Suppression of Mutant Protein Expression in SCA3 and SCA1 Mice Using a CAG Repeat-Targeting Antisense Oligonucleotide.

Suppression of Mutant Protein Expression in SCA3 and SCA1 Mice Using a CAG Repeat-Targeting Antisense Oligonucleotide.

Publication date: Sep 06, 2019

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 mice. These findings support the therapeutic potential of a single CAG repeat-targeting AON for the treatment of multiple polyglutamine disorders.

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Kourkouta, E., Weij, R., Gonz’alez-Barriga, A., Mulder, M., Verheul, R., Bosgra, S., Groenendaal, B., Puoliv”ali, J., Toivanen, J., van Deutekom, J.C.T., and Datson, N.A. Suppression of Mutant Protein Expression in SCA3 and SCA1 Mice Using a CAG Repeat-Targeting Antisense Oligonucleotide. 06673. 2019 Mol Ther Nucleic Acids (17):

Concepts Keywords
Antisense Oligonucleotide Ataxin 1
Ataxia Neurodegenerative disorders
Brain Trinucleotide repeat disorders
Exon Proteins
Gene Autosomal dominant disorders
Huntington Nervous system
Intracerebroventricular Organ systems
Mice Branches of biology
Mutant Rare diseases
Neurodegenerative Disorders
Nucleic
Oligonucleotide
Pathogenic

Semantics

Type Source Name
gene UNIPROT GKN2
gene UNIPROT INPP5K
gene UNIPROT PLEKHM2
gene UNIPROT SPHKAP
gene UNIPROT SNW1
gene UNIPROT CCAR1
gene UNIPROT ARR3
gene UNIPROT CASR
gene UNIPROT CXADR
gene UNIPROT NR1I3
gene UNIPROT SPG7
gene UNIPROT CSF2
disease DOID spinal muscular atrophy
disease MESH spinal muscular atrophy
pathway BSID Translation
disease MESH Atrophy
gene UNIPROT LARGE1
disease MESH abnormalities
disease MESH gait
gene UNIPROT CAT
gene UNIPROT CRAT
gene UNIPROT GLYAT
gene UNIPROT ATXN7
gene UNIPROT ATXN2
disease DOID spinocerebellar ataxia
gene UNIPROT LY6E
disease MESH point mutations
disease MESH spinocerebellar ataxias
gene UNIPROT NFKBIZ
disease MESH ataxia
gene UNIPROT TNIP1
gene UNIPROT TRIM37
gene UNIPROT CD69
gene UNIPROT DNMT1
gene UNIPROT SLC35G1
gene UNIPROT DESI1
disease MESH pus
disease MESH development
gene UNIPROT HTT
disease MESH trinucleotide repeat expansions
disease MESH **p
drug DRUGBANK Proline
gene UNIPROT OCA2
gene UNIPROT NOVA2
disease DOID spinal bulbar muscular atrophy
gene UNIPROT ST13
gene UNIPROT REG3A
gene UNIPROT HHIP
gene UNIPROT DEPP1
gene UNIPROT GOPC
drug DRUGBANK Albendazole
disease MESH stop codon
gene UNIPROT IK
disease DOID Spinocerebellar ataxia type 3
disease MESH neurodegenerative disorders
disease MESH Spinocerebellar ataxia type 3
gene UNIPROT ATXN3
gene UNIPROT ATXN1
disease DOID muscular dystrophy
disease MESH muscular dystrophy
gene UNIPROT SRSF6
drug DRUGBANK Amino acids

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