CAG repeat-binding small molecule improves motor coordination impairment in a mouse model of Dentatorubral-pallidoluysian atrophy.

Dentatorubral-pallidoluysian atrophy (DRPLA) is a devastating genetic disease presenting myoclonus, epilepsy, ataxia, and dementia. DRPLA is caused by the expansion of a CAG repeat in the ATN1 gene. Aggregation of the polyglutamine-expanded ATN1 protein causes neuro-degeneration of the dentatorubral and pallidoluysian systems. The expanded CAG repeats are unstable, and ongoing repeat expansions contribute to disease onset, progression, and severity. Inducing contractions of expanded repeats can be a means to treat DRPLA, for which no disease-modifying or curative therapies exist at present. Previously, we characterized a small molecule, naphthyridine-azaquinolone (NA), which binds to CAG slip-out structures and induces repeat contraction in Huntington's disease mice. Here, we demonstrate that long-term intracerebroventricular infusion of NA leads to repeat contraction, reductions in mutant ATN1 aggregation, and improved motor phenotype in a murine model of DRPLA. Furthermore, NA-induced contraction resulted in the modification of repeat-length-dependent dysregulation of gene expression profiles in DRPLA mice. Our study reveals the therapeutic potential of repeat contracting small molecules for repeat expansion disorders, such as DRPLA.

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

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 MutSß. 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.