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Activating frataxin expression by repeat-targeted nucleic acids

Liande Li,Masayuki Matsui,D. Corey

Published 2016 in Nature Communications

ABSTRACT

Friedreich’s ataxia is an incurable genetic disorder caused by a mutant expansion of the trinucleotide GAA within an intronic FXN RNA. This expansion leads to reduced expression of frataxin (FXN) protein and evidence suggests that transcriptional repression is caused by an R-loop that forms between the expanded repeat RNA and complementary genomic DNA. Synthetic agents that increase levels of FXN protein might alleviate the disease. We demonstrate that introducing anti-GAA duplex RNAs or single-stranded locked nucleic acids into patient-derived cells increases FXN protein expression to levels similar to analogous wild-type cells. Our data are significant because synthetic nucleic acids that target GAA repeats can be lead compounds for restoring curative FXN levels. More broadly, our results demonstrate that interfering with R-loop formation can trigger gene activation and reveal a new strategy for upregulating gene expression. Expansion of the trinucleotide GAA within an intronic FXN RNA can cause Friedreich's Ataxia (FRDA), an incurable genetic disorder. Here, the authors show that anti-GAA duplex RNAs or single-stranded locked nucleic acids increases FXN protein expression in patient-derived cells to levels similar to wild-type cells.

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