Townsend DeWayne, Blankinship Michael J, Allen James M, Gregorevic Paul, Chamberlain Jeffrey S, Metzger Joseph M
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
Mol Ther. 2007 Jun;15(6):1086-92. doi: 10.1038/sj.mt.6300144. Epub 2007 Apr 17.
Duchenne muscular dystrophy (DMD) is a fatal disease of striated muscle deterioration resulting from the loss of the cytoskeletal protein dystrophin. Most patients develop significant cardiomyopathy, with heart failure being the second leading cause of death in DMD. Compared with the extensive studies on skeletal muscle defects and potential therapy in DMD, very little attention has been directed at the increasing incidence of heart failure in DMD. Here we show that a single systemic injection of recombinant adeno-associated virus (rAAV2/6) harboring micro-dystrophin leads to extensive cardiac transduction, with micro-dystrophin correctly localized at the periphery of the cardiac myocytes and functionally associated with the sarcolemmal membrane. Significantly, micro-dystrophin gene transfer corrected the baseline end-diastolic volume defect in the mdx mouse heart and prevented cardiac pump failure induced by dobutamine stress testing in vivo, although several parameters of systolic function were not corrected. These results demonstrate that systemic gene delivery of micro-dystrophin can restore ventricular distensibility and protect the mdx myocardium from pump dysfunction during adrenergic stimulation in vivo.
杜兴氏肌肉萎缩症（DMD）是一种由于细胞骨架蛋白肌营养不良蛋白缺失导致的致命性横纹肌退化疾病。大多数患者会出现严重的心肌病，心力衰竭是DMD患者的第二大死因。与对DMD骨骼肌缺陷及潜在治疗方法的广泛研究相比，DMD患者中不断增加的心力衰竭发病率很少受到关注。在此我们表明，单次全身注射携带微肌营养不良蛋白的重组腺相关病毒（rAAV2/6）可导致广泛的心脏转导，微肌营养不良蛋白正确定位于心肌细胞周边，并与肌膜在功能上相关联。值得注意的是，微肌营养不良蛋白基因转移纠正了mdx小鼠心脏的基线舒张末期容积缺陷，并预防了体内多巴酚丁胺应激试验诱导的心脏泵衰竭，尽管收缩功能的几个参数未得到纠正。这些结果表明，微肌营养不良蛋白的全身基因递送可恢复心室扩张能力，并在体内肾上腺素能刺激期间保护mdx心肌免受泵功能障碍的影响。
