Short antisense oligonucleotides alleviate the pleiotropic toxicity of RNA harboring expanded CGG repeats

Magdalena Derbis, Emre Kul, Daria Niewiadomska, Michał Sekrecki, Agnieszka Piasecka, Katarzyna Taylor, Renate K. Hukema, Oliver Stork and Krzysztof Sobczak ()
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Magdalena Derbis: Uniwersytetu Poznanskiego 6
Emre Kul: Otto von Guericke University
Daria Niewiadomska: Uniwersytetu Poznanskiego 6
Michał Sekrecki: Uniwersytetu Poznanskiego 6
Agnieszka Piasecka: Uniwersytetu Poznanskiego 6
Katarzyna Taylor: Uniwersytetu Poznanskiego 6
Renate K. Hukema: Department of Clinical Genetics, Erasmus MC
Oliver Stork: Otto von Guericke University
Krzysztof Sobczak: Uniwersytetu Poznanskiego 6

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Fragile X-associated tremor/ataxia syndrome (FXTAS) is an incurable neurodegenerative disorder caused by expansion of CGG repeats in the FMR1 5’UTR. The RNA containing expanded CGG repeats (rCGGexp) causes cell damage by interaction with complementary DNA, forming R-loop structures, sequestration of nuclear proteins involved in RNA metabolism and initiation of translation of polyglycine-containing protein (FMRpolyG), which forms nuclear insoluble inclusions. Here we show the therapeutic potential of short antisense oligonucleotide steric blockers (ASOs) targeting directly the rCGGexp. In nuclei of FXTAS cells ASOs affect R-loop formation and correct miRNA biogenesis and alternative splicing, indicating that nuclear proteins are released from toxic sequestration. In cytoplasm, ASOs significantly decrease the biosynthesis and accumulation of FMRpolyG. Delivery of ASO into a brain of FXTAS mouse model reduces formation of inclusions, improves motor behavior and corrects gene expression profile with marginal signs of toxicity after a few weeks from a treatment.

Date: 2021
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DOI: 10.1038/s41467-021-21021-w

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