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)：这项建议的长期目标是研究腺相关病毒(AAV)血清9型载体系统剂量对纠正庞贝病患者心肺功能不全和骨骼肌无力的疗效。Pompe病是由于溶酶体酶酸性α-葡萄糖苷酶(GAA)的缺乏或缺失而引起的，结果是糖原积聚阻碍了心脏、呼吸和神经肌肉功能。呼吸衰竭是庞贝患者发病率和死亡率的主要原因。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对呼吸机依赖型儿童Pompe患者的rAAV1-CMV-HGAA横隔膜的肌肉注射。在这个项目中，我们建议在最近的试验经验的基础上，纳入创新的、机械性的结果衡量标准，并用一种新的给药方法和先进的血清型来推进治疗方法(AAV9)。中心假设是，肌肉和神经组织中GAA活性的恢复是安全的，将扭转庞培病儿童的心肺功能不全和骨骼肌无力。我们建议利用尖端的成像和电生理方式来描述载体作用的机制。此外，我们还开发了一种治疗性AAV构建物的创新制造技术，该构建物具有更好的神经组织转导、组织特异性结蛋白启动子和密码子优化的GAA cDNA。基于强劲的初步数据，这项提案将测试两个具体目标： 目的1.确定系统注射rAAV9-DES-HGAA对幼猴的安全性和逆行神经转导作用(与其他支持IND的灵长类动物研究同时进行)。 目的2.评价系统性rAAV9-HGAA治疗早发性Pompe病的安全性和有效性。 这项建议将在三个主要领域显著推进这一领域：(1)阐明AAV9系统递送的安全性；(2)治疗庞培病的神经和肌肉无力成分；(3)调查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有效性。