diagnostic; Disease model; Drug Formulations; Evaluation; Felis catus; Florida; G(M2) Ganglioside; Gangliosidoses; Gangliosidoses GM2; General Hospitals; Goals; Heterozygote; Hex B; Hexosaminidases; Human; Inherited; Injection of therapeutic agent; Institution; Lesion; Life; Lysosomal Storage Diseases; Magnetic Resonance Imaging; Massachusetts; Measurement; Mediating; Metabolic; Methodology; Motor; Mus; Neurodegenerative Disorders; Neurologic; Organ; Patients; Peripheral; Phase; Procedures; Research Ethics Committees; Research Personnel; Safety; Sandhoff Disease; Scientist; Serum; Severity of illness; Structure; System; Target Populations; Tay-Sachs Disease; Testing; Thalamic structure; Therapeutic Effect; Therapeutic Equivalency; Time; Toxic effect; Toxicology; Wild Type Mouse; adeno-associated viral vector; beta-n-acetylhexosaminidase; clinically relevant; college; enzyme activity; experience; gait examination; gene therapy; humane endpoint; member; mouse model; neurochemistry; pre-clinical; programs; public health relevance; research study; safety study; stability testing; therapeutic effectiveness; tool; vector

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.

描述（由申请方提供）：泰-萨二氏病（TSD）和桑德霍夫病（SD）是由γ S-N-乙酰氨基己糖苷酶（Hex）活性缺陷引起的密切相关的溶酶体贮积病。这些遗传性神经退行性疾病被统称为“GM 2神经节苷脂病”，于1881年首次描述，但迄今为止仍然是致命的。在GM 2神经节苷脂沉积症的小鼠模型中使用AAV基因疗法的初步结果是极其令人鼓舞的，其中通过颅内注射载体治疗的小鼠的存活时间比未治疗的小鼠长>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），制备用于GLP毒性和生物分布研究的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），为人类临床试验准备有前途的AAV载体系统。该项目将由Tay-Sachs基因治疗联盟（www.tsgtconsortium.com）的成员进行，该联盟是一组在神经节苷脂和基因治疗方面具有良好记录的科学家，来自4个机构：马萨诸塞州。General Hospital，Univ. of剑桥（UK），Boston College and奥本大学在GM 2小鼠中的研究将首先证明双侧注射到丘脑和小脑深部核中的新AAV载体制剂的生物等效性，随后是长达20个月龄的长期功效和安全性研究。在GM 2猫中，我们将首先测试在4周龄时双侧注射到相同结构中的新AAV载体制剂的治疗效果的稳定性，并验证临床相关工具以评估治疗。最后，我们将评估AAV载体制剂在允许存活长达2岁的GM 2猫中的长期安全性和功效。一旦这一阶段完成，Genzyme公司将生产GMP级载体，用于佛罗里达大学鲍威尔基因治疗中心的GLP毒性和生物分布研究。在本项目的最后一年，将在经验丰富的监管顾问的协助下获得监管批准。从该项目中获得的经验和方法将可立即应用于超过40种溶酶体贮积病，其中大多数涉及大脑。 公共卫生关系：在GM 2小鼠中证明非常有效的AAV基因治疗系统将被优化用于Tay-Sachs和Sandhoff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。