title: Effect of 2'-O-[2-[2-(N,N-dimethylamino)ethoxy]ethyl] modification on activity of gapmer antisense oligonucleotides containing 2',4'-constrained 2'-O-ethyl nucleic acid.
abstract: We evaluated the effect of combining 2'-O-[2-[2-(N,N-dimethylamino)ethoxy]ethyl] (2'-O-DMAEOE), a 2'-cationic modification, with a 2',4'-constrained 2'-O-ethyl nucleic acid (cEt BNA) on the activity of an antisense oligonucleotide (ASO) using PTEN as a model target. Our results suggest that replacing one cEt BNA nucleotide with 2'-O-DMAEOE nucleotide at the 5'-end of a 2-10-2 gapmer ASO maintained the potency relative to parent ASO in liver. The cationic 2'-O-DMAEOE modification did not improve the activity of ASO in extra-hepatic tissues. Results from this study provide guidance to design improved antisense oligonucleotide drugs.
authors: Antisense Drug Discovery, Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States. Electronic address: spandey@isisph.com.
authors: Sanjay K
authors: SK
authors: Pandey
authors: Antisense Drug Discovery, Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States.
authors: Anna
authors: A
authors: Nowak
authors: Medicinal Chemistry, Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States.
authors: Jake
authors: J
authors: Perkins
authors: Antisense Drug Discovery, Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States.
authors: Annie
authors: A
authors: Ferng
authors: Medicinal Chemistry, Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States.
authors: Thazha P
authors: TP
authors: Prakash
mesh_terms: D000818:Animals; D002460:Cell Line; D004980:Ethane / Q000031:analogs & derivatives* / Q000737:chemistry; D004987:Ethers / Q000737:chemistry*; D008099:Liver / Q000378:metabolism; D051379:Mice; D009696:Nucleic Acids / Q000737:chemistry*; D016376:Oligonucleotides, Antisense / Q000737:chemistry* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010710:Phosphates / Q000737:chemistry; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism; D044366:Transition Temperature
chemical_list: C478253:2'-O-(2-(2-(N,N-dimethylamino)ethoxy)ethyl); D004987:Ethers; D009696:Nucleic Acids; D016376:Oligonucleotides, Antisense; D010710:Phosphates; D012333:RNA, Messenger; C083120:phosphorodithioic acid; D051059:PTEN Phosphohydrolase; D004980:Ethane
keywords: Antisense; Cationic modification; DMAEOE; Oligonucleotide; cEt BNA