RNA therapeutics: beyond RNA interference and antisense oligonucleotides

Nat Rev Drug Discov. 2012 Jan 20;11(2):125-40. doi: 10.1038/nrd3625.

Abstract

Here, we discuss three RNA-based therapeutic technologies exploiting various oligonucleotides that bind to RNA by base pairing in a sequence-specific manner yet have different mechanisms of action and effects. RNA interference and antisense oligonucleotides downregulate gene expression by inducing enzyme-dependent degradation of targeted mRNA. Steric-blocking oligonucleotides block the access of cellular machinery to pre-mRNA and mRNA without degrading the RNA. Through this mechanism, steric-blocking oligonucleotides can redirect alternative splicing, repair defective RNA, restore protein production or downregulate gene expression. Moreover, they can be extensively chemically modified to acquire more drug-like properties. The ability of RNA-blocking oligonucleotides to restore gene function makes them best suited for the treatment of genetic disorders. Positive results from clinical trials for the treatment of Duchenne muscular dystrophy show that this technology is close to achieving its clinical potential.

Publication types

  • Review

MeSH terms

  • Alternative Splicing / drug effects
  • Alternative Splicing / genetics
  • Animals
  • Anti-Bacterial Agents / therapeutic use
  • Antiviral Agents / therapeutic use
  • Gene Expression / drug effects
  • Gene Expression / genetics
  • Humans
  • Morpholinos / genetics
  • Morpholinos / therapeutic use
  • Muscular Dystrophy, Duchenne / drug therapy
  • Muscular Dystrophy, Duchenne / genetics
  • Myotonic Dystrophy / drug therapy
  • Myotonic Dystrophy / genetics
  • Oligodeoxyribonucleotides, Antisense / pharmacology
  • Oligodeoxyribonucleotides, Antisense / therapeutic use*
  • Phosphorothioate Oligonucleotides / genetics
  • Phosphorothioate Oligonucleotides / therapeutic use
  • RNA Interference* / drug effects
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • beta-Thalassemia / drug therapy
  • beta-Thalassemia / genetics

Substances

  • Anti-Bacterial Agents
  • Antiviral Agents
  • Morpholinos
  • Oligodeoxyribonucleotides, Antisense
  • Phosphorothioate Oligonucleotides
  • RNA, Messenger
  • RNA, Small Interfering