Suppression of Mutant Protein Expression in SCA3 and SCA1 Mice Using a CAG Repeat-Targeting Antisense Oligonucleotide.
CAG repeat
SCA1
SCA3
antisense oligonucleotide
exon skip
polyglutamine disorders
Journal
Molecular therapy. Nucleic acids
ISSN: 2162-2531
Titre abrégé: Mol Ther Nucleic Acids
Pays: United States
ID NLM: 101581621
Informations de publication
Date de publication:
06 Sep 2019
06 Sep 2019
Historique:
received:
21
05
2019
revised:
26
06
2019
accepted:
08
07
2019
pubmed:
9
8
2019
medline:
9
8
2019
entrez:
9
8
2019
Statut:
ppublish
Résumé
Spinocerebellar ataxia type 3 (SCA3) and type 1 (SCA1) are dominantly inherited neurodegenerative disorders that are currently incurable. Both diseases are caused by a CAG-repeat expansion in exon 10 of the Ataxin-3 and exon 8 of the Ataxin-1 gene, respectively, encoding an elongated polyglutamine tract that confers toxic properties to the resulting proteins. We have previously shown lowering of the pathogenic polyglutamine protein in Huntington's disease mouse models using (CUG)7, a CAG repeat-targeting antisense oligonucleotide. Here we evaluated the therapeutic capacity of (CUG)7 for SCA3 and SCA1, in vitro in patient-derived cell lines and in vivo in representative mouse models. Repeated intracerebroventricular (CUG)7 administration resulted in a significant reduction of mutant Ataxin-3 and Ataxin-1 proteins throughout the brain of SCA3 and SCA1 mouse models, respectively. Furthermore, in both a SCA3 patient cell line and the MJD84.2 mouse model, (CUG)7 induced formation of a truncated Ataxin-3 protein species lacking the polyglutamine stretch, likely arising from (CUG)7-mediated exon 10 skipping. In contrast, skipping of exon 8 of Ataxin-1 did not significantly contribute to the Ataxin-1 protein reduction observed in (CUG)7-treated SCA1
Identifiants
pubmed: 31394429
pii: S2162-2531(19)30194-5
doi: 10.1016/j.omtn.2019.07.004
pmc: PMC6695277
pii:
doi:
Types de publication
Journal Article
Langues
eng
Pagination
601-614Informations de copyright
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
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