Stabilization of expanded (CTG)â¢(CAG) repeats by antisense oligonucleotides.
Mol Ther
; 19(12): 2222-7, 2011 Dec.
Article
em En
| MEDLINE
| ID: mdl-21971425
ABSTRACT
Myotonic dystrophy type 1 (DM1) is caused by expansion of a CTG repeat in the gene DMPK. The expansion is highly unstable in somatic cells, a feature that may contribute to disease progression. The RNA expressed from the mutant allele exerts a toxic gain of function, due to the presence of an expanded CUG repeat (CUG(exp)). This RNA dominant mechanism is amenable to therapeutic intervention with antisense oligonucleotides (ASOs). For example, CAG-repeat ASOs that bind CUG(exp) RNA are beneficial in DM1 models by altering the protein interactions or metabolism of the toxic RNA. Because CUG(exp) RNA has been shown to aggravate instability of expanded CTG repeats, we studied whether CAG-repeat ASOs may also affect this aspect of DM1. In human cells the instability of (CTG)(800) was suppressed by addition of CAG-repeat ASOs to the culture media. In mice that carry a DMPK transgene the somatic instability of (CTG)(800) was suppressed by direct injection of CAG-repeat ASOs into muscle tissue. These results raise the possibility that early intervention with ASOs to reduce RNA or protein toxicity may have the additional benefit of stabilizing CTGCAG repeats at subpathogenic lengths.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oligonucleotídeos Antissenso
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Proteínas Serina-Treonina Quinases
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Neoplasias do Colo
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Expansão das Repetições de Trinucleotídeos
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Fibrossarcoma
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Distrofia Miotônica
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article