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Non-coding RNAs as drug targets

Nature Reviews Drug Discovery volume 16, pages 167–179 (2017)Cite this article

Subjects

Key Points

  • Non-coding RNAs (ncRNAs) — which include microRNAs (miRNAs), repetitive RNAs, intronic RNAs, and long ncRNAs (lncRNAs) — are a diverse group of biomolecules with broad potential to control gene expression.

  • Compounds that target ncRNAs have the potential to control expression of disease-related genes

  • Development of compounds to target ncRNAs can benefit from understanding the lessons learnt from decades of research using antisense oligonucleotides (ASOs) and duplex RNAs to control expression of mRNA.

  • ASOs that affect splicing or that are complementary to miRNAs are already being tested in multiple clinical trials in a variety of diseases, including cancer and muscular dystrophy

  • lncRNAs can affect transcription or splicing and are emerging as a promising class of novel drug targets.

Abstract

Most of the human genome encodes RNAs that do not code for proteins. These non-coding RNAs (ncRNAs) may affect normal gene expression and disease progression, making them a new class of targets for drug discovery. Because their mechanisms of action are often novel, developing drugs to target ncRNAs will involve equally novel challenges. However, many potential problems may already have been solved during the development of technologies to target mRNA. Here, we discuss the growing field of ncRNA — including microRNA, intronic RNA, repetitive RNA and long non-coding RNA — and assess the potential and challenges in their therapeutic exploitation.

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Figure 1: Regulating RNA levels or splicing with ASOs and duplex RNAs.
Figure 2: ASOs and duplex RNAs targeting repetitive RNAs.
Figure 3: Modulating gene expression by targeting cis-acting non-coding RNAs or promoter RNAs.

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Acknowledgements

This work was supported by the National Institutes of Health (GM106151, GM73042 and GM118103) and the Robert Welch Foundation (I-1244). D.R.C. holds the Rusty Kelley Professorship in Medical Sciences.

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Authors and Affiliations

  1. Departments of Pharmacology and Biochemistry, UT Southwestern, Dallas, 75390–9041, Texas, USA

    Masayuki Matsui & David R. Corey

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  1. Masayuki Matsui
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Correspondence to David R. Corey.

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Glossary

Antisense oligonucleotides

(ASOs). Synthetic single-stranded oligonucleotides that are designed to bind to complementary cellular RNA sequences by Watson–Crick base pairing.

Droplet digital PCR

(ddPCR). A PCR technology that uses nanolitre-sized oil–water emulsion droplets as PCR reaction vessels and quantifies concentrations of target DNA templates based on counting the number of PCR-positive droplets using a flow cytometer.

Long non-coding RNAs

(lncRNAs). Relatively long (>200 nucleotides) non-coding RNA transcripts.

MicroRNAs

(miRNAs). Small (~22 nucleotides) non-coding transcripts that are generally thought to silence gene translation through RNA interference.

Non-coding RNAs

(ncRNAs). RNA transcripts that do not code for protein.

Off-target effect

Phenotypic effects in a cell or animal that occur upon addition of a synthetic compound and that are not caused by interactions with the intended cellular target.

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Matsui, M., Corey, D. Non-coding RNAs as drug targets. Nat Rev Drug Discov 16, 167–179 (2017). https://doi.org/10.1038/nrd.2016.117

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