title: Targeting CAG repeat RNAs reduces Huntington's disease phenotype independently of huntingtin levels.
abstract: Huntington's disease (HD) is a polyglutamine disorder caused by a CAG expansion in the Huntingtin (HTT) gene exon 1. This expansion encodes a mutant protein whose abnormal function is traditionally associated with HD pathogenesis; however, recent evidence has also linked HD pathogenesis to RNA stable hairpins formed by the mutant HTT expansion. Here, we have shown that a locked nucleic acid-modified antisense oligonucleotide complementary to the CAG repeat (LNA-CTG) preferentially binds to mutant HTT without affecting HTT mRNA or protein levels. LNA-CTGs produced rapid and sustained improvement of motor deficits in an R6/2 mouse HD model that was paralleled by persistent binding of LNA-CTG to the expanded HTT exon 1 transgene. Motor improvement was accompanied by a pronounced recovery in the levels of several striatal neuronal markers severely impaired in R6/2 mice. Furthermore, in R6/2 mice, LNA-CTG blocked several pathogenic mechanisms caused by expanded CAG RNA, including small RNA toxicity and decreased Rn45s expression levels. These results suggest that LNA-CTGs promote neuroprotection by blocking the detrimental activity of CAG repeats within HTT mRNA. The present data emphasize the relevance of expanded CAG RNA to HD pathogenesis, indicate that inhibition of HTT expression is not required to reverse motor deficits, and further suggest a therapeutic potential for LNA-CTG in polyglutamine disorders.
authors.forename: Laura
authors.initials: L
authors.lastname: Rué
authors.forename: Mónica
authors.initials: M
authors.lastname: Bañez-Coronel
authors.forename: Jordi
authors.initials: J
authors.lastname: Creus-Muncunill
authors.forename: Albert
authors.initials: A
authors.lastname: Giralt
authors.forename: Rafael
authors.initials: R
authors.lastname: Alcalá-Vida
authors.forename: Gartze
authors.initials: G
authors.lastname: Mentxaka
authors.forename: Birgit
authors.initials: B
authors.lastname: Kagerbauer
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Zomeño-Abellán
authors.forename: Zeus
authors.initials: Z
authors.lastname: Aranda
authors.forename: Veronica
authors.initials: V
authors.lastname: Venturi
authors.forename: Esther
authors.initials: E
authors.lastname: Pérez-Navarro
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
authors.forename: Eulàlia
authors.initials: E
authors.lastname: Martí
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D000071058:Huntingtin Protein / Q000096:biosynthesis / Q000235:genetics; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016372:RNA, Antisense / Q000235:genetics / Q000494:pharmacology; D018911:Trinucleotide Repeats
chemical_list: C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D016372:RNA, Antisense