SINEUP non-coding RNAs rescue defective frataxin expression and activity in a cellular model of Friedreich's Ataxia.
Nucleic Acids Res
; 47(20): 10728-10743, 2019 11 18.
Article
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| MEDLINE
| ID: mdl-31584077
ABSTRACT
Friedreich's ataxia (FRDA) is an untreatable disorder with neuro- and cardio-degenerative progression. This monogenic disease is caused by the hyper-expansion of naturally occurring GAA repeats in the first intron of the FXN gene, encoding for frataxin, a protein implicated in the biogenesis of iron-sulfur clusters. As the genetic defect interferes with FXN transcription, FRDA patients express a normal frataxin protein but at insufficient levels. Thus, current therapeutic strategies are mostly aimed to restore physiological FXN expression. We have previously described SINEUPs, natural and synthetic antisense long non-coding RNAs, which promote translation of partially overlapping mRNAs through the activity of an embedded SINEB2 domain. Here, by in vitro screening, we have identified a number of SINEUPs targeting human FXN mRNA and capable to up-regulate frataxin protein to physiological amounts acting at the post-transcriptional level. Furthermore, FXN-specific SINEUPs promote the recovery of disease-associated mitochondrial aconitase defects in FRDA-derived cells. In summary, we provide evidence that SINEUPs may be the first gene-specific therapeutic approach to activate FXN translation in FRDA and, more broadly, a novel scalable platform to develop new RNA-based therapies for haploinsufficient diseases.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Ataxia de Friedreich
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Regulación de la Expresión Génica
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ARN no Traducido
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Proteínas de Unión a Hierro
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Modelos Biológicos
Límite:
Humans
Idioma:
En
Revista:
Nucleic Acids Res
Año:
2019
Tipo del documento:
Article
País de afiliación:
Italia