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  • Perspective
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Noncoding RNA therapeutics — challenges and potential solutions

Nature Reviews Drug Discovery volume 20, pages 629–651 (2021)Cite this article

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Abstract

Therapeutic targeting of noncoding RNAs (ncRNAs), such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), represents an attractive approach for the treatment of cancers, as well as many other diseases. Over the past decade, substantial effort has been made towards the clinical application of RNA-based therapeutics, employing mostly antisense oligonucleotides and small interfering RNAs, with several gaining FDA approval. However, trial results have so far been ambivalent, with some studies reporting potent effects whereas others demonstrated limited efficacy or toxicity. Alternative entities such as antimiRNAs are undergoing clinical testing, and lncRNA-based therapeutics are gaining interest. In this Perspective, we discuss key challenges facing ncRNA therapeutics — including issues associated with specificity, delivery and tolerability — and focus on promising emerging approaches that aim to boost their success.

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Fig. 1: MicroRNA biogenesis pathway and ways to interfere therapeutically.
Fig. 2: Modes of action of small-molecule inhibitors that target miRNAs and lncRNAs.

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Acknowledgements

G.A.C. is the Felix L. Haas Endowed Professor in Basic Science. Work in G.A.C.’s laboratory is supported by National Institutes of Health (NIH/NCATS) grant UH3TR00943-01 through the NIH Common Fund, Office of Strategic Coordination (OSC), the NCI grants 1R01 CA182905-01 and 1R01CA222007-01A1, an NIGMS 1R01GM122775-01 grant, a Team DOD (CA160445P1) grant, a Chronic Lymphocytic Leukaemia Moonshot Flagship project, a CLL Global Research Foundation 2019 grant, a CLL Global Research Foundation 2020 grant, donor support through J. Ajani and the Estate of C.G. Johnson, Jr. S.M.E. was supported by a Fulbright foundation fellowship and is currently supported by the Science and Technology Development Fund (STDF, grant #26388). Work in M.F.’s laboratory is supported by the National Institutes of Health (NIH/NCI) grant 5P30CA071789-20 and by the NIH/NCI grants R01CA215753 and R01CA219024.

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Authors and Affiliations

  1. Translational Molecular Pathology, MD Anderson Cancer Center, Texas State University, Houston, TX, USA

    Melanie Winkle & George A. Calin

  2. Medical Biochemistry Department, Medical Research Division - Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences - National Research Centre, Cairo, Egypt

    Sherien M. El-Daly

  3. Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, HI, USA

    Muller Fabbri

  4. The RNA Interference and Non-codingRNA Center, MD Anderson Cancer Center, Texas State University, Houston, TX, USA

    George A. Calin

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Winkle, M., El-Daly, S.M., Fabbri, M. et al. Noncoding RNA therapeutics — challenges and potential solutions. Nat Rev Drug Discov 20, 629–651 (2021). https://doi.org/10.1038/s41573-021-00219-z

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