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

 描述（由申请方提供）：本提案的长期目标是研究腺相关病毒（AAV）血清型9载体全身给药纠正庞贝氏症患者心肺功能不全和骨骼肌无力的疗效。庞贝氏症由溶酶体酶酸性α葡糖苷酶（GAA）的缺乏或不存在引起，并且因此，糖原积累阻碍心脏、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I/II期临床试验，用于多种遗传性疾病，包括我们正在进行的在呼吸机依赖性小儿庞贝氏症患者中向膈肌肌内施用rAAV 1-CMV-hGAA。在这个项目中，我们建议建立在这个最近的试验的经验，纳入创新的，机械的结果措施，并推进治疗方法与新的交付方法和先进的血清型（AAV 9）。中心假设是肌肉和神经组织中GAA活性的恢复是安全的，并且将逆转患有庞贝氏症的儿童的心脏舒张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表征矢量作用机制。此外，我们已经开发了用于治疗性AAV构建体的创新制造技术，其具有改善的神经组织转导、组织特异性结蛋白启动子和密码子优化的GAA cDNA。根据强有力的初步数据，该提案将测试两个具体目标： 目标1。确定婴儿恒河猴中全身rAAV 9-DES-hGAA给药的安全性和逆行神经转导（与其他IND使能灵长类动物研究同时进行）。 目标2.评估全身性rAAV 9-hGAA在早发性庞贝氏症儿童中的安全性和有效性。 该提案将在三个主要领域显著推进该领域：（1）阐明AAV 9全身递送的安全性;（2）治疗庞贝氏症中的神经和肌肉无力成分;以及（3）研究成像和神经生理学测试作为心肺和骨骼肌功能的生物标志物的效用。

 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.