Role of ncRNA in Drug Discovery

It is well known that the majority of RNA in the cell does not code for proteins. There are many non-coding RNAs (ncRNA) including housekeeping RNA such as transfer RNA (tRNA) and ribosomal RNA (rRNA), and regulatory RNA such as circular RNA (circRNA), long non-coding RNA (lncRNA), PIWI-interacting RNA (piRNA), and micro RNA (miRNA).

RNA molecule

Image Credit: Zita/

The different modes of action of ncRNAs compared to proteins and other small molecules within the cell poses unique challenges to the development of medical therapies. However, lessons learned from the targeting of coding RNA, i.e. messenger RNA (mRNA), as a therapeutic target provides some insight.

In mRNA therapy, an oligonucleotide is synthesized that complements an mRNA which has been implicated in a specific disease. The drug then blocks the mRNA from being translated, ideally then alleviating symptoms of the disease.

miRNA therapeutics

miRNA is a type of ncRNA involved in post-transcriptional regulation of gene expression. It is imperfectly complementary to a small region of mRNA. In binding the mRNA target it inhibits the translation by competing with rRNA and tRNA for the mRNA substrate.

Many different miRNAs have been implicated in cardiac hypertrophy. For example, miR-133 has been shown to prevent the translation of a variety of genes involved in hypertrophy and reduced levels of miR-133 are observed in hypertrophic models.

miRNA has also been shown to regulate apoptosis. miR-24 directly represses the BH3-only domain of the pro-apoptotic protein BIM. This helps to reduce the loss of cardiac tissue in the event of cardiac stress, such as during a myocardial infarction.

There are two main modes of miRNA therapeutics. miRNA inhibition blocks miRNA activity, so it cannot bind its target mRNA, where a miRNA is upregulated in the course of a disease. miRNA replacement uses artificial double-stranded miRNA to replace a miRNA that has been downregulated as part of a disease course.

Anti-sense oligonucleotides (ASOs) are the most common type of miRNA inhibitors. These are chemically modified to improve pharmacodynamics and complementary to target miRNA, reducing the level of pathogenic miRNA in the cell. They have been proven to be effective in humans.

A more recent class of miRNA inhibitors are miRNA sponges. They contain multiple miRNA binding sites, so can sequester different miRNAs at the same time, this can be used as an alternative to a cocktail of ASOs. Sponges can also provide longer-term repression and have been effective in the photoreceptor cells of the eye.

Restoring miRNA activity in cells is generally more complex, however, there have been some successful attempts. This involves using double-stranded miRNA mimics in the cell which is then synthesized into single-stranded miRNA which can act to regulate the target mRNA.

lncRNA therapeutics

lncRNA is a wide range of different RNAs longer than 200 nucleotide bases, the function of these remains largely unknown, as does their potential as therapeutic targets. Compared to miRNA and mRNA therapeutics they also pose a variety of problems.

They can act in both nucleus and cytoplasm of the cell, so depending on the mode of activity the type of entry into the cell can vary greatly. A different design of therapeutic is necessary where entry into the nucleus is required.

There is also much less conservation between lncRNA across species, so reducing the utility of animal models, complicating development due to the need to jump from human cell lines to humans. mRNA and miRNA are conserved across species due to its relation to essential protein sequences, whereas lncRNA comes from intergenic regions of DNA.

An example of these issues is with metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). It is a lncRNA that is heavily overexpressed in lung cancer cells, and one of few lncRNAs which is conserved between mammalian species.

It has been implicated in different activities in the nucleus, including alternative splicing and nuclear organization. However significant gaps remain in our understanding of its function, and while ASOs against MALAT1 has been shown to reduce levels of metastasis in mice models, there is still a long way to go before a therapeutic could be used in humans.

In this and other lncRNAs implicated in disease pathogenesis more research is required before a therapy can be developed. Determining the specific mechanism of lncRNA activity is essential in this and will also help to improve our knowledge of lncRNA in cellular processes.


Therapies targeting ncRNA represent an important area of future medical advances. The steps made in miRNA therapy show the efficacy of such therapies and the potential for these innovations in areas such as cancer and cardiac disease.

Further research is especially necessary for the development of therapies targeting lncRNA to overcome the problems described above. Other RNAs such as circRNA are also affected by these problems, particularly the lack of conservation across species, and represent other areas of future research.


  • Bernardo, B. C. et al. (2015) ‘miRNA therapeutics: A new class of drugs with potential therapeutic applications in the heart’, Future Medicinal Chemistry. doi: 10.4155/fmc.15.107.
  • Crooke, S. T. et al. (2018) ‘RNA-Targeted Therapeutics’, Cell Metabolism. doi: 10.1016/j.cmet.2018.03.004.
  • Matsui, M. and Corey, D. R. (2017) ‘Non-coding RNAs as drug targets’, Nature Reviews Drug Discovery. doi: 10.1038/nrd.2016.117.

Further Reading

Last Updated: Oct 22, 2020

Gwillym Preece

Written by

Gwillym Preece

Gwillym has a strong passion for understanding new developments in science, particularly those within microbiology and infectious disease control. He has a B.Sc. in microbiology from the University of Sheffield where he gained knowledge in the molecular mechanisms of infectious disease, with a particular focus on tuberculosis and Staphylococcus aureus .


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