Lead compound discovery for myotonic dystrophy

Myotonic dystrophy is a debilitating genetic disorder which currently does not have a therapeutic treatment. It is understood that CTG expansions lead to formation of stable poly(CUG) mRNA which mislocalize splicing factors such as MBNL1 and lead to missplicing in the cell. One therapeutic strategy is to target such mutant mRNA with small molecules to prevent the sequestration of splicing factors which will prevent the multiple missplicing events in the cell and rescue the symptoms of the disorder. In the following thesis I describe my work in identifying small molecule inhibitors of the RNA-protein complex through the optimization of gel shift assays for characterization of rationally-designed compounds and the development of a fluorescence anisotropy assay for a high-throughput screening of the NCI Diversity Set III compound library. From such studies I was able to identify several lead compounds that are successful at inhibiting the pathological nuclear aggregation