Aslesh Tejal, Erkut Esra, Yokota Toshifumi
Neuroscience and Mental Health Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
Expert Opin Biol Ther. 2021 Aug;21(8):1049-1061. doi: 10.1080/14712598.2021.1872539. Epub 2021 Jan 25.
: Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder that affects approximately one in 3500-5000 male births. Patients experience muscle degeneration, loss of ambulation, and eventual death from cardiac or respiratory failure in early adulthood due to a lack of functional dystrophin protein, which is required to maintain the integrity of muscle cell membranes. Out-of-frame mutations in the gene generally lead to no dystrophin protein expression and a more severe phenotype (DMD). Conversely, in-frame mutations are often associated with milder Becker muscular dystrophy (BMD) with a truncated dystrophin expression.: Genome editing via the clustered regularly interspaced short palindromic repeats (CRISPR) system can induce permanent corrections of the gene, thus becoming an increasingly popular potential therapeutic method. In this review, we outline recent developments in CRISPR/Cas9 genome editing for the correction of DMD, both and , as well as novel delivery methods.: Despite recent advances, many limitations to CRISPR/Cas9 therapy are still prevalent such as off-target editing and immunogenicity. Specifically, for DMD, intervention time and efficient delivery to cardiac and skeletal muscles also present inherent challenges. Research needs to focus on the therapeutic safety and efficacy of this approach.
杜兴氏肌肉营养不良症(DMD)是一种X连锁隐性神经肌肉疾病,在每3500 - 5000例男性新生儿中约有1例受影响。由于缺乏维持肌肉细胞膜完整性所需的功能性抗肌萎缩蛋白,患者会出现肌肉退化、失去行走能力,并在成年早期最终因心脏或呼吸衰竭而死亡。该基因的移码突变通常导致无抗肌萎缩蛋白表达,从而表现出更严重的表型(DMD)。相反,框内突变通常与较轻的贝克肌肉营养不良症(BMD)相关,其抗肌萎缩蛋白表达截短。通过成簇规律间隔短回文重复序列(CRISPR)系统进行基因组编辑可以诱导该基因的永久校正,因此成为一种越来越受欢迎的潜在治疗方法。在本综述中,我们概述了CRISPR/Cas9基因组编辑在纠正DMD方面的最新进展,包括体内和体外的进展,以及新的递送方法。尽管最近取得了进展,但CRISPR/Cas9治疗仍存在许多限制,如脱靶编辑和免疫原性。具体而言,对于DMD,干预时间以及向心脏和骨骼肌的有效递送也存在固有挑战。研究需要关注这种方法的治疗安全性和有效性。