Gregorevic Paul, Blankinship Michael J, Allen James M, Chamberlain Jeffrey S
Department of Neurology, University of Washington, Seattle, Washington 98195-7720, USA.
Mol Ther. 2008 Apr;16(4):657-64. doi: 10.1038/mt.2008.28. Epub 2008 Mar 4.
Restoring dystrophin expression in the muscles of patients with Duchenne muscular dystrophy (DMD) may halt or reverse the degenerative wasting and weakness that causes premature death. However, the therapeutic efficacy of an intervention may be limited by the extent of disease progression prior to treatment. In this study, we considered the potential for ameliorating the pathology in a mouse model of advanced-stage muscular dystrophy by systemic administration of recombinant adeno-associated viral (rAAV6) vectors encoding a microdystrophin expression construct. The treatment of 20-month-old mdx mice restored body-wide expression of a dystrophin-based protein in striated musculature. In aged mice that received treatment, the resultant dystrophin expression was associated with improved hindlimb and respiratory muscle morphology and function, concomitant with reduced muscle fiber degeneration. The findings demonstrate that an established dystrophic state remains amenable to improvement with appropriate intervention and, by some measures, may even achieve benefits similar to those observed with intervention early in disease progression. The capacity to ameliorate the pathology in an animal model of advanced-stage muscular dystrophy suggests that interventions ultimately proven to exert a therapeutic effect in young patients may offer benefits to older patients or those with advanced conditions of progressive muscular dystrophy.
在杜兴氏肌营养不良症（DMD）患者的肌肉中恢复肌营养不良蛋白的表达，可能会阻止或逆转导致过早死亡的退行性消瘦和肌无力。然而，一种干预措施的治疗效果可能会受到治疗前疾病进展程度的限制。在本研究中，我们考虑了通过全身注射编码微肌营养不良蛋白表达构建体的重组腺相关病毒（rAAV6）载体，来改善晚期肌营养不良症小鼠模型病理状况的可能性。对20月龄的mdx小鼠进行治疗后，在横纹肌组织中恢复了基于肌营养不良蛋白的蛋白质在全身的表达。在接受治疗的老龄小鼠中，由此产生的肌营养不良蛋白表达与后肢和呼吸肌形态及功能的改善相关，同时肌肉纤维变性减少。这些发现表明，既定的营养不良状态通过适当干预仍可得到改善，并且从某些指标来看，甚至可能获得与疾病进展早期干预所观察到的益处相似的效果。在晚期肌营养不良症动物模型中改善病理状况的能力表明，最终被证明对年轻患者有治疗作用的干预措施，可能会对老年患者或患有进行性肌营养不良症晚期的患者有益。
