Targeting Several CAG Expansion Diseases by a Single Antisense Oligonucleotide

PLoS One

Barry A. Pepers¹  Johan T. den Dunnen¹  Melvin M. Evers¹  Gert-Jan B. van Ommen¹  Willeke M. C. van Roon-Mom¹  Annemieke Aartsma-Rus²  Judith C. T. van Deutekom³  Susan A. M. Mulders³ 

[1] Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands;Leiden Genome Technology Center, Leiden University Medical Center, Leiden, The Netherlands;Prosensa Therapeutics B.V., Leiden, The Netherlands

关键词: Transfection;    Fibroblasts;    Messenger RNA;    Polymerase chain reaction;    Small interfering RNAs;    Cultured fibroblasts;    Gel electrophoresis;    Huntington disease;   

DOI  :  10.1371/journal.pone.0024308

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY