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Background  Mutations in the  DMD  gene encoding dystrophin—a critical structural element in muscle cells—cause Duchenne muscular dystrophy (DMD), which is the most common fatal genetic disease. Clustered regularly interspaced short palindromic repeat (CRISPR)-mediated gene editing is a promising strategy for permanently curing DMD.    Methods  In this study, we developed a novel strategy for reframing  DMD  mutations via CRISPR-mediated large-scale excision of exons 46–54. We compared this approach with other DMD rescue strategies by using DMD patient-derived primary muscle-derived stem cells (DMD-MDSCs). Furthermore, a patient-derived xenograft (PDX) DMD mouse model was established by transplanting DMD-MDSCs into immunodeficient mice. CRISPR gene editing components were intramuscularly delivered into the mouse model by adeno-associated virus vectors.    Results  Results demonstrated that the large-scale excision of mutant  DMD  exons showed high efficiency in restoring dystrophin protein expression. We also confirmed that CRISPR from  Prevotella  and  Francisella  1(Cas12a)-mediated genome editing could correct  DMD  mutation with the same efficiency as CRISPR-associated protein 9 (Cas9). In addition, more than 10% human DMD muscle fibers expressed dystrophin in the PDX DMD mouse model after treated by the large-scale excision strategies. The restored dystrophin in vivo was functional as demonstrated by the expression of the dystrophin glycoprotein complex member β-dystroglycan.    Conclusions  We demonstrated that the clinically relevant CRISPR/Cas9 could restore dystrophin in human muscle cells in vivo in the PDX DMD mouse model. This study demonstrated an approach for the application of gene therapy to other genetic diseases.    Supplementary Information  The online version contains supplementary material available at 10.1186/s13073-021-00876-0.

In vivo genome editing in mouse restores dystrophin expression in Duchenne muscular dystrophy patient muscle fibers