The therapeutic potential of targeting RNA

Myotonic Dystrophy (DM) is the most common form of muscular dystrophy in adults. Symptoms include muscle weakness and wasting, cataracts, diabetes, and irregular heartbeat. DM is an inherited condition that exists in two forms: DM1 and DM2. Both are caused by a different piece of faulty DNA. Recent experiments point to a common mechanism underlying both forms of DM. In both forms of DM the faulty DNA is made into RNA but this gets stuck in the nucleus and can be seen down the microscope as spots in the cells of DM patients. We have shown that three particular proteins, called muscleblind proteins, are present in the spots in DM cells. We aim to develop methods to study the faulty RNA, which will allow the development of assays or tests for drugs to treat the disorder. It is possible that the methods developed here may be applied to other human disorders.

Myotonic Dystrophy (DM) is the most common form of muscular dystrophy affecting adults. Symptoms include muscle weakness and wasting, myotonia, cardiac arrhythmias, diabetes, cataracts and premature balding in men. Two different mutations cause this condition. In 98 per cent of patients the disease is associated with a triplet repeat (CTG) expansion in the 3? untranslated region of the DMPK gene (DM1). In two percent the underlying mutation is a tetranucleotide (CCTG) expansion in an intron of the gene ZNF9 (DM2). In both cases the faulty gene is transcribed but the mutant RNA is trapped in the nuclei of DM cells, forming foci, which sequester muscleblind-like proteins. We propose a series of experiments to examine synthetic repeat-containing RNAs and in-vitro transcribed repeat expansion RNAs. We will produce the mutant RNAs and label them, and interacting molecules, using fluorophores to establish the methods to screen in vitro for compounds that may be useful as a therapy for DM. We hope to extend this work in the future to other mutant RNAs in human disease.