In vivo antisense activity of ENA oligonucleotides targeting PTP1B mRNA in comparison of that of 2'-MOE-modified oligonucleotides.

The 2'-0-(2-methoxy)ethyl (2'-MOE)-modified gapmer antisense oligonucleotide ISIS113715, which targets protein-tyrosine phosphatase IB (PTP1B) mRNA, increases insulin sensitivity and normalizes plasma glucose levels in diabetic ob/ob and db/db mice. In the present study, the efficacy of the isosequential 2'-O,4'-C-ethylene-bridged nucleic acid (ENA)-modified oligonucleotide ENA-1 was compared with that of ISIS113715 in order to further improve the down-regulation of PTP1B in db/db mice. Intraperitoneal administration of ENA-1 more effectively decreased the plasma glucose levels in db/db mice than ISIS113715. Moreover, ENA-1 decreased the expression of PTP1B in the liver and fat of db/db mice more effectively than ISIS113715. These data indicate that ENA modifications enhance the ability of antisense oligonucleotides and make them superior to second-generation 2'-MOE modifications. We would like to thank to Drs. Shinya Tsutsumi and Kenji Kawai for the T(m) measurement and autoradiography experiments. ENA is a registered trademark of Mitsubishi-Kagaku Foods Corporation.