Gene Therapy for Cardiac and Skeletal Myopathies

描述(申请人提供)：庞贝病(1：40000活产，糖原储存疾病II型，酸性麦芽糖酶缺乏症；MIM 232300)的特征是严重的心肌病和呼吸肌无力，影响个体的早期。这些作用是由编码酸性α-葡萄糖苷酶(GAA)的单一缺陷基因介导的，导致肌肉组织中糖原积累。糖原沉积破坏心肌和骨骼肌的结构和功能，并导致衰弱，往往是致命的情况。目前，庞贝病没有有效的治疗方法，治疗选择严重有限。酶替代疗法(ERT)是庞贝病唯一被批准的治疗方法，必须经常使用，并且只对患者提供部分好处。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培病的影响。这项建议包括两项研究，旨在确定重组腺相关病毒(RAAV)介导的GAA在庞贝病动物模型中的有效性和纠正程度。具体目的：1)测试全身注射编码HGAA的rAAV可减轻心脏骨骼肌病的假说；2)测试在老年动物模型上应用rAAV2/9-HGAA治疗将纠正晚期庞培病的假说。综上所述，这项拟议的工作将为基因治疗纠正GAA缺陷组织的方式提供新的见解。除了与庞培病患者相关外，这项工作还将产生深远的影响，为出现替代心血管和骨骼肌疾病的患者提供一种新的治疗选择。

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.