Therapeutic Approaches for Dominant Muscle Diseases: Highlight on Myotonic Dystrophy.

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.

Gain of RNA function in pathological cases: Focus on myotonic dystrophy.

Expansion of repeated sequences in non-coding regions of different genes causes a number of inherited diseases including myotonic dystrophies, Huntington disease-like 2, Fragile X tremor/ataxia syndrome and spinocerebellar ataxia 8, 10, 12, 31. Involvement of an RNA gain-of-function mechanism in pathological case has been described and studied in-depth in myotonic dystrophy type 1 (DM1). This inherited neuromuscular disorder is caused by a (CTG)n >50 expansion in the 3' non-coding region of the dystrophia myotonica-protein kinase (DMPK) gene. Expanded CUG transcripts (CUGexp-RNAs) are sequestered in the nucleus within small aggregates and interfere with the regulatory splicing activities of MBNL1 and CELF1 RNA-binding proteins, leading to the misregulation of the alternative splicing of several transcripts. Despite the relevance of aberrant splicing events in this complex pathology, the CUGexp-RNAs trans-dominant effects alter other splicing-independent processes that may also contribute to DM1 pathogenesis. This review will focus on toxic RNA gain-of-function as a pathologic mechanism for DM1 and other repeat expansion disorders.