Journal Article

Targeting Several CAG Expansion Diseases by a Single Antisense Oligonucleotide

Aartsma-Rus, Annemieke, van Deutekom, Judith C. T., den Dunnen, Johan T., Pepers, Barry A., van Ommen, Gert-Jan B., van Roon-Mom, Willeke M. C., Evers, Melvin M., Mulders, Susan A. M.

2011

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acids / Antisense oligonucleotides / Ataxia / Ataxin / Ataxin-1 / Ataxin-3 / Ataxins / Atrophy / Biology / Cell Line / Dentatorubral-pallidoluysian atrophy / Expansion / Fibroblasts / Fibroblasts - drug effects / Fibroblasts - metabolism / Fibroblasts - pathology / Gene Expression Regulation - drug effects / Genomes / Glutamine / Hereditary diseases / Humans / Huntingtin / Huntingtin Protein / Huntington's disease / Huntingtons disease / Lymphoblasts / Machado-Joseph disease / Mathematical models / MicroRNAs / Molecular Targeted Therapy / Muscular dystrophy / Mutant Proteins - genetics / Mutant Proteins - metabolism / Myoclonic Epilepsies, Progressive - genetics / Nerve Tissue Proteins - genetics / Nerve Tissue Proteins - metabolism / Nervous system diseases / Neurodegeneration / Neurodegenerative diseases / Neurodegenerative Diseases - genetics / Neurodegenerative Diseases - therapy / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Oligonucleotides / Oligonucleotides, Antisense - pharmacology / Peptides - metabolism / Phosphorothioate / Polyglutamine / Proteins / Repressor Proteins - genetics / Repressor Proteins - metabolism / RNA / RNA, Messenger - genetics / RNA, Messenger - metabolism / Rodents / Spinocerebellar ataxia / Spinocerebellar Ataxias - genetics / Transcription / Trinucleotide repeat diseases / Trinucleotide Repeat Expansion - genetics / Trinucleotide repeats