title: Targeting several CAG expansion diseases by a single antisense oligonucleotide.
abstract: 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.
authors: Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors: Melvin M
authors: MM
authors: Evers
authors: Barry A
authors: BA
authors: Pepers
authors: Judith C T
authors: JC
authors: van Deutekom
authors: Susan A M
authors: SA
authors: Mulders
authors: Johan T
authors: JT
authors: den Dunnen
authors: Annemieke
authors: A
authors: Aartsma-Rus
authors: Gert-Jan B
authors: GJ
authors: van Ommen
authors: Willeke M C
authors: WM
authors: van Roon-Mom
mesh_terms: D000067696:Ataxin-1; D000067699:Ataxin-3; D000067528:Ataxins; D002460:Cell Line; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D000071058:Huntingtin Protein; D058990:Molecular Targeted Therapy; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D020191:Myoclonic Epilepsies, Progressive / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000628:therapy*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010455:Peptides / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020754:Spinocerebellar Ataxias / Q000235:genetics; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D010455:Peptides; D012333:RNA, Messenger; D012097:Repressor Proteins; C097188:polyglutamine; C092341:ATXN3 protein, human; D000067699:Ataxin-3