Abstract
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.
Highlights
Academic Editor: Ivano CondòDuchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder characterized by severe muscle wasting, cardiomyopathy, and elevated creatinine kinase levels [1,2]
This study demonstrated that clustered regularly interspaced short palindromic repeats (CRISPR) can be utilized in the N- or C-terminal functional domains, as long as particular amino acid residues are preserved to retain functionality
CRISPR-mediated gene editing remains a promising therapeutic for the correction of DMD mutations
Summary
Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder characterized by severe muscle wasting, cardiomyopathy, and elevated creatinine kinase levels [1,2]. Owing to its large size, there are multiple opportunities for mutations such as large deletions, point mutations, and duplications throughout the DMD gene [11]. The majority of these mutations disrupt the open reading frame (ORF), resulting in a frameshift and subsequently the production of a truncated, non-functional dystrophin protein [12]. As the reading frame is maintained, a semi-functional dystrophin protein is expressed, allowing for some maintenance of muscle function. This has inspired therapeutic strategies including gene editing and exon skipping as a means of restoring the ORF in DMD patients.
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