SINEUP non-coding RNAs rescue defective frataxin expression and activity in a cellular model of Friedreich's Ataxia. Issue 20 (4th October 2019)

• Record Type: Journal Article
• Authors: Bon, Carlotta; Luffarelli, Riccardo; Russo, Roberta; Fortuni, Silvia; Pierattini, Bianca; Santulli, Chiara; Fimiani, Cristina; Persichetti, Francesca; Cotella, Diego; Mallamaci, Antonello; Santoro, Claudio; Carninci, Piero; Espinoza, Stefano; Testi, Roberto; Zucchelli, Silvia; Condò, Ivano; Gustincich, Stefano
• Is Part Of: Nucleic acids research. Volume 47:Issue 20(2019)
• Page Start: 10728
• Page End: 10743
• Publication Date: 2019-10-04
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkz798
• Languages: English
• ISSNs: 0305-1048

Abstract

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.