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ResearchIn-Press PreviewNeuroscienceTherapeutics
Open Access | 10.1172/JCI164792
1Department of Genomic Neurology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
2Liaison Laboratory Research Promotion Center, Kumamoto University, Kumamoto, Japan
3Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, Japan
4Division of Developmental Genetics, Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan
5Department of Neurology, Kumamoto University, Kumamoto, Japan
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Ikenoshita, S.
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1Department of Genomic Neurology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
2Liaison Laboratory Research Promotion Center, Kumamoto University, Kumamoto, Japan
3Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, Japan
4Division of Developmental Genetics, Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan
5Department of Neurology, Kumamoto University, Kumamoto, Japan
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Matsuo, K.
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1Department of Genomic Neurology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
2Liaison Laboratory Research Promotion Center, Kumamoto University, Kumamoto, Japan
3Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, Japan
4Division of Developmental Genetics, Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan
5Department of Neurology, Kumamoto University, Kumamoto, Japan
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1Department of Genomic Neurology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
2Liaison Laboratory Research Promotion Center, Kumamoto University, Kumamoto, Japan
3Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, Japan
4Division of Developmental Genetics, Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan
5Department of Neurology, Kumamoto University, Kumamoto, Japan
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Kawakubo, K.
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1Department of Genomic Neurology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
2Liaison Laboratory Research Promotion Center, Kumamoto University, Kumamoto, Japan
3Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, Japan
4Division of Developmental Genetics, Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan
5Department of Neurology, Kumamoto University, Kumamoto, Japan
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Asamitsu, S.
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1Department of Genomic Neurology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
2Liaison Laboratory Research Promotion Center, Kumamoto University, Kumamoto, Japan
3Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, Japan
4Division of Developmental Genetics, Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan
5Department of Neurology, Kumamoto University, Kumamoto, Japan
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1Department of Genomic Neurology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
2Liaison Laboratory Research Promotion Center, Kumamoto University, Kumamoto, Japan
3Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, Japan
4Division of Developmental Genetics, Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan
5Department of Neurology, Kumamoto University, Kumamoto, Japan
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Usuki, S.
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1Department of Genomic Neurology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
2Liaison Laboratory Research Promotion Center, Kumamoto University, Kumamoto, Japan
3Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, Japan
4Division of Developmental Genetics, Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan
5Department of Neurology, Kumamoto University, Kumamoto, Japan
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Hirose, Y.
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1Department of Genomic Neurology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
2Liaison Laboratory Research Promotion Center, Kumamoto University, Kumamoto, Japan
3Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, Japan
4Division of Developmental Genetics, Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan
5Department of Neurology, Kumamoto University, Kumamoto, Japan
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1Department of Genomic Neurology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
2Liaison Laboratory Research Promotion Center, Kumamoto University, Kumamoto, Japan
3Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, Japan
4Division of Developmental Genetics, Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan
5Department of Neurology, Kumamoto University, Kumamoto, Japan
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Araki, K.
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1Department of Genomic Neurology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
2Liaison Laboratory Research Promotion Center, Kumamoto University, Kumamoto, Japan
3Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, Japan
4Division of Developmental Genetics, Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan
5Department of Neurology, Kumamoto University, Kumamoto, Japan
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Ueda, M.
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1Department of Genomic Neurology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
2Liaison Laboratory Research Promotion Center, Kumamoto University, Kumamoto, Japan
3Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, Japan
4Division of Developmental Genetics, Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan
5Department of Neurology, Kumamoto University, Kumamoto, Japan
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Sugiyama, H.
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1Department of Genomic Neurology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
2Liaison Laboratory Research Promotion Center, Kumamoto University, Kumamoto, Japan
3Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, Japan
4Division of Developmental Genetics, Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan
5Department of Neurology, Kumamoto University, Kumamoto, Japan
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Shioda, N.
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Published September 14, 2023 - More info
Expansion of CAG and CTG (CWG) triplet repeats causes several inherited neurological diseases. The CWG repeat diseases are thought to involve complex pathogenic mechanisms through expanded CWG repeat-derived RNAs in a non-coding and polypeptides in a coding region, respectively. However, an effective therapeutic approach has not been established for the CWG repeat diseases. Here, we show that a CWG repeat DNA-targeting compound, cyclic pyrrole¬–imidazole polyamide (CWG-cPIP), suppresses the pathogenesis of coding and non-coding CWG repeat diseases. CWG-cPIP binds to the hairpin form of mismatched CWG DNA, interfering with transcription elongation by RNA polymerase through a preferential activity towards repeat-expanded DNA. We found that CWG-cPIP selectively inhibits pathogenic mRNA transcripts from expanded CWG repeats, reducing CUG RNA foci and polyglutamine accumulation in cells from patients with myotonic dystrophy type-1 (DM1) and Huntington’s disease (HD). Treatment with CWG-cPIP ameliorated behavioral deficits in adeno-associated virus-mediated CWG repeat-expressing mice and a genetic mouse model of HD, without cytotoxicity or off-target effects. Together, we present a novel candidate compound that targets expanded CWG repeat DNA independent of its genomic location and reduces both pathogenic RNA and protein levels. CWG-cPIP may be used for the treatment of CWG repeat diseases and for improving clinical outcomes.