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MicroRNA therapeutics: towards a new era for the management of cancer and other diseases

Key Points

  • MicroRNAs (miRNAs) belong to class of small non-coding RNAs that are involved in development and diseases. miRNAs control gene expression by targeting mRNAs based on sequence complementarity.

  • miRNAs can serve as oncomiRs by targeting tumour suppressor mRNAs and as tumour suppressor miRNAs by targeting mRNAs that encode oncoproteins.

  • The deregulation of miRNAs in disease conditions can be harnessed as potential therapeutics by either miRNA replacement therapy using miRNA mimics or inhibition of miRNA function by antimiRs.

  • Two of the major focus areas in the development of miRNA therapeutics are enhancing the in vivo stability of therapeutic RNA molecules and designing optimal delivery systems for disease-specific release with minimal toxicity.

  • Numerous preclinical studies utilizing various disease models have tested the use of these new-generation therapeutics, and several miRNA-based therapeutics have advanced into clinical testing.

Abstract

In just over two decades since the discovery of the first microRNA (miRNA), the field of miRNA biology has expanded considerably. Insights into the roles of miRNAs in development and disease, particularly in cancer, have made miRNAs attractive tools and targets for novel therapeutic approaches. Functional studies have confirmed that miRNA dysregulation is causal in many cases of cancer, with miRNAs acting as tumour suppressors or oncogenes (oncomiRs), and miRNA mimics and molecules targeted at miRNAs (antimiRs) have shown promise in preclinical development. Several miRNA-targeted therapeutics have reached clinical development, including a mimic of the tumour suppressor miRNA miR-34, which reached phase I clinical trials for treating cancer, and antimiRs targeted at miR-122, which reached phase II trials for treating hepatitis. In this article, we describe recent advances in our understanding of miRNAs in cancer and in other diseases and provide an overview of current miRNA therapeutics in the clinic. We also discuss the challenge of identifying the most efficacious therapeutic candidates and provide a perspective on achieving safe and targeted delivery of miRNA therapeutics.

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Figure 1: miRNA biogenesis.
Figure 2: Summary of the key steps in the development of miRNA therapeutics.

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Acknowledgements

The authors thank L. Jacob and A. Jiao for helpful comments on this manuscript. The authors acknowledge support from the Ludwig Center at Harvard, Boston, Massachusetts, USA, and grants from the US National Institutes of Health (R01 CA157749; P50 CA177444).

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Correspondence to Frank J. Slack.

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F.J.S is an adviser to Mirna Therapeutics and miRagen Therapeutics. R.R. declares no competing interests.

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Selected list of siRNA therapeutics in clinical trials (PDF 174 kb)

Glossary

Non-coding RNA

Naturally transcribed RNA molecule that does not encode any protein. Family members include microRNAs and long non-coding RNAs.

miRNA mimics

(MicroRNA mimics). Synthetically derived small RNA molecule duplexes, which, upon introduction into the cells, behave similarly to endogenous miRNAs.

AntimiRs

Also called microRNA (miRNA) inhibitors, antimiRs are small, synthetically derived molecules, which have sequence complementary to target mature miRNAs. They are known to sequester target miRNAs and are used to suppress miRNA function.

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Rupaimoole, R., Slack, F. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov 16, 203–222 (2017). https://doi.org/10.1038/nrd.2016.246

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