Silencing disease genes in the laboratory and the clinic

J Pathol. 2012 Jan;226(2):365-79. doi: 10.1002/path.2993. Epub 2011 Nov 9.


Synthetic nucleic acids are commonly used laboratory tools for modulating gene expression and have the potential to be widely used in the clinic. Progress towards nucleic acid drugs, however, has been slow and many challenges remain to be overcome before their full impact on patient care can be understood. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) are the two most widely used strategies for silencing gene expression. We first describe these two approaches and contrast their relative strengths and weaknesses for laboratory applications. We then review the choices faced during development of clinical candidates and the current state of clinical trials. Attitudes towards clinical development of nucleic acid silencing strategies have repeatedly swung from optimism to depression during the past 20 years. Our goal is to provide the information needed to design robust studies with oligonucleotides, making use of the strengths of each oligonucleotide technology.

Publication types

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

MeSH terms

  • Alternative Splicing / genetics
  • Cells, Cultured
  • Clinical Trials as Topic
  • Gene Silencing / drug effects*
  • Genetic Therapy / methods*
  • Humans
  • MicroRNAs / antagonists & inhibitors
  • Oligonucleotides, Antisense / therapeutic use*
  • Protein Biosynthesis / drug effects
  • RNA, Small Interfering / therapeutic use*
  • Research Design


  • MicroRNAs
  • Oligonucleotides, Antisense
  • RNA, Small Interfering