AAV vector-mediated microdystrophin expression in a relatively small percentage of mdx myofibers improved the mdx phenotype
AAV vector-mediated microdystrophin expression in a relatively small percentage of mdx myofibers improved the mdx phenotype
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DOI：
10.1016/j.ymthe.2004.07.025
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发表时间：
2004-11-01
影响因子：
12.4
通讯作者：
Takeda, S
中科院分区：
文献类型：
--
作者：
Yoshimura, M;Sakamoto, M;Takeda, S
Duchenne肌营养不良症(DMD)是一种由dystrophin基因突变引起的致命的骨骼肌疾病。腺相关病毒(AAV)载体介导的基因治疗是治疗该病的一种有前途的方法。虽然杆状截短的微肌萎缩蛋白基因已经被证明可以改善营养不良的表型，但通过AAV载体进行有效的基因治疗所需的微肌营养不良蛋白的表达水平尚未确定。在此，我们构建了在肌肉特异性MCK启动子控制下表达微肌营养不良蛋白(DeltaCS1)的AAV2-MCKDeltaCS1重组AAV2-MCKDeltaCS1载体，并将其注射到10日龄和5周龄mdx小鼠的TA肌肉中。AAV2-MCKDeltaCS1介导的基因转移到5周龄的MDX肌肉中，导致了微肌营养不良蛋白的广泛和长期的表达，并显著改善了力的产生。有趣的是，10日龄的注射肌肉在有限数量的肌纤维中表达微肌营养不良蛋白，但显示出微肌营养不良蛋白阳性的肌肉纤维肥大和相当大的收缩力量恢复。因此，AAV2-MCKDeltaCS1有望成为DMD基因治疗的有力工具。
Duchenne muscular dystrophy (DMD) is a lethal disorder of skeletal muscle caused by mutations in the dystrophin gene. Adeno-associated virus (AAV) vector-mediated gene therapy is a promising approach to the disease. Although a rod-truncated microdystrophin gene has been proven to ameliorate dystrophic phenotypes, the level of microdystrophin expression required for effective gene therapy by an AAV vector has not been determined yet. Here, we constructed a recombinant AAV type 2 vector, AAV2-MCKDeltaCS1, expressing microdystrophin (DeltaCS1) under the control of a muscle-specific MCK promoter and injected it into TA muscles of 10-day-old and 5-week-old mdx mice. AAV2-MCKDeltaCS1-mediated gene transfer into 5-week-old mdx muscle resulted in extensive and long-term expression of microdystrophin and significantly improved force generation. Interestingly, 10-day-old injected muscle expressed microdystrophin in a limited number of myofibers but showed hypertrophy of microdystrophin-positive muscle fibers and considerable recovery of contractile force. Thus, we concluded that AAV2-MCKDeltaCS1 could be a powerful tool for gene therapy of DMD.