Molecular Therapies for Myotonic Dystrophy Type 1: From Small Drugs to Gene Editing

Abstract

Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy affecting many different body tissues, predominantly skeletal and cardiac muscles and the central nervous system. The expansion of CTG repeats in the DM1 protein-kinase (DMPK) gene is the genetic cause of the disease. The pathogenetic mechanisms are mainly mediated by the production of a toxic expanded CUG transcript from the DMPK gene. With the availability of new knowledge, disease models, and technical tools, much progress has been made in the discovery of altered pathways and in the potential of therapeutic intervention, making the path to the clinic a closer reality. In this review, we describe and discuss the molecular therapeutic strategies for DM1, which are designed to directly target the CTG genomic tract, the expanded CUG transcript or downstream signaling molecules.

Keywords: DM1 mice; antisense oligonucleotides; gene editing; molecular therapy; myotonic dystrophy; trinucleotide-expansion disease.

Figure 1

DM1 pathogenetic mechanisms and therapeutic strategies. The actions of molecular therapies for DM1 at different pathogenetic levels are illustrated: (1) at DMPK gene, drugs can inhibit CTG-repeat transcription and induce repeat contraction; ZFN, TALEN or CRISPR/Cas9 nucleases can modify gene sequence by inducing CTG-repeat contractions or deletions, or by inserting premature polyadenylation signals; (2) mutated DMPK mRNA can be functionally inactivated by drugs inducing degradation or binding to CUG repeats; (3) MBNL can be released from CUG repeats by disruption of MBNL:CUG interaction through competitive binding, and CELF levels can be regulated by protein kinase C and glycogen synthase kinase 3β; (4) altered signaling pathways downstream of DMPK transcript can be rescued by modulation of splicing and miRNAs; circRNAs and RAN translation could also be targets of future therapies.