Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, 8613-114 Street, Edmonton, AB T6G 2H7, Canada.
The Friends of Garrett Cumming Research & Muscular Dystrophy Canada HM Toupin Neurological Science Research Chair, 8613-114 Street, Edmonton, AB T6G 2H7, Canada.
Int J Mol Sci. 2022 Feb 6;23(3):1832. doi: 10.3390/ijms23031832.
Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder with a prevalence of approximately 1 in 3500-5000 males. DMD manifests as childhood-onset muscle degeneration, followed by loss of ambulation, cardiomyopathy, and death in early adulthood due to a lack of functional dystrophin protein. Out-of-frame mutations in the dystrophin gene are the most common underlying cause of DMD. Gene editing via the clustered regularly interspaced short palindromic repeats (CRISPR) system is a promising therapeutic for DMD, as it can permanently correct DMD mutations and thus restore the reading frame, allowing for the production of functional dystrophin. The specific mechanism of gene editing can vary based on a variety of factors such as the number of cuts generated by CRISPR, the presence of an exogenous DNA template, or the current cell cycle stage. CRISPR-mediated gene editing for DMD has been tested both in vitro and in vivo, with many of these studies discussed herein. Additionally, novel modifications to the CRISPR system such as base or prime editors allow for more precise gene editing. Despite recent advances, limitations remain including delivery efficiency, off-target mutagenesis, and long-term maintenance of dystrophin. Further studies focusing on safety and accuracy of the CRISPR system are necessary prior to clinical translation.
杜氏肌营养不良症（DMD）是一种 X 连锁隐性神经肌肉疾病，男性患病率约为每 3500-5000 人中就有 1 人患病。DMD 表现为儿童期起病的肌肉退化，随后因缺乏功能性肌营养不良蛋白而丧失行走能力、发生心肌病，并在成年早期死亡。肌营养不良蛋白基因的无义突变是 DMD 的最常见根本原因。通过成簇规律间隔短回文重复序列（CRISPR）系统进行基因编辑是治疗 DMD 的一种很有前途的方法，因为它可以永久纠正 DMD 突变，从而恢复阅读框，使功能性肌营养不良蛋白得以产生。基因编辑的具体机制可能因 CRISPR 产生的切割数量、是否存在外源 DNA 模板或当前细胞周期阶段等多种因素而有所不同。CRISPR 介导的 DMD 基因编辑已在体外和体内进行了测试，本文讨论了其中的许多研究。此外，CRISPR 系统的新型修饰，如碱基编辑或先导编辑，可实现更精确的基因编辑。尽管最近取得了进展，但仍存在一些限制因素，包括递送效率、脱靶突变和肌营养不良蛋白的长期维持。在临床转化之前，有必要对 CRISPR 系统的安全性和准确性进行进一步研究。
