Perspectives on gene therapy in myotonic dystrophy type 1

Myotonic dystrophy type 1 (DM1) is an autosomal dominant neuromuscular disorder caused by a CTG expansion mutation located in the 3' untranslated region of the DMPK (DM1 protein kinase) gene. According to current evidence, mutant DMPK mRNAs containing the trinucleotide expansion are retained in the nucleus, entrapping Muscleblind (MBNL1) protein and several transcription factors in ribonuclear foci and stabilizing CUG binding protein, Elav-like family member 1 (CELF1), which ultimately causes aberrant pre-mRNA splicing and gene expression of particular genes and associated pathogenesis in patients with DM1. At present, treatment for DM1 is limited to symptomatic intervention, and there is no therapeutic approach to prevent or reverse disease progression. This Mini-Review is focused on the experimental advances obtained in cell-based and animal models toward the development of therapeutic treatments against DM1, providing a discussion of their potential application in clinical trials. Because the central core of DM1 pathogenesis is gain-of-function of mutant RNA, most studies target the mutant RNA by use of antisense oligonucleotides or small chemical compounds to eliminate or ameliorate its toxic effects. However, alternative strategies focused on reversing DM1 features without targeting of mutant DMPK RNA have recently emerged.