Expression of dystrophin driven by the 1.35-kb MCK promoter ameliorates muscular dystrophy in fast, but not in slow muscles of transgenic Mdx mice
Expression of dystrophin driven by the 1.35-kb MCK promoter ameliorates muscular dystrophy in fast, but not in slow muscles of transgenic Mdx mice
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DOI：
10.1016/s1525-0016(03)00129-1
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发表时间：
2003-07-01
影响因子：
12.4
通讯作者：
Lochmüller, H
中科院分区：
文献类型：
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作者：
Dunant, P;Larochelle, N;Lochmüller, H
杜氏肌营养不良症的成功基因治疗可能需要在所有受影响的肌肉中终身表达治疗基因。最有前途的基因递送载体，病毒载体，遭受几个限制，包括免疫原性，治疗基因表达的损失，和有限的包装能力。因此，以前进行了各种努力来使用小的治疗基因，并将它们置于强大的肌肉特异性启动子的控制下。在这里，我们报告的影响下，一个短的肌肉特异性启动子（MCK 1.35 kb）的控制下的minidystrophin（6.3 kb）在大多数的寿命（4-20个月）的转基因小鼠模型。肌营养不良蛋白的表达在所有年龄保持稳定和肌肉特异性。营养不良的表型大大改善，最重要的是，肢体肌肉的肌肉功能显着改善，不仅在年轻的成年人，但也在老年小鼠相比，非转基因同窝出生。肌营养不良蛋白的表达在快速收缩的骨骼肌如胫骨前肌和趾长伸肌中很强，但在心脏、膈肌和慢收缩肌中很弱或不表达。此外，表达在糖酵解中很强，但在快速收缩肌肉的氧化纤维中很弱。这项研究可能有重要意义的设计未来的基因治疗试验肌营养不良症。
Successful gene therapy of Duchenne muscular dystrophy may require the lifelong expression of a therapeutic gene in all affected muscles. The most promising gene delivery vehicles, viral vectors, suffer from several limitations, including immunogenicity, loss of therapeutic gene expression, and a limited packaging capacity. Therefore, various efforts were previously undertaken to use small therapeutic genes and to place them under the control of a strong and muscle-specific promoter. Here we report the effects of a minidystrophin (6.3 kb) under the control of a short muscle-specific promoter (MCK 1.35 kb) over most of the lifetime (4-20 months) of a transgenic mouse model. Dystrophin expression remained stable and muscle-specific at all ages. The dystrophic phenotype was greatly ameliorated and, most importantly, muscle function in limb muscles was significantly improved not only in young adult but also in aged mice compared to nontransgenic littermates. Dystrophin expression was strong in fast-twitch skeletal muscles such as tibialis anterior and extensor digitorum longus, but weak or absent in heart, diaphragm, and slow-twitch muscles. Additionally, expression was strong in glycolytic but weak in oxidative fibers of fast-twitch muscles. This study may have important implications for the design of future gene therapy trials for muscular dystrophy.