TY - JOUR T1 - Interaction of modified oligonucleotides with nuclear proteins, formation of novel nuclear structures and sequence-independent effects on RNA processing JF - bioRxiv DO - 10.1101/446773 SP - 446773 AU - Loren L Flynn AU - Li Ruohan AU - May T Aung-Htut AU - Ianthe L Pitout AU - Jack Cooper AU - Alysia Hubbard AU - Lisa Griffiths AU - Charlie Bond AU - Steve D Wilton AU - Archa H Fox AU - Sue Fletcher Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/10/18/446773.abstract N2 - Oligonucleotides and nucleic acid analogues that alter gene expression are showing therapeutic promise for selected human diseases. The modification of synthetic nucleic acids to protect against nuclease degradation and to influence drug function is common practice, however, such modifications may also confer unexpected physicochemical and biological properties. Here we report backbone-specific effects of modified oligonucleotides on subnuclear organelles, altered distribution of nuclear proteins, the appearance of novel structured nuclear inclusions, and modification of RNA processing in cultured cells transfected with antisense oligonucleotides on a phosphorothioate backbone. Phosphodiester and phosphorodiamidate morpholino oligomers elicited no such consequences. Disruption of subnuclear structures and proteins elicit severe phenotypic disturbances, revealed by transcriptomic analysis of fibroblasts exhibiting such disruption. These data suggest that the toxic effects and adverse events reported after clinical evaluation of phosphorothioate nucleic acid drugs may be mediated, at least in part, by non-specific interaction of nuclear components with the phosphorothioate backbone.AbbreviationsAOantisense oligonucleotideSMAspinal muscular atrophyDMDDuchenne muscular dystrophyPMOphosphorodiamidate morpholino oligomerALSamyotrophic lateral sclerosis ER -