A slipped-CAG DNA-binding small molecule induces trinucleotide-repeat contractions in vivo

Nat Genet. 2020 Feb;52(2):146-159. doi: 10.1038/s41588-019-0575-8. Epub 2020 Feb 14.


In many repeat diseases, such as Huntington's disease (HD), ongoing repeat expansions in affected tissues contribute to disease onset, progression and severity. Inducing contractions of expanded repeats by exogenous agents is not yet possible. Traditional approaches would target proteins driving repeat mutations. Here we report a compound, naphthyridine-azaquinolone (NA), that specifically binds slipped-CAG DNA intermediates of expansion mutations, a previously unsuspected target. NA efficiently induces repeat contractions in HD patient cells as well as en masse contractions in medium spiny neurons of HD mouse striatum. Contractions are specific for the expanded allele, independently of DNA replication, require transcription across the coding CTG strand and arise by blocking repair of CAG slip-outs. NA-induced contractions depend on active expansions driven by MutSβ. NA injections in HD mouse striatum reduce mutant HTT protein aggregates, a biomarker of HD pathogenesis and severity. Repeat-structure-specific DNA ligands are a novel avenue to contract expanded repeats.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Corpus Striatum / drug effects
  • DNA / metabolism
  • DNA Mismatch Repair / drug effects
  • DNA Replication / drug effects
  • Disease Models, Animal
  • Humans
  • Huntingtin Protein / genetics*
  • Huntingtin Protein / metabolism
  • Huntington Disease / drug therapy
  • Huntington Disease / genetics*
  • Huntington Disease / pathology
  • Male
  • Mice
  • Mice, Transgenic
  • Microsatellite Instability
  • Mutation
  • Naphthyridines / pharmacology*
  • Quinolones / pharmacology*
  • Ribonucleases / metabolism
  • TATA-Box Binding Protein / genetics
  • Transcription, Genetic
  • Trinucleotide Repeat Expansion / drug effects*


  • HTT protein, human
  • Htt protein, mouse
  • Huntingtin Protein
  • Naphthyridines
  • Quinolones
  • TATA-Box Binding Protein
  • TBP protein, human
  • naphthyridine-azaquinolone
  • DNA
  • Ribonucleases