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Nucleic Acids Symposium Series 2007 51(1):111-112; doi:10.1093/nass/nrm056
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© 2007 Oxford University Press

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

Makoto Koizumi1,*, Miho Takagi-Sato2, Ryo Okuyama3, Kazushi Araki3, Weiyong Sun4 and Daisuke Nakai5

1Advanced Technology Research Laboratories, 2Medicinal Chemistry Research Laboratories 1, 3Biological Research Laboratories II, 4R&D Planning Department, 5Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi-Sankyo Co., Ltd. 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan

*Corresponding Author. E-mail: koizumi.makoto.h7{at}daiichisankyo.co.jp

Abstract

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 Tm measurement and autoradiography experiments. ENA is a registered trademark of Mitsubishi-Kagaku Foods Corporation.


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