RNAseq of brain tissue derived from mouse model of neurodegenerative disorder treated with antisense oligonucleotides

The Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is neurodegenerative disorder caused by expansion of CGG repeats (CGGexp) in 5' untranslated region of FMR1 gene encoding FMRP protein. The CGGexp-induced biosynthesis and accumulation of the aggregated form of polyglycine protein (FMRpolyG), which is a product of Repeat-Associated Non-AUG translation of long CGG repeats is considered to be main factor triggering neurodegenerative processes in FXTAS patients. Since the causative molecular targets are well defined, FXTAS is highly amenable to the development of RNA targeting therapy. We showed high efficiency of antisense oligonucleotides (ASOs) as potential therapeutic agent. Short ASOs composed of locked nucleic acid residues bind along the CGGexp RNA (rCGGexp) with very high affinity both in vitro and in vivo. These ASOs were delivered directly into cerebrospinal fluid in brain of mouse model expressing the transgene with 90 CGG repeats exclusively in neural cells. Importantly, reduction of FMRpolyG intranuclear inclusions in the cerebellum positively correlates with behavioral features of FXTAS in treated animals. Moreover, gene expression analysis and gene ontology classification performed basing on RNAseq results showed significant correction of ASOs treated FXTAS mice towards control mice. Our data demonstrate that short ASOs rescue effects of toxic rCGGexp and can be considered as therapeutic strategy in FXTAS.