Gene Therapy for Cardiac and Skeletal Myopathies

心脏和骨骼肌病的基因治疗

• 批准号: 7925661
• 负责人: Darin J Falk
• 金额: $ 5.22万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-08 至 2012-09-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7925661
• 关键词: Acids; Adolescent; Adult; Affect; Age; Alpha-glucosidase; Animal Model; Animals; Architecture; Area; Attenuated; Biochemical; Birth; CMV promoter; Cardiac; Cardiomyopathies; Cardiovascular system; Data; Deposition; Desmin; Development; Diagnosis; Disease; Early Diagnosis; Enzymes; Exhibits; Functional disorder; Genes; Glycogen; Glycogen storage disease type II; Human; Individual; Infant; Investigation; Laboratories; Life; Life Cycle Stages; Live Birth; Mechanics; Mediating; Mediator of activation protein; Modeling; Morbidity - disease rate; Mus; Muscle; Muscle Weakness; Muscle function; Muscular Dystrophies; Myopathy; Patients; Recombinant adeno-associated virus (rAAV); Recombinants; Research; Respiratory Failure; Respiratory Muscles; Respiratory physiology; Serotyping; Skeletal Muscle; Staging; Techniques; Technology; Testing; Tissues; Viral; Work; aged; base; enzyme replacement therapy; experience; gene replacement therapy; gene therapy; glucosidase; infancy; insight; mature animal; novel; novel therapeutic intervention; novel therapeutics; respiratory; skeletal; success

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.

描述（由申请人提供）：庞贝病（1:40000 活产儿、糖原累积病 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，影响个体在幼年时的情况。这些效应是由编码酸性α-葡萄糖苷酶（GAA）的​​单个缺陷基因介导的，导致肌肉组织内糖原积累。糖原沉积会破坏心肌和骨骼肌的结构和功能，导致衰弱甚至致命的情况。目前，庞贝病尚无有效治疗方法，治疗选择也受到严重限制。酶替代疗法 (ERT) 是庞贝病唯一被批准的治疗方法，必须经常进行，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。该提案中包括两项研究，旨在确定利用重组腺相关病毒 (rAAV) 介导的 GAA 递送在庞贝病动物模型中的功效和校正程度。具体目标： 1) 检验全身递送编码 hGAA 的 rAAV 可减轻心脏骨骼肌病的假设； 2) 检验以下假设：在老年动物模型中施用 rAAV2/9-hGAA 疗法将导致庞贝病晚期得到纠正。总而言之，拟议的工作将为基因疗法纠正 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，这项工作还将产生深远的影响，为患有其他心血管和骨骼肌疾病的患者提供一种新颖的治疗选择。