Modular flexibility of dystrophin: Implications for gene therapy of Duchenne muscular dystrophy
Modular flexibility of dystrophin: Implications for gene therapy of Duchenne muscular dystrophy
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DOI：
10.1038/nm0302-253
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发表时间：
2002-03-01
期刊：
影响因子：
82.9
通讯作者：
Chamberlain, JS
中科院分区：
文献类型：
--
作者：
Harper, SQ;Hauser, MA;Chamberlain, JS
由于肌营养不良蛋白基因的巨大尺寸，开发杜氏肌营养不良症（DMD）基因治疗的尝试变得复杂。我们已经进行了详细的抗肌萎缩蛋白结构域的功能分析，并表明，该蛋白质的多个区域可以删除各种组合，以产生高功能的迷你和微型抗肌萎缩蛋白。在转基因mdx小鼠（DMD的模型）中的研究揭示，营养不良的多种功能特征被这些截短的肌营养不良蛋白中的一些所阻止。表达最小肌营养不良蛋白的肌肉被完全保护免受肌肉活动引起的损伤，并且与正常肌肉在形态上没有不同。此外，注射腺相关病毒携带微肌营养不良蛋白到营养不良的肌肉的免疫活性mdx小鼠的结果在一个惊人的逆转这种疾病的组织病理学特征。这些结果表明，营养不良的病理可以预防和逆转的基因治疗使用微肌营养不良蛋白。
Attempts to develop gene therapy for Duchenne muscular dystrophy (DMD) have been complicated by the enormous size of the dystrophin gene. We have performed a detailed functional analysis of dystrophin structural domains and show that multiple regions of the protein can be deleted in various combinations to generate highly functional mini- and micro-dystrophins. Studies in transgenic mdx mice, a model for DMD, reveal that a wide variety of functional characteristics of dystrophy are prevented by some of these truncated dystrophins. Muscles expressing the smallest dystrophins are fully protected against damage caused by muscle activity and are not morphologically different from normal muscle. Moreover, injection of adeno-associated viruses carrying micro-dystrophins into dystrophic muscles of immunocompetent mdx mice results in a striking reversal of histopathological features of this disease. These results demonstrate that the dystrophic pathology can be both prevented and reversed by gene therapy using micro-dystrophins.