Gene Therapy for Cardiac and Skeletal Myopathies

描述（由申请人提供）：庞贝病（1:40000活产，糖原储存病II型，酸性麦尔糖酶缺乏症；MIM 232300）以严重心肌病和呼吸肌无力为特征，可在早期影响个体。这些影响是由编码酸-葡萄糖苷酶（GAA）的单个缺陷基因介导的，导致糖原在肌肉组织内积累。糖原沉积破坏了心脏和骨骼肌的结构和功能，导致身体虚弱，往往是致命的疾病。目前，没有有效的治疗庞贝病和治疗方案严重有限。酶替代疗法（ERT）是Pompe病唯一被批准的治疗方法，必须频繁使用，并且只能为患者提供部分益处。因此，我们实验室的重点是开发一种新的治疗方法来逆转或改善庞贝病的影响。本提案中包括两项研究，旨在利用重组腺相关病毒（rAAV）介导的GAA在Pompe病动物模型中传递的疗效和纠正程度。具体目的：1)验证全身递送编码hGAA的rAAV可减轻心肌病的假设；2)验证老龄动物模型给予rAAV2/9-hGAA治疗可纠正晚期Pompe病的假设。综上所述，这项工作将为基因治疗纠正GAA缺陷组织的方式提供新的见解。除了与庞贝病患者相关外，这项工作还将为患有其他心血管和骨骼肌疾病的患者提供一种新的治疗选择，从而产生深远的影响。

DESCRIPTION (provided by applicant): Pompe disease (1:40000 live births, glycogen storage disease type II, acid maltase deficiency; MIM 232300) is characterized by severe cardiomyopathy and respiratory muscle weakness that affects individuals at an early age. These effects are mediated by a single defective gene encoding the enzyme acid a-glucosidase (GAA), resulting in glycogen accumulation within muscle tissue. Glycogen deposits disrupt the architecture and function of both cardiac and skeletal muscle and cause a debilitating and often fatal condition. Presently, there is no effective cure for Pompe disease and treatment options are severely limited. Enzyme replacement therapy (ERT), the only approved treatment for Pompe disease, must be administered frequently and only provides partial benefit to the patient. Therefore, the focus of our laboratory is to develop a novel therapeutic approach to reverse or ameliorate the effects of Pompe disease. Included in this proposal are two studies aimed to establish the efficacy and degree of correction utilizing recombinant adeno-associated viral (rAAV)-mediated delivery of GAA in an animal model of Pompe disease. Specific Aims: 1) To test the hypothesis that systemic delivery of rAAV encoding hGAA attenuates cardioskeletal myopathy; 2) To test the hypothesis that administration of rAAV2/9-hGAA therapy in an aged animal model will result in correction of advanced stages of Pompe disease. Taken together, the proposed work will provide new insights into the manner in which gene therapy can correct GAA deficient tissue. Aside from its relevance to patients with Pompe disease, this work will have a profound impact by offering a novel therapeutic option to patients who present alternative cardiovascular and skeletal muscle disease.