Gene Therapy for Cardiac and Skeletal Myopathies

描述（由申请方提供）：庞贝氏症（1：40000活产，糖原累积病II型，酸性麦芽糖酶缺乏症; MIM 232300）的特征是严重心肌病和呼吸肌无力，影响早期个体。这些作用由编码酶酸性α-葡糖苷酶（GAA）的单个缺陷基因介导，导致肌肉组织内的糖原积累。糖原沉积破坏了心脏和骨骼肌的结构和功能，并导致衰弱和往往致命的疾病。目前，庞贝氏症没有有效的治疗方法，治疗选择非常有限。酶替代疗法（ERT）是唯一获批的庞贝氏症治疗方法，必须频繁给药，并且只能为患者提供部分获益。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氏症的影响。本提案中包括两项研究，旨在确定在庞贝氏症动物模型中利用重组腺相关病毒（rAAV）介导的GAA递送的疗效和校正程度。具体目标：1）测试编码hGAA的rAAV的全身递送减弱心脏骨骼肌病的假设; 2）测试在老年动物模型中施用rAAV 2/9-hGAA疗法将导致庞贝氏症晚期的矫正的假设。两者合计，拟议的工作将提供新的见解的方式，基因治疗可以纠正GAA缺乏组织。除了与庞贝氏症患者的相关性外，这项工作还将通过为存在替代性心血管和骨骼肌疾病的患者提供新的治疗选择而产生深远的影响。

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.