Myotonic Dystrophy: Therapeutic Strategies for the Future

Abstract

Summary: Myotonic dystrophy (DM) is a dominantly inherited neurodegenerative disorder for which there is no cure or effective treatment. Investigation of DM pathogenesis has identified a novel disease mechanism that requires development of innovative therapeutic strategies. It is now clear that DM is not caused by expression of a mutant protein. Instead, DM is the first recognized example of an RNA-mediated disease. Expression of the mutated gene gives rise to an expanded repeat RNA that is directly toxic to cells. The mutant RNA is retained in the nucleus, forming ribonuclear inclusions in affected tissue. A primary consequence of RNA toxicity in DM is dysfunction of two classes of RNA binding proteins, which leads to abnormal regulation of alternative splicing, or spliceopathy, of select genes. Spliceopathy now is known to cause myotonia and insulin resistance in DM. As our understanding of pathogenesis continues to improve, therapy targeted directly at the RNA disease mechanism will begin to replace the supportive care currently available. New pharmacologic approaches to treat myotonia and muscle wasting in DM type 1 are already in early clinical trials, and therapies designed to reverse the RNA toxicity have shown promise in preclinical models by correcting spliceopathy and eliminating myotonia. The well-defined ribonuclear inclusions may serve as convenient therapeutic targets to identify new agents that modify RNA toxicity. Continued development of appropriate model systems will allow testing of additional therapeutic strategies as they become available. Although DM is a decidedly complex disorder, its RNA-mediated disease mechanism may prove to be highly susceptible to therapy.

Emerging role for PLCβ1 MiRNA and disease

“…The presence of the mutated gene produces an expanded repeat RNA that is highly noxious to cells. The mutant RNA is accumulated in the nucleus compartment, originating ribonuclear clusters in pathological tissue [19] . There are two types of DM caused by microsatellite expansions in two different genes.…”

Myotone Dystrophien – und ihre Differenzialdiagnosen

“…B. mit Tolperison, Methocarbamol, Gabapentin, Pregabalin, L-Dopa, Azetazolamid, Amytryptilin, Mirtazapin oder Citalopram erfolgreich behandelt. Opiate und nichtopiathaltige Schmerzmittel sowie Antiphlogistika sind meist unwirksam [13,14,15,16,19]. Systematische Studien fehlen.…”

RNA Mapping of Mutant Myotonic Dystrophy Protein Kinase 3'-Untranslated Region Transcripts

“…Recently, several gene therapy protocols, based on inhibitory RNA or short oligonucleotides that target the toxic mDMPK transcript, have been described for DM1 therapy (Wheeler, 2008). For the successful application of the RNA-or oligonucleotide-mediated strategies to clinical DM1 treatment, specificity, safety, and efficacy, in addition to delivery issues, are important criteria to be considered.…”

“…Another developed ribozyme that targets downstream of the expanded CUG repeats (Rib 854) could be useful to replace the toxic RNA that is entrapped in the nucleus with RNA that can be released into the cytoplasm. Recent findings showed that mDMPK 3'-UTR that is aberrantly retained in the nucleus could be transported extensively to the cytoplasm when it has attached to its 3'-end the woodchuck posttranscriptional regulatory element (WPRE), which can naturally accumulate hepatitis transcripts in the cytoplasm, resulting in an increase in myoblast differentiation whose initiation is failed in mutant 3'-UTR-expressing cells (Mastroyiannopoulos et al, 2005 and2008).…”

“…The pathogenesis of DM1 is directly mediated by a toxic mDMPK RNA that is entrapped in the affected cell nucleus. A number of pieces of evidence suggest that pleiotropic effects of aberrant interactions between the mDMPK transcripts that are retained in the nucleus and RNAbinding proteins, such as muscleblind-like 1, change the metabolism of target mRNAs, including splicing (Wheeler, 2008). Additively, decreased DMPK protein levels in DM1 patients due to loss of cytoplasm-localized mRNA for translation could cause physiological and functional alterations in phosphorylation of target proteins, including CUG-binding protein 1, and hence has been suggested as a contributor to the pathology of the disease (Kaliman and Llagostera, 2008).…”