title: Comparing in vitro and in vivo activity of 2'-O-[2-(methylamino)-2-oxoethyl]- and 2'-O-methoxyethyl-modified antisense oligonucleotides.
abstract: A number of 2'- O-modified antisense oligonucleotides have been reported for their potential use in oligonucleotide-based therapeutics. To date, most of the in vivo data has been generated for 2'-O-MOE (2'-O-methoxyethyl)- and 2'-O-Me (2'-O-methyl)-modified ASOs (antisense oligonucleotides). We now report the synthesis and biological activity of another 2'-O-modification, namely 2'-O-[2-(methylamino)-2-oxoethyl] (2'-O-NMA). This modification resulted in an increase in the affinity of antisense oligonucleotides to complementary RNA similar to 2'-O-MOE-modified ASOs as compared to first-generation antisense oligodeoxynucleotides. The ASO modified with 2'-O-NMA reduced expression of PTEN mRNA in vitro and in vivo in a dose-dependent manner similar to 2'-O-MOE modified ASO. Importantly, toxicity parameters such as AST, ALT, organ weights, and body weights were found to be normal similar to 2'-O-MOE ASO-treated animal models. The data generated in these experiments suggest that 2'-O-NMA is a useful modification for potential application in both antisense and other oligonucleotide-based drug discovery efforts.
authors.affiliation: Department of Medicinal Chemistry and Antisense Core Research, Isis Pharmaceuticals Inc., 1896 Rutherford Road, Carlsbad, California 92008, USA. tprakash@isisph.com
authors.forename: Thazha P
authors.initials: TP
authors.lastname: Prakash
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Kawasaki
authors.forename: Edward V
authors.initials: EV
authors.lastname: Wancewicz
authors.forename: Lijiang
authors.initials: L
authors.lastname: Shen
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Ross
authors.forename: Balkrishen
authors.initials: B
authors.lastname: Bhat
authors.forename: Muthiah
authors.initials: M
authors.lastname: Manoharan
mesh_terms: D000818:Animals; D002460:Cell Line; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009693:Nucleic Acid Hybridization; D020320:Oligoribonucleotides, Antisense / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D013329:Structure-Activity Relationship
chemical_list: D020320:Oligoribonucleotides, Antisense; D012333:RNA, Messenger; D051059:PTEN Phosphohydrolase