Phosphorothioate oligonucleotides reduce PrP levels and prion infectivity in cultured cells

Mol Med. Mar-Apr 2007;13(3-4):190-8. doi: 10.2119/2006–00073.Karpuj.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Fluoresceins
  • Fluorescent Dyes
  • Mice
  • Mice, Transgenic
  • Neuroblastoma / pathology
  • Oligonucleotides / chemistry
  • Oligonucleotides / pharmacology*
  • Phosphates / chemistry*
  • PrPC Proteins / genetics
  • PrPC Proteins / metabolism*
  • PrPSc Proteins / metabolism*
  • Prions / antagonists & inhibitors
  • Prions / genetics
  • Prions / pathogenicity*
  • Time Factors
  • Tumor Cells, Cultured

Substances

  • Fluoresceins
  • Fluorescent Dyes
  • Oligonucleotides
  • Phosphates
  • PrPC Proteins
  • PrPSc Proteins
  • Prions
  • calcein AM
  • phosphorodithioic acid