title: Mutant CAG Repeats Effectively Targeted by RNA Interference in SCA7 Cells.
abstract: Spinocerebellar ataxia type 7 (SCA7) is a human neurodegenerative polyglutamine (polyQ) disease caused by a CAG repeat expansion in the open reading frame of theATXN7gene. The allele-selective silencing of mutant transcripts using a repeat-targeting strategy has previously been used for several polyQ diseases. Herein, we demonstrate that the selective targeting of a repeat tract in a mutantATXN7transcript by RNA interference is a feasible approach and results in an efficient decrease of mutant ataxin-7 protein in patient-derived cells. Oligonucleotides (ONs) containing specific base substitutions cause the downregulation of theATXN7mutant allele together with the upregulation of its normal allele. The A2 ON shows high allele selectivity at a broad range of concentrations and also restoresUCHL1expression, which is downregulated in SCA7.
authors.affiliation: Department of Molecular Biomedicine, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14 Str., 61-704 Poznan, Poland. agaban@ibch.poznan.pl.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Fiszer
authors.affiliation: Department of Molecular Biomedicine, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14 Str., 61-704 Poznan, Poland. wroblewska.jp@gmail.com.
authors.forename: Joanna P
authors.initials: JP
authors.lastname: Wroblewska
authors.affiliation: Department of Molecular Biomedicine, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14 Str., 61-704 Poznan, Poland. poz.bartosznowak@gmail.com.
authors.forename: Bartosz M
authors.initials: BM
authors.lastname: Nowak
authors.affiliation: Department of Molecular Biomedicine, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14 Str., 61-704 Poznan, Poland. wlodkrzy@ibch.poznan.pl.
authors.forename: Wlodzimierz J
authors.initials: WJ
authors.lastname: Krzyzosiak
keywords: CAG repeats; allele-selective silencing; polyglutamine diseases; siRNA; spinocerebellar ataxia type 7