title: Peptide nucleic acids conjugated to short basic peptides show improved pharmacokinetics and antisense activity in adipose tissue.
abstract: A peptide nucleic acid (PNA) targeting a splice junction of the murine PTEN primary transcript was covalently conjugated to various basic peptides. When systemically administered to healthy mice, the conjugates displayed sequence-specific alteration of PTEN mRNA splicing as well as inhibition of full length PTEN protein expression. Correlating activity with drug concentration in various tissues indicated strong tissue-dependence, with highest levels of activity observed in adipose tissue. While the presence of a peptide carrier was found to be crucial for efficient delivery to tissue, little difference was observed between the various peptides evaluated. A second PNA-conjugate targeting the murine insulin receptor primary transcript showed a similar activity profile, suggesting that short basic peptides can generally be used to effectively deliver peptide nucleic acids to adipose tissue.
authors.affiliation: Isis Pharmaceuticals, Inc., Carlsbad, California 92008, USA.
authors.forename: Edward V
authors.initials: EV
authors.lastname: Wancewicz
authors.forename: Martin A
authors.initials: MA
authors.lastname: Maier
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Siwkowski
authors.forename: Klaus
authors.initials: K
authors.lastname: Albertshofer
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Winger
authors.forename: Andres
authors.initials: A
authors.lastname: Berdeja
authors.forename: Hans
authors.initials: H
authors.lastname: Gaus
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Vickers
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
authors.forename: Richard H
authors.initials: RH
authors.lastname: Griffey
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Nulf
authors.forename: Jiaxin
authors.initials: J
authors.lastname: Hu
authors.forename: David R
authors.initials: DR
authors.lastname: Corey
authors.forename: Eric E
authors.initials: EE
authors.lastname: Swayze
authors.forename: Garth A
authors.initials: GA
authors.lastname: Kinberger
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004337:Drug Carriers; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000737:chemistry*; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis* / Q000235:genetics; D020135:Peptide Nucleic Acids / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D022821:RNA Splice Sites; D012326:RNA Splicing; D016372:RNA, Antisense / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011972:Receptor, Insulin / Q000096:biosynthesis* / Q000235:genetics; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D004337:Drug Carriers; D009842:Oligopeptides; D020135:Peptide Nucleic Acids; D022821:RNA Splice Sites; D016372:RNA, Antisense; D012333:RNA, Messenger; D011972:Receptor, Insulin; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse