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The genetic cause of DM1 is the expansion of unstable CTG\u2010repeats in the 3\u2032 untranslated region (UTR) of the <jats:italic>DMPK<\/jats:italic> gene, resulting in the accumulation of toxic CUG\u2010transcripts that sequester RNA\u2010binding proteins and form nuclear foci in DM1 affected tissues and, consequently, alter various cellular processes. Therapeutic gene editing for treatment of monogenic diseases is a powerful technology that could in principle remove definitively the disease\u2010causing genetic defect. The precision and efficiency of the molecular mechanisms are still under investigation in view of a possible use in clinical practice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here, we describe the application of the clustered regularly interspaced short palindromic repeats (CRISPR)\/CRISPR\u2010associated protein 9 (Cas9) strategy to remove the CTG\u2010expansion in the <jats:italic>DMPK<\/jats:italic> gene in a mouse model carrying the human transgene from a DM1 patient. To optimise the editing efficiency in vivo, we identified new tools that allowed to improve the expression levels and the activity of the CRISPR\/Cas9 machinery. Newly designed guide RNA pairs were tested in DM1\u2010patient derived cells before in vivo application. Edited cells were analysed to assess the occurrence of off\u2010target and the accuracy of on\u2010target genomic events. Gene editing\u2010dependent and \u2010independent mechanisms leading to decreased accumulation of the mutated <jats:italic>DMPK<\/jats:italic> transcripts were also evaluated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results and Conclusion<\/jats:title><jats:p>Systemic delivery of CRISPR\/Cas9 components in DM1 mice, through myotropic adeno\u2010associated viral vectors, led to significant improvement of molecular alterations in the heart and skeletal muscle. Importantly, a persistent increase of body weight, improvement of muscle strength and body composition parameters were observed in treated animals. Accurate evaluation of CRISPR\/Cas9\u2010mediated\u2010phenotypic recovery in vivo is a crucial preclinical step for the development of a gene therapy for DM1 patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>In vivo application of a therapeutic gene editing strategy for permanent deletion of the pathogenetic CTG\u2010repeat amplification in the <jats:italic>DMPK<\/jats:italic> gene that causes myotonic dystrophy type 1.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Following treatment, diseased mice show a significant improvement of both molecular and phenotypic defects.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.70227","type":"journal-article","created":{"date-parts":[[2025,2,16]],"date-time":"2025-02-16T23:42:41Z","timestamp":1739749361000},"source":"Crossref","is-referenced-by-count":9,"title":["Muscle\u2010specific gene editing improves 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