The Promise of miRNAs as Therapeutic Agents in Treating Disease

When researchers first identified a new family of seemingly non-functional “junk” RNA molecules, it’s unlikely they could have predicted the power and promise of these nucleic acids. The small, non-coding, single-stranded RNAs – typically 21-25 base pairs in length – were first discovered over 20 years ago in C. elegans, yet they were quickly found to be ubiquitous in species from worms to flies to plants to mammals. The role of these novel RNAs in the regulation of developmental pathways in worms, coupled with their prevalence, inspired researchers to better understand their significance.

We now know that miRNAs (for microRNAs) serve as post-transcriptional repressors of gene expression by targeting degradation of mRNA or interfering with mRNA translation. While small, each can have a big effect; a single miRNA can regulate dozens to hundreds of distinct target genes. They’ve been implicated in a variety of critical cellular processes such as differentiation, development, metabolism, signal transduction, apoptosis and proliferation.

Tissue-specific expression patterns revealed that specific miRNAs are enriched in mammalian tissues including adult brain, lung, spleen, liver, kidney and heart.  More compelling was the identification of abnormal miRNA expression in tumorigenic cell lines. It’s no wonder that this growing family quickly became ripe for exploration in disease development.

Basic research on miRNA is making its way into the clinic.
Research on miRNA is making its way into the clinic.

Within only a few years, a rapidly expanding body of research supported the theory that miRNA expression may indeed play a role in the development of human diseases including cardiovascular disease, cancer, diabetes, cystic fibrosis, and liver disease. Investigations into the expression of miRNAs in cardiovascular disease, in particular, have demonstrated not only their value as disease markers, but also how their dysregulation is linked to disease processes.

More recently a new possibility is being explored: can miRNA be manipulated to interfere with disease progression?

In only the past few years there have been numerous reports detailing the use of miRNAs as therapeutic agents. One of the first such examples described gain- and loss-of-function studies using miRNAs in mouse models to study cardiac biology. The researchers reasoned that if they could induce cardiac events with potent levels of miRNAs they might be able to reverse, or silence, the effect by the delivery of “anti-miRNAs.” The synergistic effects of miRNAs, along with their stability and favorable half-life in cells, has elevated their potential as disease fighting tools. Cardiovascular disease has been an especially productive model system for testing the effects of miRNAs as therapeutic agents.

Alzheimer’s disease (AD) is another disease being tested for potential miRNA-based therapy. A study published just last month reported on a member of the miR-15/107 “superfamily,” miR-16, which specifically inhibits the expression of genes associated with AD biomarkers Aβ and Tau, as well as brain inflammation and oxidative stress. miR-16 mimics delivered into the brain of mice resulted in a reduction of these target genes, thus supporting the potential of miR-16 as an excellent candidate for future drug development.

In a yet a different arena, the results of the first Phase II clinical trial designed to test an miRNA inhibitor, miravirsen, were recently published. Investigators found that by inhibiting a specific miRNA, miR-122, associated with hepatitis C virus (HCV) infection, patients with chronic infection showed dose-dependent reductions in their HCV RNA levels. Again, more promise.

It’s exciting to follow the progress of scientists pursuing the therapeutic applications of miRNA biology – and truly a testament to how basic molecular biology discoveries can be applied to a clinical setting. This “bench-to-bedside” concept serves as inspiration and fuels so many to keep plugging away. The emerging miRNA story also serves to remind us to never underestimate the power of short, generic, non-coding nucleic acids, or any seemingly insignificant scientific discovery.

Additional reading:

  1. van Rooij, E. et al. (2008) Toward microRNA-based therapeutics for heart disease – the sense in antisense. Circ. Res. 103, 919-28.
  2. Bernardo, B.C. et al. (2015) miRNA therapeutics: a new class of drugs with potential therapeutic applications in the heart. Future Med. Chem. 7, 1771-92.
  3. Kwekkeboom, R.F. et al. (2014) Targeted delivery of miRNA therapeutics for cardiovascular diseases: opportunities and challenges. Clin. Sci. 127, 351-65.
  4. He, L. & Hannon, G. J. (2004) MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 5, 522-31.
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Nicole Sandler

Nicole enjoys being a member of the Promega Connections blog team. A former molecular biologist, she earned her PhD from the University of Pennsylvania but realized that writing about science was a more fulfilling way to apply her knowledge and passion for the field. She's excited that her longtime writing career has now landed her at Promega, a company she once relied on for restriction enzymes and buffers as a research scientist.

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