In Vivo Genome Editing Restores Dystrophin Expression and Cardiac Function in Dystrophic Mice


Cardiomyopathy is the leading cause of death in patients with Duchenne muscular dystrophy (DMD), affecting over 90% of patients.1 Currently, no effective treatments exist for this condition and most patients die in early adulthood. Genome editing has already shown potential restoring dystrophin protein expression in skeletal muscles in the mdx mouse, which is often used as an animal model of DMD.2

This study is the first to investigate the utility of genome editing in cardiac muscle. SpCas9 (clustered regularly interspaced short palindromic repeat–associated 9 from Streptococcus pyogenes)/guide RNA constructs were delivered into the heart muscle of mdx/Utr+/− mice, which are similar to the mdx mice previously studied but develop more severe cardiomyopathy at an earlier stage, using an adenovirus (AAV) carrier.

A single intervention was found not only to restore dystrophin expression 7 days after treatment, but also to reduce the amount of fibrosis in the heart. Cardiac muscle function was also tested by measuring muscle contractility at 10 weeks; a statistically significant improvement was seen. This study has therefore demonstrated that genome editing is an extremely promising therapeutic option for DMD. It has the advantage of conferring permanent effects following a single treatment. However, further research is required to investigate potentially dangerous off-target mutations at genomic locations that resemble the intended target, which have previously occurred in occurred with SpCas9 gene therapy.3 The Cas 9 protein may also activate immunologic responses. Another concern is the delivery efficiency: AAV is the most efficient and widely used vehicles but is limited in its capacity, delivery efficiency, tissue specificity, immune activating potential and dosage control. These issues need to be addressed before the method progresses to clinical investigations. Nevertheless, this is an important study, demonstrating the great promise that gene therapy holds as a potential treatment option for DMD.


  1. Moriuchi T, Kagawa N, Mukoyama M, et al., Autopsy analyses of the muscular dystrophies, Tokushima J Exp Med, 1993;40:83-93;8211986.
  2. Xu L, Park KH, Zhao L, et al., CRISPR-mediated Genome Editing Restores Dystrophin Expression and Function in mdx Mice, Mol Ther, 2016;24:564-9;10.1038/mt.2015.192;26449883.
  3. Cho SW, Kim S, Kim Y, et al., Analysis of off-target effects of CRISPR/Cas-derived RNA-guided endonucleases and nickases, Genome Res, 2014; 24:132-41; 10.1101/gr.162339.113;24253446.

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