Krzysztof Sobczak Lab: Short antisense oligonucleotides alleviate the pleiotropic toxicity of RNA harboring expanded CGG repeats published in Nature Communications, 24th February 2021

Magdalena Derbis, Emre Kul, Daria Niewiadomska, Michał Sekrecki, Agnieszka Piasecka, Katarzyna Taylor, Renate K. Hukema & Oliver Stork led by IMBB director Krzysztof Sobczak have published their work on the antisense oligonucleotides alleviating the toxicity of RNA with expanded CGG repeats   in  Nature communications – congratulations! Check out the paper!

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. Our researchers showed 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.