Phase II Study of AAV9-GAA Gene Transfer in Pompe Disease

AAV9-GAA 基因转移治疗庞贝病的 II 期研究

• 批准号: 9444518
• 负责人: BARRY J BYRNE
• 金额: $ 40.31万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-16 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9444518
• 关键词: Acids; Action Potentials; Affect; Age; Alveolar; Area; Biological Markers; Blood - brain barrier anatomy; Cardiopulmonary; Child; Childhood; Clinical; Clinical Research; Clinical Trials; Codon Nucleotides; Collaborations; Complementary DNA; Cytomegalovirus; Data; Dependence; Dependovirus; Desmin; Dose; Electrophysiology (science); Enrollment; Environmental air flow; Enzymes; Failure; Frequencies; Functional disorder; Future; Gene Transduction Agent; Gene Transfer; Genes; Glucan 1,4-alpha-Glucosidase; Glycogen; Glycogen storage disease type II; Goals; Human; Hypercapnic respiratory failure; Image; Imaging Techniques; Immune response; Infant; Inflammatory Response; Inherited; Intramuscular; Intramuscular Injections; Investigational Therapies; Knowledge; Life; Longitudinal Studies; Macaca mulatta; Measures; Methods; Modality; Morbidity - disease rate; Motor; Motor Neurons; Muscle; Muscle function; Mutation; Neuromuscular Diseases; Outcome Measure; Paresis; Participant; Patients; Phase; Primates; Procedures; Recombinant adeno-associated virus (rAAV); Research; Respiratory Diaphragm; Respiratory Failure; Respiratory physiology; Safety; Serotyping; Signal Transduction; Skeletal Muscle; Source; Striated Muscles; Survivors; Techniques; Testing; Therapeutic; Tissues; Toxic effect; United States National Institutes of Health; Ventilator; adeno-associated viral vector; base; clinically significant; congenital myopathy; early onset; enzyme replacement therapy; experience; follow-up; gene correction; gene product; gene therapy; glucosidase; heart function; improved; infancy; innovation; insight; mortality; motor disorder; motor function improvement; motor neuron function; neuromuscular; neuromuscular function; neurophysiology; non-invasive imaging; nonhuman primate; novel; phase 2 study; pre-clinical; preservation; promoter; public health relevance; relating to nervous system; respiratory; restoration; skeletal muscle weakness; vector

 DESCRIPTION (provided by applicant): The long-term goal of this proposal is to investigate the efficacy of systemic dosing of adeno associated virus (AAV) serotype 9 vector to correct cardiorespiratory insufficiency and skeletal muscle weakness in Pompe disease. Pompe disease results from a deficiency or absence of the lysosomal enzyme acid alpha glucosidase (GAA), and in result, glycogen accumulation impedes cardiac, respiratory and neuromuscular function. Respiratory failure is the leading cause of morbidity and mortality in Pompe patients. AAV vectors for gene therapy are currently under phase I/II clinical trials for multiple inherited conditions, including our ongoing intramuscular administration to the diaphragm of rAAV1-CMV-hGAA in ventilator-dependent pediatric Pompe patients. In this project, we propose to build upon experience from this recent trial, to incorporate innovative, mechanistic outcome measures, and to advance the therapeutic approach with a novel delivery method and advanced serotype (AAV9). The central hypothesis is that restoration of GAA activity in muscle and neural tissue is safe and will reverse cardio-ventilatory insufficiency and skeletal muscle weakness in children with Pompe disease. We propose to utilize cutting-edge imaging and electrophysiological modalities to characterize mechanisms of vector action. In addition, we have developed innovative manufacturing techniques for a therapeutic AAV construct with improved transduction to neural tissue, tissue-specific desmin promoter, and codon-optimized GAA cDNA. Based upon strong preliminary data, this proposal will test two specific aims: Aim 1. Determine the safety and the retrograde neuro-transduction of systemic rAAV9-DES-hGAA dosing in infant rhesus monkeys (done concurrently with other IND-enabling primate studies). Aim 2. Evaluate the safety and efficacy of systemic rAAV9-hGAA in children with early-onset Pompe disease. This proposal will significantly advance the field in three major areas: (1) elucidate the safety o AAV9 systemic delivery; (2) treatment of the neural as well as the muscular components of weakness in Pompe disease; and (3) investigate the utility of imaging and neurophysiological tests as biomarkers of cardiorespiratory and skeletal muscle function.

 描述（由申请人提供）：本提案的长期目标是研究全身给药腺相关病毒（AAV）血清型 9 载体对纠正庞贝病心肺功能不全和骨骼肌无力的功效。庞贝氏病是由于溶酶体酶酸性 α 葡萄糖苷酶 (GAA) 缺乏或缺失引起的，糖原积累会阻碍心脏、呼吸和神经肌肉功能。呼吸衰竭是庞贝氏症患者发病和死亡的主要原因。用于基因治疗的 AAV 载体目前正在进行针对多种遗传性疾病的 I/II 期临床试验，包括我们正在进行的 rAAV1-CMV-hGAA 呼吸机依赖儿科庞贝氏症患者膈肌注射。在这个项目中，我们建议借鉴最近试验的经验，纳入创新的机械结果测量，并通过新型递送方法和高级血清型（AAV9）推进治疗方法。核心假设是，恢复肌肉和神经组织中的 GAA 活性是安全的，并且可以逆转患有庞贝病的儿童的心肺通气不足和骨骼肌无力。我们建议利用尖端成像和电生理学方式来表征矢量作用机制。此外，我们还开发了治疗性 AAV 构建体的创新制造技术，改进了神经组织转导、组织特异性结蛋白启动子和密码子优化的 GAA cDNA。基于强有力的初步数据，该提案将测试两个具体目标： 目标 1. 确定幼年恒河猴全身 rAAV9-DES-hGAA 给药的安全性和逆行神经转导（与其他支持 IND 的灵长类动物研究同时进行）。 目标 2. 评估全身性 rAAV9-hGAA 对早发庞贝病儿童的安全性和有效性。 该提案将在三个主要领域显着推进该领域的发展：（1）阐明 AAV9 全身递送的安全性； (2)治疗庞贝病中的神经和肌肉无力； (3) 研究成像和神经生理学测试作为心肺和骨骼肌功能生物标志物的效用。