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

Masayuki Nakamori, Gagan B. Panigrahi, Stella Lanni, Terence Gall-Duncan, Hideki Hayakawa, Hana Tanaka, Jennifer Luo, Takahiro Otabe, Jinxing Li, Akihiro Sakata, Marie Christine Caron, Niraj Joshi, Tanya Prasolava, Karen Chiang, Jean Yves Masson, Marc S. Wold, Xiaoxiao Wang, Marietta Y.W.T. Lee, John Huddleston, Katherine M. MunsonScott Davidson, Mehdi Layeghifard, Lisa Monique Edward, Richard Gallon, Mauro Santibanez-Koref, Asako Murata, Masanori P. Takahashi, Evan E. Eichler, Adam Shlien, Kazuhiko Nakatani, Hideki Mochizuki, Christopher E. Pearson

Research output: Contribution to journalArticlepeer-review

68 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)146-159
Number of pages14
JournalNature genetics
Issue number2
Publication statusPublished - Feb 1 2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Genetics


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