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.
Koizumi
Makoto
M
Advanced Technology Research Laboratories, R&D Planning Department, Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi-Sankyo Co., Ltd. 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. koizumi.makoto.h7@daiichisankyo.co.jp
Takagi-Sato
Miho
M
Okuyama
Ryo
R
Araki
Kazushi
K
Sun
Weiyong
W
Nakai
Daisuke
D
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D051379:Mice; D008820:Mice, Obese; D009841:Oligonucleotides / Q000737:chemistry* / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000737:chemistry* / Q000494:pharmacology*; D009843:Oligoribonucleotides / Q000494:pharmacology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism
D001786:Blood Glucose; C528346:ENA-1 oligonucleotide; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D009843:Oligoribonucleotides; D012333:RNA, Messenger; C496122:ISIS-113715; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse