Lim Kenji Rowel Q, Yoon Chantal, Yokota Toshifumi
Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, 8812-112 St., Edmonton, AB T6G 2H7, Canada.
The Friends of Garret Cumming Research and Muscular Dystrophy Canada HM Toupin Neurological Science Research Chair, 8812-112 St., Edmonton, AB T6G 2H7, Canada.
J Pers Med. 2018 Nov 24;8(4):38. doi: 10.3390/jpm8040038.
Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive neuromuscular disease prevalent in 1 in 3500 to 5000 males worldwide. As a result of mutations that interrupt the reading frame of the gene (), DMD is characterized by a loss of dystrophin protein that leads to decreased muscle membrane integrity, which increases susceptibility to degeneration. CRISPR/Cas9 technology has garnered interest as an avenue for DMD therapy due to its potential for permanent exon skipping, which can restore the disrupted reading frame in DMD and lead to dystrophin restoration. An RNA-guided DNA endonuclease system, CRISPR/Cas9 allows for the targeted editing of specific sequences in the genome. The efficacy and safety of CRISPR/Cas9 as a therapy for DMD has been evaluated by numerous studies in vitro and in vivo, with varying rates of success. Despite the potential of CRISPR/Cas9-mediated gene editing for the long-term treatment of DMD, its translation into the clinic is currently challenged by issues such as off-targeting, immune response activation, and sub-optimal in vivo delivery. Its nature as being mostly a personalized form of therapy also limits applicability to DMD patients, who exhibit a wide spectrum of mutations. This review summarizes the various CRISPR/Cas9 strategies that have been tested in vitro and in vivo for the treatment of DMD. Perspectives on the approach will be provided, and the challenges faced by CRISPR/Cas9 in its road to the clinic will be briefly discussed.
杜兴氏肌肉营养不良症（DMD）是一种致命的X连锁隐性神经肌肉疾病，在全球每3500至5000名男性中就有1例患病。由于突变中断了基因（）的阅读框，DMD的特征是肌营养不良蛋白缺失，导致肌膜完整性下降，进而增加了退变易感性。CRISPR/Cas9技术因其具有永久外显子跳跃的潜力而成为DMD治疗的一个有吸引力的途径，这可以恢复DMD中被破坏的阅读框并导致肌营养不良蛋白恢复。CRISPR/Cas9是一种RNA引导的DNA内切酶系统，可对基因组中的特定序列进行靶向编辑。许多体外和体内研究评估了CRISPR/Cas9作为DMD治疗方法的有效性和安全性，成功率各不相同。尽管CRISPR/Cas9介导的基因编辑有潜力用于DMD的长期治疗，但其转化为临床应用目前受到脱靶、免疫反应激活和体内递送效果不佳等问题的挑战。其作为一种主要的个性化治疗形式的性质也限制了其对表现出广泛突变的DMD患者的适用性。本综述总结了已在体外和体内测试用于治疗DMD的各种CRISPR/Cas9策略。将提供对该方法的观点，并简要讨论CRISPR/Cas9在进入临床过程中面临的挑战。
