title: Phosphorothioate oligonucleotides reduce PrP levels and prion infectivity in cultured cells.
abstract: Prions are composed solely of the disease-causing prion protein (PrPSc) that is formed from the cellular isoform PrPC by a posttranslational process. Here we report that short phosphorothioate DNA (PS-DNA) oligonucleotides diminished the levels of both PrPC and PrPSc in prion-infected neuroblastoma (ScN2a) cells. The effect of PS-DNA on PrP levels was independent of the nucleotide sequence. The effective concentration (EC50) of PS-DNA required to achieve half-maximal diminution of PrPSc was approximately 70 nM, whereas the EC50 of PS-DNA for PrPC was more than 50-fold greater. This finding indicated that diminished levels of PrPSc after exposure to PS-DNA are unlikely to be due to decreased PrPC levels. Bioassays in transgenic mice demonstrated a substantial diminution in the prion infectivity after ScN2a cells were exposed to PS-DNAs. Whether PS-DNA will be useful in the treatment of prion disease in people or livestock remains to be established.
authors.affiliation: Institute for Neurodegenerative Diseases and Department of Neurology, University of California, San Francisco, CA 94143-0518, USA.
authors.forename: Marcela V
authors.initials: MV
authors.lastname: Karpuj
authors.forename: Kurt
authors.initials: K
authors.lastname: Giles
authors.forename: Sagit
authors.initials: S
authors.lastname: Gelibter-Niv
authors.forename: Michael R
authors.initials: MR
authors.lastname: Scott
authors.forename: Vishwanath R
authors.initials: VR
authors.lastname: Lingappa
authors.forename: Francis C
authors.initials: FC
authors.lastname: Szoka
authors.forename: David
authors.initials: D
authors.lastname: Peretz
authors.forename: Wilfred
authors.initials: W
authors.lastname: Denetclaw
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Prusiner
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005452:Fluoresceins; D005456:Fluorescent Dyes; D051379:Mice; D008822:Mice, Transgenic; D009447:Neuroblastoma / Q000473:pathology; D009841:Oligonucleotides / Q000737:chemistry / Q000494:pharmacology*; D010710:Phosphates / Q000737:chemistry*; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism*; D018620:PrPSc Proteins / Q000378:metabolism*; D011328:Prions / Q000037:antagonists & inhibitors / Q000235:genetics / Q000472:pathogenicity*; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D005452:Fluoresceins; D005456:Fluorescent Dyes; D009841:Oligonucleotides; D010710:Phosphates; D018621:PrPC Proteins; D018620:PrPSc Proteins; D011328:Prions; C085925:calcein AM; C083120:phosphorodithioic acid