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

Carlotta Bon, Riccardo Luffarelli, Roberta Russo, Silvia Fortuni, Bianca Pierattini, Chiara Santulli, Cristina Fimiani, Francesca Persichetti, Diego Cotella, Antonello Mallamaci, Claudio Santoro, Piero Carninci, Stefano Espinoza, Roberto Testi, Silvia Zucchelli, Ivano Condò, Stefano Gustincich; Nucleic Acids Research, , gkz798, doi:10.1093/nar/gkz798

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