Development of Therapeutic Approaches for Myotonic Dystrophies Type 1 and Type 2

Abstract

Myotonic Dystrophies type 1 (DM1) and type 2 (DM2) are complex multisystem diseases without disease-based therapies. These disorders are caused by the expansions of unstable CTG (DM1) and CCTG (DM2) repeats outside of the coding regions of the disease genes: DMPK in DM1 and CNBP in DM2. Multiple clinical and molecular studies provided a consensus for DM1 pathogenesis, showing that the molecular pathophysiology of DM1 is associated with the toxicity of RNA CUG repeats, which cause multiple disturbances in RNA metabolism in patients’ cells. As a result, splicing, translation, RNA stability and transcription of multiple genes are misregulated in DM1 cells. While mutant CCUG repeats are the main cause of DM2, additional factors might play a role in DM2 pathogenesis. This review describes current progress in the translation of mechanistic knowledge in DM1 and DM2 to clinical trials, with a focus on the development of disease-specific therapies for patients with adult forms of DM1 and congenital DM1 (CDM1).

Bruno 1/CELF regulates splicing and cytoskeleton dynamics to ensure correct sarcomere assembly in Drosophila flight muscles

“…When we rescued the bru1 M3 mutant with Fln-Gal4 driven UAS-Bru1, we were able to largely restore mature patterns of alternative splicing and partially abrogate hypercontraction and myofiber loss, but we could not rescue myofibril and sarcomere structural defects ( Fig 8 ). Given the parallels between Bru1 and CELF1 function in flies and vertebrates, our results provide mechanistic insight into the variable efficacy and phenotypes observed during the development of DM1 therapeutics [ 141 , 142 ]. Current nucleic acid therapeutics or genome modification approaches are focused on restoring MBNL function by increasing MBNL expression levels, blocking MBNL binding to CTG-repeats or editing the DMPK locus [ 143 , 144 ], in turn decreasing CELF1 activity.…”

Modeling Myotonic Dystrophy Type 2 Using Drosophila melanogaster

“…The finding that these two distinct mutations cause largely similar clinical syndromes has highlighted that they share similar molecular mechanisms [ 30 ]. However, additional pathogenic mechanisms like changes in gene expression, microRNA, epigenetic modifications, protein translation, and metabolism may contribute to disease pathology and clarify the phenotypic differences between these two types of myotonic dystrophies [ 1 ].…”

Expert Insights from a Delphi-driven Neurologists’ Panel: Real-world Mexiletine use in Patients with Myotonic Disorders in Italy

“…NDM onset is usually at a young age, and patients report muscle stiffness, weakness, fatigue, and pain with a different magnitude and frequency depending on the ion channel carrying the genetic mutation [ 4 ]. For DM1, clinical symptoms may also begin in childhood and are multisystemic, manifesting in heart defects, cognitive impairment, respiratory and gastrointestinal disorders, and myotonia, and are characterized by progressive muscle wasting and weakness [ 11 ]. DM2 symptoms are similar to DM1, with muscle pain being a prominent feature.…”