Potent and nontoxic antisense oligonucleotides containing locked nucleic acids

Proc Natl Acad Sci U S A. 2000 May 9;97(10):5633-8. doi: 10.1073/pnas.97.10.5633.


Insufficient efficacy and/or specificity of antisense oligonucleotides limit their in vivo usefulness. We demonstrate here that a high-affinity DNA analog, locked nucleic acid (LNA), confers several desired properties to antisense agents. Unlike DNA, LNA/DNA copolymers were not degraded readily in blood serum and cell extracts. However, like DNA, the LNA/DNA copolymers were capable of activating RNase H, an important antisense mechanism of action. In contrast to phosphorothioate-containing oligonucleotides, isosequential LNA analogs did not cause detectable toxic reactions in rat brain. LNA/DNA copolymers exhibited potent antisense activity on assay systems as disparate as a G-protein-coupled receptor in living rat brain and an Escherichia coli reporter gene. LNA-containing oligonucleotides will likely be useful for many antisense applications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Biological Transport
  • Breast Neoplasms
  • Caudate Nucleus / drug effects
  • Cerebral Ventricles / drug effects
  • Cerebral Ventricles / physiology
  • Drug Design
  • Enzyme Activation
  • Female
  • Humans
  • Oligodeoxyribonucleotides, Antisense / chemistry*
  • Oligodeoxyribonucleotides, Antisense / pharmacokinetics
  • Oligodeoxyribonucleotides, Antisense / pharmacology*
  • Putamen / drug effects
  • Rats
  • Receptors, Opioid, delta / genetics
  • Ribonuclease H / drug effects
  • Ribonuclease H / metabolism
  • Stereotaxic Techniques
  • Thionucleotides
  • Tumor Cells, Cultured


  • Oligodeoxyribonucleotides, Antisense
  • Receptors, Opioid, delta
  • Thionucleotides
  • Ribonuclease H