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ResearchIn-Press PreviewNeuroscienceTherapeutics Open Access | 10.1172/JCI164792

A cyclic pyrrole-imidazole polyamide reduces pathogenic RNA in CAG/CTG triplet repeat neurological disease models

Susumu Ikenoshita,1 Kazuya Matsuo,1 Yasushi Yabuki,1 Kosuke Kawakubo,1 Sefan Asamitsu,1 Karin Hori,1 Shingo Usuki,2 Yuki Hirose,3 Toshikazu Bando,3 Kimi Araki,4 Mitsuharu Ueda,5 Hiroshi Sugiyama,3 and Norifumi Shioda1

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

Find articles by Ikenoshita, S. in: JCI | PubMed | Google Scholar |

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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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

Find articles by Kawakubo, K. in: JCI | PubMed | Google Scholar |

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

Find articles by Asamitsu, S. in: JCI | PubMed | Google Scholar |

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

Find articles by Hori, K. in: JCI | PubMed | Google Scholar

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

Find articles by Usuki, S. in: JCI | PubMed | Google Scholar |

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

Find articles by Hirose, Y. in: JCI | PubMed | Google Scholar |

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

Find articles by Bando, T. in: JCI | PubMed | Google Scholar

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

Find articles by Araki, K. in: JCI | PubMed | Google Scholar |

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

Find articles by Ueda, M. in: JCI | PubMed | Google Scholar |

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

Find articles by Sugiyama, H. in: JCI | PubMed | Google Scholar |

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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Published September 14, 2023 - More info

J Clin Invest. https://doi.org/10.1172/JCI164792.
Copyright © 2023, Ikenoshita et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 14, 2023 - Version history
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Abstract

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.

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Version history
  • Version 1 (September 14, 2023): In-Press Preview
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