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

• Published in: The Journal of clinical investigation 2023-11, Vol.133 (22), p.1-14
• Main Authors: Ikenoshita, Susumu, Matsuo, Kazuya, Yabuki, Yasushi, Kawakubo, Kosuke, Asamitsu, Sefan, Hori, Karin, Usuki, Shingo, Hirose, Yuki, Bando, Toshikazu, Araki, Kimi, Ueda, Mitsuharu, Sugiyama, Hiroshi, Shioda, Norifumi
• Format: Article
• Language: English
• Subjects: Analysis; Animal models; Animals; Biomedical research; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA-directed RNA polymerase; Genes; Genetic aspects; Genetic transcription; Health aspects; Humans; Huntington Disease - drug therapy; Huntington Disease - genetics; Huntington's disease; Huntingtons disease; Imidazole; Imidazoles - pharmacology; Messenger RNA; Mice; Microsatellites (Genetics); Myotonic dystrophy; Myotonic Dystrophy - genetics; Nervous system diseases; Neurological diseases; Non-coding RNA; Nylons - pharmacology; Pathogenesis; Polyamides; Polyglutamine; Polypeptides; Proteins; RNA; RNA - genetics; RNA polymerase; Toxicity; Transcription elongation; Trinucleotide repeat diseases; Trinucleotide Repeat Expansion - genetics; Trinucleotide Repeats; Viroids
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI164792

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 noncoding region 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), suppressed the pathogenesis of coding and noncoding CWG repeat diseases. CWG-cPIP bound to the hairpin form of mismatched CWG DNA, interfering with transcription elongation by RNA polymerase through a preferential activity toward repeat-expanded DNA. We found that CWG-cPIP selectively inhibited 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 in a genetic mouse model of HD, without cytotoxicity or off-target effects. Together, we present a candidate compound that targets expanded CWG repeat DNA independently 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 improvement of clinical outcomes.