title: Direct comparison of in vivo antisense activity of ENA oligonucleotides targeting PTP1B mRNA with that of 2'-O-(2-methoxy)ethyl-modified oligonucleotides.
abstract: Protein-tyrosine phosphatase 1B (PTP1B) inhibitory activity of the 2'-O-(2-methoxy)ethyl (2'- MOE)-modified gapmer antisense oligonucleotide, ISIS113715, was previously reported. This antisense oligonucleotide increases insulin sensitivity and normalizes plasma glucose levels in diabetic ob/ob and db/db mice. In the present study, the isosequential 2'-O,4'-C-ethylene-bridged nucleic acid (ENA)-modified oligonucleotide, ENA-1, was synthesized, and its ability to further improve the downregulation of PTP1B in db/db mice was examined. We demonstrated that, compared with ISIS113715, intraperitoneal and subcutaneous administration of ENA-1 more effectively decreased the plasma glucose levels in db/db mice. Moreover, ENA-1 decreased expression of PTP1B in the liver and fat of db/db mice more effectively than ISIS113715. We describe for the first time the functional comparison of 2'-MOE- and ENA-modified antisense oligonucleotides. Our data indicate that the enhancement of the efficacy of antisense oligonucleotides by ENA modifications is superior to that of second-generation 2'-MOE modifications in certain aspects.
authors.affiliation: Core Technology Research Laboratories, Sankyo Co., Ltd., Tokyo 140-8710, Japan. koizum@sankyo.co.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Koizumi
authors.forename: Miho
authors.initials: M
authors.lastname: Takagi-Sato
authors.forename: Ryo
authors.initials: R
authors.lastname: Okuyama
authors.forename: Kazushi
authors.initials: K
authors.lastname: Araki
authors.forename: Weiyong
authors.initials: W
authors.lastname: Sun
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakai
authors.forename: Shinya
authors.initials: S
authors.lastname: Tsutsumi
authors.forename: Kenji
authors.initials: K
authors.lastname: Kawai
mesh_terms: D000818:Animals; D006358:Hot Temperature; D008297:Male; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000378:metabolism*; D009843:Oligoribonucleotides; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D016372:RNA, Antisense / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics; D054411:Receptors, Leptin
chemical_list: C119446:2'-O-(2-methoxyethyl)-RNA; D016376:Oligonucleotides, Antisense; D009843:Oligoribonucleotides; D016372:RNA, Antisense; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse