Locked nucleic acid (LNA) mediated improvements in siRNA stability and functionality

Nucleic Acids Res. 2005 Jan 14;33(1):439-47. doi: 10.1093/nar/gki193. Print 2005.


Therapeutic application of the recently discovered small interfering RNA (siRNA) gene silencing phenomenon will be dependent on improvements in molecule bio-stability, specificity and delivery. To address these issues, we have systematically modified siRNA with the synthetic RNA-like high affinity nucleotide analogue, Locked Nucleic Acid (LNA). Here, we show that incorporation of LNA substantially enhances serum half-life of siRNA's, which is a key requirement for therapeutic use. Moreover, we provide evidence that LNA is compatible with the intracellular siRNA machinery and can be used to reduce undesired, sequence-related off-target effects. LNA-modified siRNAs targeting the emerging disease SARS, show improved efficiency over unmodified siRNA on certain RNA motifs. The results from this study emphasize LNA's promise in converting siRNA from a functional genomics technology to a therapeutic platform.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Chlorocebus aethiops
  • Humans
  • Oligonucleotides
  • Oligonucleotides, Antisense / chemistry*
  • PC12 Cells
  • RNA Interference
  • RNA Stability
  • RNA, Small Interfering / blood
  • RNA, Small Interfering / chemistry*
  • RNA, Small Interfering / pharmacology*
  • Rats
  • Vero Cells


  • Oligonucleotides
  • Oligonucleotides, Antisense
  • RNA, Small Interfering
  • locked nucleic acid