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RNA-based diagnostic and therapeutic strategies for cardiovascular disease

Nature Reviews Cardiology volume 16, pages 661–674 (2019)Cite this article

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Abstract

Cardiovascular diseases are the leading cause of death globally and are associated with increasing financial expenditure. With the availability of next-generation sequencing technologies since the early 2000s, non-coding RNAs such as microRNAs, long non-coding RNAs and circular RNAs have been assessed as potential therapeutic targets for numerous diseases, including cardiovascular diseases. In this Review, we summarize current approaches employed to screen for novel coding and non-coding RNA candidates with diagnostic and therapeutic potential in cardiovascular disease, including next-generation sequencing, functional high-throughput RNA screening and single-cell sequencing technologies. Furthermore, we highlight viral-based delivery tools that have been widely used to evaluate the therapeutic utility of both coding and non-coding RNAs in the context of cardiovascular disease. Finally, we discuss the potential of using oligonucleotide-based molecular products such as modified RNA, small interfering RNA and RNA mimics/inhibitors for the treatment of cardiovascular diseases. Given that many non-coding RNAs have not yet been functionally annotated, the number of potential RNA diagnostic and therapeutic targets for cardiovascular diseases will continue to expand for years to come.

Key points

  • RNA sequencing technology has been used to identify non-coding RNAs that might have a role in the pathogenesis of cardiovascular disease and that might be used as treatment targets.

  • Advantages of non-coding RNAs as diagnostic biomarkers include ease of detection in body fluids, cell type-specific expression patterns and fluctuations in expression levels in response to stress or disease.

  • Transcripts of non-coding RNAs can be packaged into viral vectors and delivered into target cells to mediate their therapeutic effect.

  • Synthetic oligonucleotides, such as microRNA mimics and modified mRNAs, have also been gaining more attention as potential RNA delivery tools, given their advantages such as ease of dosage control and low immunogenicity.

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Fig. 1: Development pipeline of RNA-based diagnostics and therapeutics for cardiovascular disease.
Fig. 2: Functional high-throughput screening.
Fig. 3: Summary scheme of viral-based and oligonucleotide-based RNA delivery.
Fig. 4: Exosome-based and nanoparticle-based RNA therapies for cardiovascular diseases.

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Acknowledgements

T.T. is supported by grants from the European Research Council (consolidator grant), the European Union (EU) Horizon 2020 programme (for CardioReGenix), the ERANet CVD (project EXPERT) and the Deutsche Forschungsgemeinschaft (Th903/19-1, Th903/20-1 and Th903/22-1). The authors thank C. Bär and S. Chatterjee (Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany) for help with manuscript editing.

Reviewer information

Nature Reviews Cardiology thanks K. Rayner, F. Martellli and the other anonymous reviewer(s), for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany

    Dongchao Lu & Thomas Thum

  2. Cardior Pharmaceuticals GmbH, Hannover Medical School, Hannover, Germany

    Thomas Thum

  3. National Heart and Lung Institute, Imperial College London, London, UK

    Thomas Thum

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  1. Dongchao Lu
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  2. Thomas Thum
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Both authors researched the data for this article, discussed the content, wrote the manuscript and reviewed and/or edited the manuscript before submission.

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Correspondence to Thomas Thum.

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Competing interests

T.T. has filed several microRNA-based and long-non-coding-RNA-based patents in cardiovascular medicine and is the founder and shareholder of Cardior Pharmaceuticals GmbH. D.L. declares no competing interests.

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Glossary

Non-coding RNAs

RNA molecules that are not translated into a protein.

microRNAs

(miRNAs). Endogenous, small non-coding RNAs ~20–22 nucleotides in length that can regulate gene expression.

Long non-coding RNAs

(lncRNAs). Non-coding RNA transcripts >200 nucleotides in length.

Circular RNAs

(circRNAs). Single-stranded, non-coding RNA transcripts that form a covalently closed continuous loop.

mRNA

A large family of RNA molecules that transfer genetic information from DNA to the ribosome.

Short hairpin RNA

(shRNA). An artificially engineered RNA molecule with a tight hairpin turn that can be used to silence gene expression.

miRNA mimics

Chemically modified RNAs that mimic endogenous microRNAs.

miRNA sponge

RNA transcripts containing multiple high-affinity microRNA (miRNA)-binding sequences that can sequester miRNAs from their endogenous target mRNAs.

Small interfering RNA

(siRNA). Small RNA transcripts ~20–22 nucleotides in length that can be used to disrupt the translation of proteins by binding to and promoting the degradation of mRNA at specific sequences.

Modified mRNA

(modRNA). Chemically modified mRNA with improved protein translation capacity, which is accomplished by reducing potential mutagenic and immunological effects.

Antisense oligonucleotides

(ASOs). Short, synthetic oligonucleotides ~15–25 nucleotides in length designed to bind to and degrade complementary RNA targets.

Locked nucleic acid

(LNA). A synthetic nucleic acid analogue containing a bridged, bicyclic sugar moiety, which has high affinity and specificity for complementary RNA and DNA.

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Lu, D., Thum, T. RNA-based diagnostic and therapeutic strategies for cardiovascular disease. Nat Rev Cardiol 16, 661–674 (2019). https://doi.org/10.1038/s41569-019-0218-x

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