RNA therapeutics: Beyond RNA interference and antisense oligonucleotides

Ryszard Kole, Adrian R. Krainer, Sidney Altman

Research output: Contribution to journalReview article

679 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)125-140
Number of pages16
JournalNature Reviews Drug Discovery
Volume11
Issue number2
DOIs
StatePublished - Feb 2012

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

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