ABSTRACT

Introduction: 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 DMD 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.

Areas covered: Genome editing via the clustered regularly interspaced short palindromic repeats (CRISPR) system can induce permanent corrections of the DMD 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 in vitro and in vivo, as well as novel delivery methods.

Expert opinion: 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.

摘要

简介：杜氏肌营养不良症 (DMD) 是一种 X 连锁隐性神经肌肉疾病，影响大约 3500-5000 名出生的男性中的一名。由于缺乏维持肌肉细胞膜完整性所必需的功能性肌营养不良蛋白，患者在成年早期会经历肌肉退化、无法行走，最终死于心脏或呼吸衰竭。DMD基因的框外突变通常导致抗肌萎缩蛋白不表达和更严重的表型 (DMD)。相反，框内突变通常与具有截短的肌营养不良蛋白表达的轻度贝克尔肌营养不良症 (BMD) 相关。

涵盖的领域：通过成簇的规则间隔短回文重复 (CRISPR) 系统进行基因组编辑可以诱导DMD基因的永久校正，从而成为一种越来越受欢迎的潜在治疗方法。在这篇综述中，我们概述了 CRISPR/Cas9 基因组编辑在体外和体内校正 DMD 方面的最新进展，以及新的递送方法。

专家意见：尽管最近取得了一些进展，但 CRISPR/Cas9 疗法的许多限制仍然普遍存在，例如脱靶编辑和免疫原性。具体而言，对于 DMD，干预时间和对心脏和骨骼肌的有效传递也存在固有的挑战。研究需要关注这种方法的治疗安全性和有效性。