Effect of 2′-O-[2-[2-(N,N-dimethylamino)ethoxy]ethyl] modification on activity of gapmer antisense oligonucleotides containing 2′,4′-constrained 2′-O-ethyl nucleic acid

We evaluated the effect of combining 2′-O-[2-[2-(N,N-dimethylamino)ethoxy]ethyl] (2′-O-DMAEOE), a 2′-cationic modification, with a 2′,4′-constrained 2′-O-ethyl nucleic acid (cEt BNA) on the activity of an antisense oligonucleotide (ASO) using PTEN as a model target. Our results suggest that replacing one cEt BNA nucleotide with 2′-O-DMAEOE nucleotide at the 5′-end of a 2-10-2 gapmer ASO maintained the potency relative to parent ASO in liver. The cationic 2′-O-DMAEOE modification did not improve the activity of ASO in extra-hepatic tissues. Results from this study provide guidance to design improved antisense oligonucleotide drugs.

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