Title:Therapeutic Approaches for Dominant Muscle Diseases: Highlight on Myotonic Dystrophy
Volume: 15
Issue: 4
Author(s): A. F. Klein, S. Dastidar, D. Furling and M. K. Chuah
Affiliation:
Keywords:
Myotonic dystrophy, DM1, DM2, DMPK, CNBP, CTG repeat, CCTG repeats, MBNL, Gene therapy, Antisense
oligonucleotides.
Abstract: Myotonic Dystrophy (DM), one of the most common neuromuscular disorders
in adults, comprises two genetically distinct forms triggered by unstable expanded
repeats in non-coding regions. The most common DM1 is caused by expanded CTG
repeats in the 3’UTR of the DMPK gene, whereas DM2 is due to large expanded CCTG repeats in the first intron of the
CNBP gene. Both mutations induce a pathogenic RNA gain-of-function mechanism. Mutant RNAs containing CUG or
CCUG expanded repeats, which are retained in the nuclei as aggregates alter activities of alternative splicing regulators
such as MBNL proteins and CELF1. As a consequence, alternative splicing misregulations of several pre-mRNAs are associated
with DM clinical symptoms. Currently, there is no available cure for this dominant neuromuscular disease. Nevertheless,
promising therapeutic strategies have been developed in the last decade. Preclinical progress in DM research
prompted the first DM1 clinical trial based on antisense oligonucleotides promoting a RNase-H-mediated degradation of
the expanded CUG transcripts. The ongoing Phase 1/2a clinical trial will hopefully give further insights into the quest to
find a bona fide cure for DM1. In this review, we will provide an overview of the different strategies that were developed
to neutralize the RNA toxicity in DM1. Different approaches including antisense oligonucleotide technologies, gene
therapies or small molecules have been tested and validated in cellular and animal models. Remaining challenges and additional
avenues to explore will be discussed.
