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  • Review Article
  • Published:

MicroRNA therapeutics for cardiovascular disease: opportunities and obstacles

Nature Reviews Drug Discovery volume 11, pages 860–872 (2012)Cite this article

Subjects

Key Points

  • MicroRNAs (miRNAs) are short, single-stranded RNAs that suppress protein expression of often several related components of complex intracellular networks, making them very potent regulators.

  • The functions of miRNAs are heightened under conditions of pathophysiological stress and disease, making them attractive candidates for therapeutic manipulation.

  • Many gain- and loss-of-function studies have shown that miRNAs have prominent roles during many different diseases, including cardiovascular disorders.

  • Several antimiR (miRNA inhibitor) chemistries exist that can induce potent and sustained inhibition of specific miRNAs.

  • This Review provides an overview of the pharmacokinetic and pharmacodynamic properties of the different antimiR therapeutics and discusses some of their differences in comparison with more classical drugs.

  • We present some recent representative examples of the therapeutic effects of antimiRs in the cardiovascular system, including in cardiac remodelling, metabolism, fibrosis, apoptosis, vascular diseases, inflammation and hypertension.

  • Last, we consider some possible future directions and present some of the challenges and questions that remain in the path towards the development of miRNA-based therapeutics in general.

Abstract

In recent years, prominent roles for microRNAs (miRNAs) have been uncovered in several cardiovascular disorders. The ability to therapeutically manipulate miRNA expression and function through systemic or local delivery of miRNA inhibitors, referred to as antimiRs, has triggered enthusiasm for miRNAs as novel therapeutic targets. Here, we focus on the pharmacokinetic and pharmacodynamic properties of current antimiR designs and their relevance to cardiovascular indications, and evaluate the opportunities and obstacles associated with this new therapeutic modality.

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Figure 1: MicroRNA biogenesis and mechanism of action.
Figure 2: AntimiR chemistries.
Figure 3: Multiple functions of miR-208 in the heart.
Figure 4: MicroRNAs often regulate related target genes.

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Acknowledgements

We gratefully acknowledge J. Cabrera for graphics.

Author information

Authors and Affiliations

  1. miRagen Therapeutics, 6200 Lookout Rd, Boulder, 80301, Colorado, USA

    Eva van Rooij

  2. Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, 75390–79148, Texas, USA

    Eric N. Olson

Authors
  1. Eva van Rooij
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  2. Eric N. Olson
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Corresponding author

Correspondence to Eric N. Olson.

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Competing interests

Work in the laboratory of Eric N. Olson was supported by grants from the US National Institutes of Health (NIH), the Robert A. Welch Foundation (Grant number I-0025), the American Heart Association, the Jon Holden DeHaan Foundation, the Donald W. Reynolds Center for Clinical Cardiovascular Research, the Fondation Leducq TransAtlantic Network of Excellence in Cardiovascular Research Program and the Cancer Prevention & Research Institute of Texas (CPRIT). Eva van Rooij and Eric N. Olson are co-founders of miRagen Therapeutics and hold equity in the company.

Related links

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FURTHER INFORMATION

ClinicalTrials.gov website

Santaris Pharma website — 3 October 2011 press release

Glossary

microRNAs

(miRNAs). Short, non-coding RNAs that suppress protein expression by most commonly binding to complementary sequences located within 3′ untranslated regions of target mRNAs.

Hepatitis C virus

(HCV). An infectious disease primarily affecting the liver.

RNA-induced silencing complex

(RISC). A multiprotein complex that incorporates a microRNA to recognize complementary sequences in mRNAs and block protein expression.

Pseudogenes

Non-coding transcripts that are often conserved across species and contain conserved microRNA binding sites that can act as decoys to interfere with microRNA activity.

AntimiRs

Antisense oligonucleotides designed to target specific microRNAs.

Pharmacokinetic

In the context of antimiR (microRNA inhibitor) designs, this refers to the potency of an antimiR in binding to and inhibiting a microRNA in vivo.

Pharmacodynamic

In the context of antimiR (microRNA inhibitor) designs, this refers to mRNA de-repression of direct microRNA targets in response to treatment with an antimiR.

Phosphorothioate

Backbone linkage in which a sulphur atom replaces one of the non-bridging oxygen atoms in the phosphate group of oligonucleotides to increase nuclease resistance.

Antagomir

A cholesterol-conjugated antimiR (microRNA inhibitor) chemistry that is complementary to the full-length sequence of the target microRNA, consisting of 2′-O-methyl (2′-O-Me) linkages and containing several phosphorothioate moieties to increase stability.

2′ sugar modifications

High-affinity 2′ sugar modifications such as 2′-O-methyl (2′-O-Me), 2′-O-methoxyethyl (2′-MOE), 2′-fluoro (2′-F) or locked nucleic acid; used in oligonucleotide chemistries to improve nuclease resistance and increase duplex melting temperature (Tm).

Locked nucleic acid

(LNA). A 2′ sugar modification in which the ribose is locked in a C3′-endo conformation by the introduction of a 2′-O-,4′-C methylene bridge that strongly increases the affinity for complementary RNA and increases the duplex melting temperature (Tm) by + 2°C to + 8°C per introduced LNA modification.

Duplex melting temperature

(Tm). The temperature at which half of a particular duplex dissociates and becomes single-stranded; in this case the temperature at which an antimiR (a microRNA inhibitor) will dissociate from complementary RNA.

Tiny

A locked nucleic acid (LNA)-containing 8-mer antimiR (microRNA inhibitor) with a complete phosphorothioate backbone targeting the seed region of a microRNA or microRNA family.

P-bodies

Cytoplasmic sites of mRNA turnover. Also referred to as stress granules.

MyomiRs

The collection of microRNAs co-expressed with three different myosin heavy chain (MYH) genes: MYH6 (miR-208a), MYH7 (miR-208b) and MYH7B (miR-499).

MED13

Mediator of RNA polymerase II transcription subunit 13 (also known as THRAP1); a component of the mediator complex that can associate with numerous nuclear hormone receptors and have key roles in metabolic control. MED13 is regulated by the microRNA miR-208.

Aneurysm

An abnormal widening or ballooning of a portion of an artery resulting from weakness in the wall of the blood vessel.

Marfan syndrome

A systemic connective tissue disorder in which aortic aneurysm formation is the leading cause of death.

Angiotensin II type 1 receptor

(AT1). The receptor through which angiotensin II exerts most of its cardiac actions. This receptor has been associated with hypertension, cardiac hypertrophy and myocardial infarction, and is a direct target of the microRNA miR-155.

Viral myocarditis

Inflammation of the heart that can lead to cardiomyopathy.

Miravirsen

Pharmacological name for antimiR-122 (a microRNA inhibitor targeting miR-122), which has shown therapeutic efficacy in clinical trials by providing long-lasting suppression of viraemia.

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van Rooij, E., Olson, E. MicroRNA therapeutics for cardiovascular disease: opportunities and obstacles. Nat Rev Drug Discov 11, 860–872 (2012). https://doi.org/10.1038/nrd3864

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