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

In many repeat diseases, like 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, independent of DNA replication, require transcription across the coding CTG strand, and arise by blocking repair of CAG slip-outs. NA-induced contractions depend upon 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.