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Gene Therapy for Neurodegenerative Lysosomal Storage Diseases

神经退行性溶酶体贮积病的基因治疗

基本信息

批准号：
7785865
负责人：
MIGUEL S ESTEVES
金额：
$ 52.71万
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：
2010
资助国家：
美国
起止时间：
2010-02-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7785865
关键词：
2 year old Acids Adolescent Adult Age of Onset Age-Months Animal Model Animals Behavioral Biochemical Biological Assay Brain Capsid Cells Cerebellar Nuclei Cerebrospinal Fluid Childhood Clinical Clinical Trials Clinical assessments Complementary DNA Complex DNA Shuffling Development Disease Disease Progression Dose Effectiveness Elderly Ensure Enzymes Family Felidae Felis catus Frequencies Functional disorder Future Galactosidase Ganglioside GM1 Gangliosidosis GM1 Gene Delivery Gene Transfer Generations Genes Goals Health Human Infant Infusion procedures Knockout Mice Libraries Live Birth Longitudinal Studies Lung Lysosomal Storage Diseases Lysosomes Magnetic Resonance Imaging Mediating Methodology Modality Modeling Modern Medicine Molecular Evolution Mus Mutation Nerve Degeneration Neuraxis Neurologic Neurons Neurosciences Organ Outcome Patients Peripheral Phase Process Research Personnel Serotyping Severity of illness Single-Gene Defect Spinal Cord Staging Surface Testing Thalamic structure Therapeutic Therapeutic Studies Time Treatment Efficacy Tropism Tyrosine Validation adeno-associated viral vector base brain size design effective therapy efficacy testing gene therapy in vivo infancy lateral ventricle meetings minimally invasive mouse model mutant nervous system disorder neurochemistry novel strategies research study therapeutic effectiveness transduction efficiency treatment strategy vector

项目摘要

DESCRIPTION (Provided by Applicant): Lysosomal storage diseases (LSDs) are single gene defects that result in the deficiency of a catabolic lysosomal enzyme and accumulation of one or more of its macromolecular substrates in the lysosome. GM1 gangliosidosis results from deficiency of the lysosomal enzyme ¿-galactosidase (¿gal), leading to progressive and fatal neurodegeneration. Human GM1 gangliosidosis occurs as three types based on disease severity and age of onset, classified as infantile, juvenile, and adult-onset forms. Gene therapy with adeno-associated viral vectors is a very promising strategy for treatment of GM1 gangliosidosis based on extraordinary preliminary results in the knockout mouse model. However, the mouse brain is 1,000-2,000 times smaller and much less complex than the brain of a human infant, requiring that results obtained in mice be reproduced in an animal with a brain size and complexity more similar to humans. The well-characterized feline model of GM1 gangliosidosis, with a brain size only 15 times smaller than a human infant, will be utilized to test therapeutic efficacy of AAV vectors in a larger and more complex brain. In addition, preliminary mouse studies employed a mouse ¿-galactosidase cDNA, although AAV vectors for human clinical trials will express human ¿gal. Therefore, it is necessary to perform bio-equivalency studies to ensure the functionality of the human ¿gal cDNA before initiating human clinical trials. The experiments in this application are designed to advance AAV gene therapy toward human clinical trials through the following specific aims. In Aim 1, short-term therapeutic studies will be performed after intraparenchymal or CSF-mediated delivery of AAV vectors to the feline GM1 brain. Also, a direct comparison of human and mouse ¿gal will be conducted in short-term experiments in GM1 mice. In Aim 2 long-term studies of therapeutic efficacy in GM1 cats and mice will be conducted using clinical, behavioral, and biochemical assays of disease progression. Finally, Aim 3 will test the principle of in vivo selection of an AAV capsid library (molecular evolution) to identify AAV vectors with tropism for the GM1 mouse central nervous system (CNS) after intravascular (iv) infusion, and then test their therapeutic efficacy in these mice. Validation of this approach to generate AAV vectors with CNS-tropism after iv infusion will pave the way for development of such vectors for human application. PROJECT NARRATIVE: The AAV vector-based approaches investigated in this project for CNS therapy in GM1-gangliosidosis are likely to be applicable to many, if not all neurodegenerative lysosomal storage diseases. The experiments proposed here are essential to determine the scalability and therapeutic efficacy of each approach applied to a much larger and complex brain such as that in GM1-gangliosidosis cats. Moreover the AAV vectors encoding the human lysosomal ¿-galactosidase enzyme developed and tested here for their therapeutic efficacy in GM1 mice and cats may ultimately progress into human clinical trials for this devastating disease for which there is no treatment. Finally, the investigators are proposing to develop a new generation of AAV vectors capable of targeting the brain through the vasculature. This new generation of AAV vectors may provide the means to develop highly effective gene therapy approaches to treat many childhood, adult, as well as geriatric neurological diseases currently beyond the reach of modern medicine.

描述（由申请人提供）：溶酶体胆积病（LSD）是单基因缺陷，其导致分解代谢溶酶体酶的缺乏和一种或多种其大分子底物在溶酶体中的积累。 GM 1神经节苷脂沉积症由溶酶体酶半乳糖苷酶（半乳糖苷酶）缺乏引起，导致进行性和致命性神经变性。人类GM 1神经节苷脂沉积症根据疾病严重程度和发病年龄分为三种类型，分为婴儿型、青少年型和成人型。腺相关病毒载体的基因治疗是一个非常有前途的策略，用于治疗GM 1神经节苷脂沉积症的基础上，在敲除小鼠模型的非凡的初步结果。然而，小鼠的大脑比人类婴儿的大脑小1，000 - 2，000倍，复杂性也低得多，因此需要在小鼠中获得的结果在具有与人类更相似的大脑大小和复杂性的动物中重现。脑大小仅比人类婴儿小15倍的GM 1神经节苷脂沉积症的良好表征的猫模型将用于测试AAV载体在更大和更复杂的脑中的治疗功效。此外，初步的小鼠研究采用小鼠半乳糖苷酶cDNA，尽管用于人类临床试验的AAV载体将表达人类半乳糖苷酶。因此，有必要在启动人体临床试验之前进行生物等效性研究，以确保人半乳糖cDNA的功能性。本申请中的实验旨在通过以下特定目的将AAV基因治疗推向人类临床试验。在目的1中，将在脑实质内或CSF介导的AAV载体递送至猫GM 1脑后进行短期治疗研究。此外，将在GM 1小鼠的短期实验中对人和小鼠半乳糖进行直接比较。在目标2中，将使用疾病进展的临床、行为和生化测定在GM 1猫和小鼠中进行治疗有效性的长期研究。最后，目标3将测试AAV衣壳文库的体内选择（分子进化）的原理，以鉴定在血管内（iv）输注后对GM 1小鼠中枢神经系统（CNS）具有嗜性的AAV载体，然后测试它们在这些小鼠中的治疗功效。验证这种方法以在静脉输注后产生具有CNS向性的AAV载体将为开发用于人类应用的此类载体铺平道路。项目叙述：在该项目中研究的用于GM 1-神经节苷脂沉积症的CNS治疗的基于AAV载体的方法可能适用于许多（如果不是所有）神经退行性溶酶体贮积病。这里提出的实验对于确定应用于更大且复杂的大脑（例如GM 1神经节苷脂沉积症猫的大脑）的每种方法的可扩展性和治疗功效至关重要。此外，编码人溶酶体半乳糖苷酶的AAV载体在这里开发和测试了它们在GM 1小鼠和猫中的治疗功效，最终可能会进入这种没有治疗方法的毁灭性疾病的人类临床试验。最后，研究人员建议开发新一代能够通过血管系统靶向大脑的AAV载体。这种新一代的AAV载体可以提供开发高效基因治疗方法的手段，以治疗目前现代医学无法达到的许多儿童、成人以及老年神经疾病。