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      RNA interference targeting CUG repeats in a mouse model of myotonic dystrophy.

      Molecular Therapy

      Trinucleotide Repeat Expansion, metabolism, genetics, RNA-Binding Proteins, RNA, Small Interfering, RNA, Messenger, RNA Interference, Protein-Serine-Threonine Kinases, Myotonin-Protein Kinase, therapy, pathology, Myotonic Dystrophy, Molecular Sequence Data, Microscopy, Fluorescence, Mice, Transgenic, Mice, In Situ Hybridization, Fluorescence, Humans, Fluorescent Antibody Technique, Exons, Electromyography, Disease Models, Animal, DNA-Binding Proteins, chemistry, Cell Nucleus, Cell Line, Tumor, Animals, Amino Acid Sequence, Alternative Splicing

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          Abstract

          Myotonic dystrophy type 1 (DM1) is an RNA dominant disease caused by expression of DM protein kinase (DMPK) transcripts that contain an expanded CUG repeat (CUG(exp)). The toxic mRNA localizes to nuclear foci and sequesters proteins involved in the regulation of alternative splicing, such as, muscleblind-like 1 (MBNL1). Here, we used synthetic short interfering RNAs (siRNAs) to target CUG repeats and test the concept that inhibiting the expression of CUG(exp) RNA can mitigate features of DM1 in transgenic mice. Intramuscular injection and electroporation of siRNA resulted in ~70-80% downregulation of CUG(exp) transcripts. A limited survey of endogenous mouse transcripts that contain nonexpanded CUG or CAG repeats showed that most were not affected, though Txlnb containing (CUG)(9) was significantly reduced. By this strategy, the number and intensity of CUG(exp) nuclear foci were reduced and splicing of MBNL1-dependent exons was improved. These data suggest that the expanded CUG repeats are a potential target for allele-selective RNA interference.

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          Author and article information

          Journal
          23183533
          3594017
          10.1038/mt.2012.222

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