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

J Clin Invest. 2023 Nov 15;133(22):e164792. 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.

Keywords: Genetic diseases; Neuroscience; Noncoding RNAs; Therapeutics; Transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA
  • Humans
  • Huntington Disease* / drug therapy
  • Huntington Disease* / genetics
  • Imidazoles / pharmacology
  • Mice
  • Myotonic Dystrophy* / genetics
  • Nylons / pharmacology
  • RNA / genetics
  • Trinucleotide Repeat Expansion / genetics
  • Trinucleotide Repeats


  • RNA
  • Nylons
  • prostaglandin-inositol cyclic phosphate
  • DNA
  • Imidazoles

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