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AAV-mediated gene therapy for GM2-gangliodoses

AAV 介导的 GM2 神经节剂量基因治疗

基本信息

批准号：
7943182
负责人：
MIGUEL S ESTEVES
金额：
$ 105.49万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
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/7943182
关键词：
2 year old Achievement Adolescent Adult Affect Age Age-Months Ataxia Bilateral Binding Biodistribution Boston Brain Cat Diseases Cerebellar Nuclei Cerebellum Cerebral cortex Cessation of life Charge Child Clinical Clinical Protocols Clinical Trials Deglutition Development Diagnostic Disease Disease model Drug Formulations Enzymes Evaluation Felis catus Florida Functional disorder G(M2) Ganglioside Gangliosidoses Gangliosidoses GM2 Gene Delivery General Hospitals Goals Heterozygote Hex B Hexosaminidases Human Infusion procedures Inherited Injection of therapeutic agent Institution Investigational Drugs Lesion Life Lysosomal Storage Diseases Magnetic Resonance Imaging Manic Massachusetts Measurement Mediating Metabolic Methodology Motor Mus Nervous system structure Neurodegenerative Disorders Neurologic Organ Patients Peripheral Persons Phase Preparation Procedures Program Development Research Ethics Committees Respiratory Tract Infections Safety Sandhoff Disease Scientist Seizures Serum Severities Severity of illness Speech Structure Symptoms System Target Populations Tay-Sachs Disease Technology Testing Thalamic structure Therapeutic Effect Therapeutic Equivalency Time Toxic effect Toxicology Translations Tremor United States Food and Drug Administration Wheelchairs Wild Type Mouse adeno-associated viral vector beta-n-acetylhexosaminidase clinically relevant college depressive symptoms enzyme activity experience gait examination gene therapy humane endpoint infancy member motor control mouse model neurochemistry pre-clinical research study retrograde transport safety study stability testing therapeutic effectiveness tool vector

项目摘要

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

Tay-Sachs病（TSD）和Sandhoff病（SD）是密切相关的溶酶体贮积病由γ S-N-乙酰氨基己糖苷酶（Hex）的活性缺陷引起。共同归类为 “GM 2神经节苷脂沉积症”，这些遗传性神经退行性疾病在1881年首次被描述，至今都是致命的AAV基因治疗在GM 2神经节苷脂沉积症小鼠模型中的初步结果表明，非常令人鼓舞的是，通过颅内注射载体治疗的小鼠的存活时间是对照组的3倍以上。未处理的小鼠。本研究的目的是为人类的AAV载体系统的研究做好准备。通过在小鼠和猫疾病模型中进行所有必要的临床前实验进行临床试验（特定目的1和2），制备用于GLP毒性和生物分布研究的GMP级载体（具体目的3），以及获得所有必要监管机构的试验启动批准（具体目标4）。该项目将由泰-萨克斯基因治疗联盟（www.tsgtconsortium.com）的成员进行，来自4个机构的科学家在神经节苷脂和基因治疗方面有着良好的记录：一般医院，剑桥大学（英国），波士顿学院和奥本大学。在GM 2小鼠中的研究将证明首先，双侧注射到丘脑和深部的新的AAV载体制剂的生物等效性，小脑核，随后进行了长达20个月的长期疗效和安全性研究。在GM 2猫中，我们将首先测试新的AAV载体制剂双侧注射到在4周龄时相同的结构，并验证临床相关的工具，以评估治疗。最后我们将评价AAV载体制剂在允许存活长达20天的GM 2猫中的长期安全性和功效。 2岁。一旦这一阶段完成，Genzyme Corporation将生产GMP级载体，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。监管在本年度最后一年，项目从这一项目中获得的经验和方法将可立即应用 40多种溶酶体贮积病，其中大部分涉及大脑。