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.

Bon, C., Luffarelli, R., Russo, R., Fortuni, S., Pierattini, B., Santulli, C., et al. (2019). SINEUP non-coding RNAs rescue defective frataxin expression and activity in a cellular model of Friedreich's Ataxia. NUCLEIC ACIDS RESEARCH, 47(20), 10728-10743 [10.1093/nar/gkz798].

SINEUP non-coding RNAs rescue defective frataxin expression and activity in a cellular model of Friedreich's Ataxia

Luffarelli R.;Fortuni S.;Testi R.;Condo I.
;
2019-01-01

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.
2019
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/04 - PATOLOGIA GENERALE
Settore BIO/13 - BIOLOGIA APPLICATA
English
Con Impact Factor ISI
https://academic.oup.com/nar/article/47/20/10728/5580914
Bon, C., Luffarelli, R., Russo, R., Fortuni, S., Pierattini, B., Santulli, C., et al. (2019). SINEUP non-coding RNAs rescue defective frataxin expression and activity in a cellular model of Friedreich's Ataxia. NUCLEIC ACIDS RESEARCH, 47(20), 10728-10743 [10.1093/nar/gkz798].
Bon, C; Luffarelli, R; Russo, R; Fortuni, S; Pierattini, B; Santulli, C; Fimiani, C; Persichetti, F; Cotella, D; Mallamaci, A; Santoro, C; Carninci, P; Espinoza, S; Testi, R; Zucchelli, S; Condo, I; Gustincich, S
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/227058
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