Oligonucleotide Therapies: The Past and the Present

Abstract

In this review we address the development of oligonucleotide (ON) medicines from a historical perspective by listing the landmark discoveries in this field. The various biological processes that have been targeted and the corresponding ON interventions found in the literature are discussed together with brief updates on some of the more recent developments. Most ON therapies act through antisense mechanisms and are directed against various RNA species, as exemplified by gapmers, steric block ONs, antagomirs, small interfering RNAs (siRNAs), micro-RNA mimics, and splice switching ONs. However, ONs binding to Toll-like receptors and those forming aptamers have completely different modes of action. Similar to other novel medicines, the path to success has been lined with numerous failures, where different therapeutic ONs did not stand the test of time. Since the first ON drug was approved for clinical use in 1998, the therapeutic landscape has changed considerably, but many challenges remain until the expectations for this new form of medicine are met. However, there is room for cautious optimism.

Figure 1.

History of oligonucleotide therapeutics. Basic biology and chemistry with yellow background and clinical applications with coral red background. ON, oligonucleotide. The different chemical structures can be found in Supplementary Fig. S1 (Supplementary Data are available online at www.liebertpub.com/hum).

Figure 2.

Schematic representation of seven mechanisms for ON medicines that have been used in the clinic. (1) Binding to Toll-like receptors (TLRs) in the endosome. (2) Small interfering RNA (siRNA). (3) Micro-RNA (miR) mimic. (4) Antagomir, sterically blocking endogenous miR. (5) Gapmer AON, inducing RNase H degradation (steric block ONs also exist). (6) Aptamer, binding alters protein surface. (7) Splice switching ON (SSO). Not depicted are anti-gene ONs, and ONs directed against nuclear regulatory RNA species, which are not yet used clinically.