Myotonic dystrophy (DM) is the most common inherited neuromuscular disorder in adults. There are two types, DM1 and DM2, both being autosomal dominant disorders caused by expansions of microsatellite repeats within non-coding regions of their respective genes. DM1 is far more common; however both forms of DM are likely to share similar pathogenic mechanisms. The DM1 mutation is an expansion of a CTG triplet repeat in the 3' untranslated region (3'UTR) of the DM protein kinase (DMPK) gene. A prevailing hypothesis in the field is that many aspects of DM are caused by the expression of the mutant mRNA. DM1 and DM2 represent the first examples of toxic RNA mediated disease pathogenesis. We have already developed and characterized extensively, a myoblast cell culture model to clearly demonstrate the toxic effects of the mutant DMPK mRNA on muscle differentiation. To study the hypothesis further, the aims of this proposal are to develop and characterize an inducible transgenic mouse model of RNA toxicity for DM type 1 (DM1) and to develop a siRNA (small interfering RNA) therapeutic approach to get rid of the toxic RNA which can be tested in both our cell culture and transgenic animal models. The development of transgenic mouse models will aid in understanding disease pathogenesis and will also provide a system with which to test out potential therapeutic .strategies. The ability to control gene expression through an inducible system will enable better characterization of and better correlation with the onset and levels of expression of the toxic RNA in DM1 and disease outcomes. Most importantly, because of this property, this model will be one of the first in which we can directly test, at the level of a whole organism, if ablation of expression of the toxic RNA after a period of exposure can reverse its toxic effects. All DM patients have endured exposure to the toxic RNA from birth and thus a model such as this one will be able to provide valuable and relevant insight into this therapeutic strategy.
