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Review
. 2018 Feb 28;46(4):1584-1600.
doi: 10.1093/nar/gkx1239.

Chemistry, mechanism and clinical status of antisense oligonucleotides and duplex RNAs

Xiulong Shen  1 , David R Corey  1
Affiliations
Review

Chemistry, mechanism and clinical status of antisense oligonucleotides and duplex RNAs

Xiulong Shen et al. Nucleic Acids Res. .

Abstract

RNA plays a central role in the expression of all genes. Because any sequence within RNA can be recognized by complementary base pairing, synthetic oligonucleotides and oligonucleotide mimics offer a general strategy for controlling processes that affect disease. The two primary antisense approaches for regulating expression through recognition of cellular RNAs are single-stranded antisense oligonucleotides and duplex RNAs. This review will discuss the chemical modifications and molecular mechanisms that make synthetic nucleic acid drugs possible. Lessons learned from recent clinical trials will be summarized. Ongoing clinical trials are likely to decisively test the adequacy of our current generation of antisense nucleic acid technologies and highlight areas where more basic research is needed.

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Figures

Figure 1.
Figure 1.
Properties of small molecule, antibody and oligonucleotide drugs.
Figure 2.
Figure 2.
Chemical modifications of oligonucleotides used in major clinical trials. (X = OH or H).
Figure 3.
Figure 3.
Conjugation of GalNAc to passenger strand of dsRNAs or ASOs to enhance delivery to the liver. ASGPR: asialoglycoprotein receptor.
Figure 4.
Figure 4.
Types of target for therapeutic oligonucleotides.
Figure 5.
Figure 5.
Mechanisms of action for therapeutic oligonucleotides. (A) control of splicing by ASOs and alternative splicing. In contrast to gapmers, ASOs that control splicing possess ribose or morpholino modifications throughout the oligomer; (B) block of translation by antisense gapmers (oligonucleotide that contain 2′-modified RNA flanking a central DNA region) targeting mRNA; (C) block of translation by a fully complementary dsRNA and RNA interference.
Figure 6.
Figure 6.
Design and clinical status of oligonucleotides drugs discussed in this review. Source material for this figure is cited as Supplementary Data. For Inclisiran, Fitusiran, and Givosiran, we could not locate publically available information and the structures shown below are based on the cited descriptions of this class of compound.
See this image and copyright information in PMC

References

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