Muscle‐specific gene editing improves molecular and phenotypic defects in a mouse model of myotonic dystrophy type 1

Clinical and Translational Medicine, Год журнала: 2025, Номер 15(2)

Опубликована: Фев. 1, 2025

Abstract Background Myotonic dystrophy type 1 (DM1) is a genetic multisystemic disease, characterised by pleiotropic symptoms that exhibit notable variability in severity, nature and age of onset. The cause DM1 the expansion unstable CTG‐repeats 3′ untranslated region (UTR) DMPK gene, resulting accumulation toxic CUG‐transcripts sequester RNA‐binding proteins form nuclear foci affected tissues and, consequently, alter various cellular processes. Therapeutic gene editing for treatment monogenic diseases powerful technology could principle remove definitively disease‐causing defect. precision efficiency molecular mechanisms are still under investigation view possible use clinical practice. Methods Here, we describe application clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‐associated protein 9 (Cas9) strategy to CTG‐expansion mouse model carrying human transgene from patient. To optimise vivo, identified new tools allowed improve expression levels activity CRISPR/Cas9 machinery. Newly designed guide RNA pairs were tested DM1‐patient derived cells before vivo application. Edited analysed assess occurrence off‐target accuracy on‐target genomic events. Gene editing‐dependent ‐independent leading decreased mutated transcripts also evaluated. Results Conclusion Systemic delivery components mice, through myotropic adeno‐associated viral vectors, led significant improvement alterations heart skeletal muscle. Importantly, persistent increase body weight, muscle strength composition parameters observed treated animals. Accurate evaluation CRISPR/Cas9‐mediated‐phenotypic recovery crucial preclinical step development therapy patients. Key points In therapeutic permanent deletion pathogenetic CTG‐repeat amplification causes myotonic 1. Following treatment, diseased mice show both phenotypic defects.

Язык: Английский

Treatments and therapies for symptoms and clinical manifestations of adult type 1 myotonic dystrophy: A scoping review

Journal of the Neurological Sciences, Год журнала: 2025, Номер 472, С. 123470 - 123470

Опубликована: Март 19, 2025

Язык: Английский