Cellular Reprogramming, Genome Editing, and Alternative CRISPR Cas9 Technologies for Precise Gene Therapy of Duchenne Muscular Dystrophy

Abstract

In the past decade, the development of two innovative technologies, namely, induced pluripotent stem cells (iPSCs) and the CRISPR Cas9 system, has enabled researchers to model diseases derived from patient cells and precisely edit DNA sequences of interest, respectively. In particular, Duchenne muscular dystrophy (DMD) has been an exemplary monogenic disease model for combining these technologies to demonstrate that genome editing can correct genetic mutations in DMD patient-derived iPSCs. DMD is an X-linked genetic disorder caused by mutations that disrupt the open reading frame of the dystrophin gene, which plays a critical role in stabilizing muscle cells during contraction and relaxation. The CRISPR Cas9 system has been shown to be capable of targeting the dystrophin gene and rescuing its expression in in vitro patient-derived iPSCs and in vivo DMD mouse models. In this review, we highlight recent advances made using the CRISPR Cas9 system to correct genetic mutations and discuss how emerging CRISPR technologies and iPSCs in a combined platform can play a role in bringing a therapy for DMD closer to the clinic.

Cardiac Protection after Systemic Transplant of Dystrophin Expressing Chimeric (DEC) Cells to the mdx Mouse Model of Duchenne Muscular Dystrophy

“…Cellular level gene therapies are emerging as innovative approaches for researchers to target DMD related cardiac manifestations, which are often the most devastating aspects of disease progression. These new cellular therapies offer the potential to cure DMD, including the cardiomyopathy characteristics [16][17][18][19][20][21][22][23]. Putten et al demonstrated that cardiac myocyte dystrophin levels as low as 4-15% of wild type mice can delay or even partially ameliorate the effects of cardiomyopathy in the mdx mice [24].…”

“…Putten et al demonstrated that cardiac myocyte dystrophin levels as low as 4-15% of wild type mice can delay or even partially ameliorate the effects of cardiomyopathy in the mdx mice [24]. Several potential gene therapies aiming at dystrophin restoration such as exon skipping, gene editing via viral vectors, and gene slicing CRISPR system delivered by adeno-associated viruses have been described in the literature, but their efficacy in dystrophin restoration for the cardiomyocytes to clinically relevant levels has been limited [16][17][18][19][20][21][22][23]25].…”

Nutritional intervention with cyanidin hinders the progression of muscular dystrophy

“…Despite the molecular mechanisms behind MDs are partially known, this class of diseases is one of the most difficult to treat. Indeed, although several clinical trials have been carried on, MDs are still orphan diseases 4 .…”

Effectiveness of pharmacological treatments in Duchenne muscular dystrophy: a protocol for a systematic review and meta-analysis

“…In recent years, the interest in the potential of gene editing has increased, since new therapeutic strategies such as inserting dystrophin functional genes through an adenovirus,21 repairing the affected gene using the CRISPR/Cas9 technique22 or transplanting muscle stem cells to the affected muscles22 23 have proven effective.…”