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.

SINEUP non-coding RNAs rescue defective frataxin expression and activity in a cellular model of Friedreich's Ataxia / 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.. - In: NUCLEIC ACIDS RESEARCH. - ISSN 1362-4962. - 47:20(2019), pp. 10728-10743. [10.1093/nar/gkz798]

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

Bon, C.;Pierattini, B.;Santulli, C.;Fimiani, C.;Mallamaci, A.;Zucchelli, S.;Gustincich, S.
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
47
20
10728
10743
10.1093/nar/gkz798
https://academic.oup.com/nar/article/47/20/10728/5580914
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/20.500.11767/117891
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