Gene therapies that restore dystrophin expression for the treatment of Duchenne muscular dystrophy.
Gene therapies that restore dystrophin expression for the treatment of Duchenne muscular dystrophy.
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DOI：
10.1007/s00439-016-1725-z
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发表时间：
2016-09
期刊：
影响因子：
5.3
通讯作者：
Gersbach, Charles A.
中科院分区：
文献类型：
--
作者：
Robinson-Hamm, Jacqueline N.;Gersbach, Charles A.
杜氏肌营养不良症是最常见的遗传性遗传疾病之一，是由编码肌营养不良蛋白的DMD基因突变引起的。基因组编辑和基因治疗的最新进展为开发潜在的治疗方法提供了希望。DMD基因的截短版本可以用病毒载体递送到受影响的组织，并在各种动物模型中显示出有希望的结果。使用CRISPR/Cas9系统的基因组编辑最近已被用于通过删除患者细胞和小鼠模型中DMD基因的一个或多个外显子来恢复肌营养不良蛋白表达，从而导致肌肉力量的功能改善。使用寡核苷酸的外显子跳跃已经在几种动物模型中成功，并在多项临床试验中进行了评估。下一代寡核苷酸制剂提供了建立在这些结果基础上的重大承诺。所有这些恢复抗肌萎缩蛋白表达的方法都是令人鼓舞的，但仍然存在许多障碍。本文综述了这些技术的现状，并总结了他们的未来发展的考虑。
Duchenne muscular dystrophy is one of the most common inherited genetic diseases and is caused by mutations to the DMD gene that encodes the dystrophin protein. Recent advances in genome editing and gene therapy offer hope for the development of potential therapeutics. Truncated versions of the DMD gene can be delivered to the affected tissues with viral vectors and show promising results in a variety of animal models. Genome editing with the CRISPR/Cas9 system has recently been used to restore dystrophin expression by deleting one or more exons of the DMD gene in patient cells and in a mouse model that led to functional improvement of muscle strength. Exon skipping with oligonucleotides has been successful in several animal models and evaluated in multiple clinical trials. Next-generation oligonucleotide formulations offer significant promise to build on these results. All these approaches to restoring dystrophin expression are encouraging, but many hurdles remain. This review summarizes the current state of these technologies and summarizes considerations for their future development.
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