Targeting several CAG expansion diseases by a single antisense oligonucleotide.

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To date there are 9 known diseases caused by an expanded polyglutamine repeat , with the most prevalent being Huntington 's disease . Huntington 's disease is a progressive autosomal dominant neurodegenerative disorder for which currently no therapy is available . It is caused by a CAG repeat expansion in the HTT gene , which results in an expansion of a glutamine stretch at the N-terminal end of the huntingtin protein . This polyglutamine expansion plays a central role in the disease and results in the accumulation of cytoplasmic and nuclear aggregates . Here , we make use of modified 2 '-O-methyl phosphorothioate (CUG )n triplet-repeat antisense oligonucleotides to effectively reduce mutant huntingtin transcript and protein levels in patient-derived Huntington 's disease fibroblasts and lymphoblasts . The most effective antisense oligonucleotide , (CUG )(7 ), also reduced mutant ataxin-1 and ataxin-3 mRNA levels in spinocerebellar ataxia 1 and 3 , respectively , and atrophin-1 in dentatorubral-pallidoluysian atrophy patient derived fibroblasts . This antisense oligonucleotide is not only a promising therapeutic tool to reduce mutant huntingtin levels in Huntington 's disease but our results in spinocerebellar ataxia and dentatorubral-pallidoluysian atrophy cells suggest that this could also be applicable to other polyglutamine expansion disorders as well .