Promising therapeutic approaches using CRISPR/Cas9 genome editing technology in the treatment of Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy is an X-linked recessive hereditary monogenic disorder caused by inability to produce dystrophin protein. In most patients, the expression of dystrophin lost due to disrupting mutations in open reading frame. Despite the efforts in a large number of different therapeutic approaches to date, the treatments available for DMD remain mitigative and supportive to improve the symptoms of the disease, rather than to be curative. The advent of CRISPR/Cas9 technology has revolutionized genome editing scope and considered as pioneer in effective genomic engineering. Deletions or excisions of intragenic DNA by CRISPR as well as a similar strategy with exon skipping at the DNA level induced by antisense oligonucleotides, are new and promising approaches in correcting DMD gene, which restore the expression of a truncated but functional dystrophin protein. Also, CRISPR/Cas9 technology can be used to treat DMD by removing duplicated exons, precise correction of causative mutation by HDR-based pathway and inducing the expression of compensatory proteins such as utrophin. In this study, we briefly explained the molecular genetics of DMD and a historical overview of DMD gene therapy. We in particular focused on CRISPR/Cas9-mediated therapeutic approaches that used to treat DMD.

Genome Editing in iPSC-Based Neural Systems: From Disease Models to Future Therapeutic Strategies

“…For example, iPSC-derived models of spinal muscular atrophy demonstrating rescue of the phenotype by CRISPR-mediated inclusion of exon 7 have paved the way toward the development of splicing modifiers, such as Risdiplam, which are now in clinical trials (Poirier et al, 2018). Similarly, in Duchenne muscular dystrophy, a variety of CRISPR-based methods have successfully restored dystrophin expression in iPSC models which was subsequently confirmed in murine and larger mammal models with current research focusing on clinical translation (Young et al, 2016;Mollanoori et al, 2020). iPSC models of Dravet syndrome (Supplementary Table 1), along with animal models, have contributed to understanding the cell-intrinsic disease mechanisms of SCN1A dysfunction.…”

Variability in Genome Editing Outcomes: Challenges for Research Reproducibility and Clinical Safety

“…In light of the benefits expected from the use of GETs, some cancer risk may become acceptable for lethal diseases, such as Duchenne muscular dystrophy, for which the use of CRISPR/Cas9 may show promise, 85 and numerous preclinical studies are ongoing. 86 Already, clinical trials to treat refractory cancer are also underway, 65 but for less immediately critical conditions, such as HIV infection, 87 the threshold of acceptability will be different. Overall, relevant risks for potential secondary cancer development or for other adverse effects remain to be evaluated.…”

Anti-inflammatory nanoparticles significantly improve muscle function in a murine model of advanced muscular dystrophy

“…Together, the data suggest that IM injection of gene editing therapeutics holds great potential for the treatment of muscular dystrophy, yet also serves to highlight the challenge of complete gene correction, and therefore the complete resolution of chronic inflammation likely required to halt disease progression. Toxicities associated with long-term treatment with antisense oligonucleotides (23,24) and immunogenicity of CRISPR delivery vectors further underscore the major unmet medical need for new strategies to treat muscular dystrophy and the interplay between such treatments, disease progression, and inflammation. The most successful strategies will likely use gene editing in combination with immunomodulation to create a tissue microenvironment that both promotes tolerance to de novo dystrophin expression (25,26) and fosters functional muscle regeneration (6).…”