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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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References

  1. Benjamin, E. J. et al. Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation 135, e146–e603 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Savarese, G. & Lund, L. H. Global public health burden of heart failure. Card. Fail. Rev. 3, 7–11 (2017).

    PubMed  PubMed Central  Google Scholar 

  3. Sullenger, B. A. & Nair, S. From the RNA world to the clinic. Science 352, 1417–1420 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Drusco, A. & Croce, C. M. MicroRNAs and cancer: a long story for short RNAs. Adv. Cancer Res. 135, 1–24 (2017).

    PubMed  Google Scholar 

  5. Thum, T. Noncoding RNAs and myocardial fibrosis. Nat. Rev. Cardiol. 11, 655–663 (2014).

    CAS  PubMed  Google Scholar 

  6. Devaux, Y. et al. Long noncoding RNAs in cardiac development and ageing. Nat. Rev. Cardiol. 12, 415–425 (2015).

    CAS  PubMed  Google Scholar 

  7. Zheng, G. X. et al. Massively parallel digital transcriptional profiling of single cells. Nat. Commun. 8, 14049 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Kolodziejczyk, A. A., Kim, J. K., Svensson, V., Marioni, J. C. & Teichmann, S. A. The technology and biology of single-cell RNA sequencing. Mol. Cell 58, 610–620 (2015).

    CAS  PubMed  Google Scholar 

  9. Han, Y., Gao, S., Muegge, K., Zhang, W. & Zhou, B. Advanced applications of RNA sequencing and challenges. Bioinform. Biol. Insights 9, 29–46 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Robertson, G. et al. De novo assembly and analysis of RNA-seq data. Nat. Methods 7, 909–912 (2010).

    CAS  PubMed  Google Scholar 

  11. Tang, F. et al. mRNA-Seq whole-transcriptome analysis of a single cell. Nat. Methods 6, 377–382 (2009).

    CAS  PubMed  Google Scholar 

  12. Frumkin, D. et al. Amplification of multiple genomic loci from single cells isolated by laser micro-dissection of tissues. BMC Biotechnol. 8, 17 (2008).

    PubMed  PubMed Central  Google Scholar 

  13. Hayashi, T. et al. Single-cell gene profiling of planarian stem cells using fluorescent activated cell sorting and its “index sorting” function for stem cell research. Dev. Growth Differ. 52, 131–144 (2010).

    CAS  PubMed  Google Scholar 

  14. Hashimshony, T., Wagner, F., Sher, N. & Yanai, I. CEL-Seq: single-cell RNA-Seq by multiplexed linear amplification. Cell Rep. 2, 666–673 (2012).

    CAS  PubMed  Google Scholar 

  15. Picelli, S. et al. Smart-seq2 for sensitive full-length transcriptome profiling in single cells. Nat. Methods 10, 1096–1098 (2013).

    CAS  PubMed  Google Scholar 

  16. Lee, R. C., Feinbaum, R. L. & Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843–854 (1993).

    CAS  PubMed  Google Scholar 

  17. Pasquinelli, A. E. et al. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature 408, 86–89 (2000).

    CAS  PubMed  Google Scholar 

  18. Rao, P. K. et al. Loss of cardiac microRNA-mediated regulation leads to dilated cardiomyopathy and heart failure. Circ. Res. 105, 585–594 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Sayed, D., Hong, C., Chen, I. Y., Lypowy, J. & Abdellatif, M. MicroRNAs play an essential role in the development of cardiac hypertrophy. Circ. Res. 100, 416–424 (2007).

    CAS  PubMed  Google Scholar 

  20. Liu, X. et al. miR-222 is necessary for exercise-induced cardiac growth and protects against pathological cardiac remodeling. Cell Metab. 21, 584–595 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Akat, K. M. et al. Comparative RNA-sequencing analysis of myocardial and circulating small RNAs in human heart failure and their utility as biomarkers. Proc. Natl Acad. Sci. USA 111, 11151–11156 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Lopez, J. P. et al. Biomarker discovery: quantification of microRNAs and other small non-coding RNAs using next generation sequencing. BMC Med. Genomics 8, 35 (2015).

    PubMed  PubMed Central  Google Scholar 

  23. Freedman, J. E. et al. Diverse human extracellular RNAs are widely detected in human plasma. Nat. Commun. 7, 11106 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Danielson, K. M. et al. Plasma circulating extracellular RNAs in left ventricular remodeling post-myocardial infarction. EBioMedicine 32, 172–181 (2018).

    PubMed  PubMed Central  Google Scholar 

  25. Neumann, A. et al. MicroRNA 628-5p as a novel biomarker for cardiac allograft vasculopathy. Transplantation 101, e26–e33 (2017).

    CAS  PubMed  Google Scholar 

  26. Wang, G. K. et al. Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardial infarction in humans. Eur. Heart J. 31, 659–666 (2010).

    PubMed  Google Scholar 

  27. Bar, C., Chatterjee, S. & Thum, T. Long noncoding RNAs in cardiovascular pathology, diagnosis, and therapy. Circulation 134, 1484–1499 (2016).

    PubMed  Google Scholar 

  28. Lee, J. H. et al. Analysis of transcriptome complexity through RNA sequencing in normal and failing murine hearts. Circ. Res. 109, 1332–1341 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Yang, K. C. et al. Deep RNA sequencing reveals dynamic regulation of myocardial noncoding RNAs in failing human heart and remodeling with mechanical circulatory support. Circulation 129, 1009–1021 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Ounzain, S. et al. Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs. Eur. Heart J. 36, 353–368a (2015).

    CAS  PubMed  Google Scholar 

  31. Kaikkonen, M. U. et al. Genome-wide dynamics of nascent noncoding RNA transcription in porcine heart after myocardial infarction. Circ. Cardiovasc. Genet. 10, e001702 (2017).

    CAS  PubMed  Google Scholar 

  32. Fiedler, J. et al. Development of long noncoding RNA-based strategies to modulate tissue vascularization. J. Am. Coll. Cardiol. 66, 2005–2015 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Kumarswamy, R. et al. Circulating long noncoding RNA, LIPCAR, predicts survival in patients with heart failure. Circ. Res. 114, 1569–1575 (2014).

    CAS  PubMed  Google Scholar 

  34. de Gonzalo-Calvo, D. et al. Circulating long-non coding RNAs as biomarkers of left ventricular diastolic function and remodelling in patients with well-controlled type 2 diabetes. Sci. Rep. 6, 37354 (2016).

    PubMed  PubMed Central  Google Scholar 

  35. Gu, M. et al. Circulating LncRNAs as novel, non-invasive biomarkers for prenatal detection of fetal congenital heart defects. Cell. Physiol. Biochem. 38, 1459–1471 (2016).

    CAS  PubMed  Google Scholar 

  36. Kitow, J. et al. Mitochondrial long noncoding RNAs as blood based biomarkers for cardiac remodeling in patients with hypertrophic cardiomyopathy. Am. J. Physiol. Heart Circ. Physiol. 311, H707–H712 (2016).

    PubMed  Google Scholar 

  37. Xu, Y. J., Huang, R. T., Gu, J. N. & Jiang, W. F. Identification of long non-coding RNAs as novel biomarker and potential therapeutic target for atrial fibrillation in old adults. Oncotarget 7, 10803–10811 (2016).

    PubMed  PubMed Central  Google Scholar 

  38. Yan, Y. Y. et al. Circulating long noncoding RNA UCA1 as a novel biomarker of acute myocardial infarction. Biomed. Res. Int. 2016, 8079372 (2016).

    PubMed  PubMed Central  Google Scholar 

  39. Gao, L. et al. Circulating long noncoding RNA HOTAIR is an essential mediator of acute myocardial infarction. Cell Physiol. Biochem. 44, 1497–1508 (2017).

    CAS  PubMed  Google Scholar 

  40. Xuan, L. N. et al. Circulating long non-coding RNAs NRON and MHRT as novel predictive biomarkers of heart failure. J. Cell. Mol. Med. 21, 1803–1814 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Gupta, S. K. et al. Quaking inhibits doxorubicin-mediated cardiotoxicity through regulation of cardiac circular RNA expression. Circ. Res. 122, 246–254 (2018).

    CAS  PubMed  Google Scholar 

  42. Aufiero, S., Reckman, Y. J., Pinto, Y. M. & Creemers, E. E. Circular RNAs open a new chapter in cardiovascular biology. Nat. Rev. Cardiol. https://doi.org/10.1038/s41569-019-0185-2 (2019).

    Article  PubMed  Google Scholar 

  43. Nigro, J. M. et al. Scrambled exons. Cell 64, 607–613 (1991).

    CAS  PubMed  Google Scholar 

  44. Sanger, H. L., Klotz, G., Riesner, D., Gross, H. J. & Kleinschmidt, A. K. Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures. Proc. Natl Acad. Sci. USA 73, 3852–3856 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Kos, A., Dijkema, R., Arnberg, A. C., van der Meide, P. H. & Schellekens, H. The hepatitis delta (delta) virus possesses a circular RNA. Nature 323, 558–560 (1986).

    CAS  PubMed  Google Scholar 

  46. Jeck, W. R. & Sharpless, N. E. Detecting and characterizing circular RNAs. Nat. Biotechnol. 32, 453–461 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Jia, W., Xu, B. & Wu, J. Circular RNA expression profiles of mouse ovaries during postnatal development and the function of circular RNA epidermal growth factor receptor in granulosa cells. Metabolism 85, 192–204 (2018).

    CAS  PubMed  Google Scholar 

  48. Legnini, I. et al. Circ-ZNF609 is a circular RNA that can be translated and functions in myogenesis. Mol. Cell 66, 22–37 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Li, L., Guo, J., Chen, Y., Chang, C. & Xu, C. Comprehensive CircRNA expression profile and selection of key CircRNAs during priming phase of rat liver regeneration. BMC Genomics 18, 80 (2017).

    PubMed  PubMed Central  Google Scholar 

  50. Luo, J. et al. Profiling circRNA and miRNA of radiation-induced esophageal injury in a rat model. Sci. Rep. 8, 14605 (2018).

    PubMed  PubMed Central  Google Scholar 

  51. Zeng, Y. et al. Altered expression profiles of circular RNA in colorectal cancer tissues from patients with lung metastasis. Int. J. Mol. Med. 40, 1818–1828 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Cao, Y. et al. Changing expression profiles of long non-coding RNAs, mRNAs and circular RNAs in ethylene glycol-induced kidney calculi rats. BMC Genomics 19, 660 (2018).

    PubMed  PubMed Central  Google Scholar 

  53. Werfel, S. et al. Characterization of circular RNAs in human, mouse and rat hearts. J. Mol. Cell Cardiol. 98, 103–107 (2016).

    CAS  PubMed  Google Scholar 

  54. Tan, W. L. et al. A landscape of circular RNA expression in the human heart. Cardiovasc. Res. 113, 298–309 (2017).

    CAS  PubMed  Google Scholar 

  55. Wu, H. J., Zhang, C. Y., Zhang, S., Chang, M. & Wang, H. Y. Microarray expression profile of circular RNAs in heart tissue of mice with myocardial infarction-induced heart failure. Cell. Physiol. Biochem. 39, 205–216 (2016).

    CAS  PubMed  Google Scholar 

  56. Tang, C. M. et al. CircRNA_000203 enhances the expression of fibrosis-associated genes by derepressing targets of miR-26b-5p, Col1a2 and CTGF, in cardiac fibroblasts. Sci. Rep. 7, 40342 (2017).

    PubMed  PubMed Central  Google Scholar 

  57. Zhou, B. & Yu, J. W. A novel identified circular RNA, circRNA_010567, promotes myocardial fibrosis via suppressing miR-141 by targeting TGF-beta1. Biochem. Biophys. Res. Commun. 487, 769–775 (2017).

    CAS  PubMed  Google Scholar 

  58. Siede, D. et al. Identification of circular RNAs with host gene-independent expression in human model systems for cardiac differentiation and disease. J. Mol. Cell Cardiol. 109, 48–56 (2017).

    CAS  PubMed  Google Scholar 

  59. Shang, F. F., Luo, S., Liang, X. & Xia, Y. Alterations of circular RNAs in hyperglycemic human endothelial cells. Biochem. Biophys. Res. Commun. 499, 551–555 (2018).

    CAS  PubMed  Google Scholar 

  60. Alhasan, A. A. et al. Circular RNA enrichment in platelets is a signature of transcriptome degradation. Blood 127, e1–e11 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Maass, P. G. et al. A map of human circular RNAs in clinically relevant tissues. J. Mol. Med. 95, 1179–1189 (2017).

    CAS  PubMed  Google Scholar 

  62. Lei, W. et al. Signature of circular RNAs in human induced pluripotent stem cells and derived cardiomyocytes. Stem Cell Res. Ther. 9, 56 (2018).

    PubMed  PubMed Central  Google Scholar 

  63. Devaux, Y. et al. Circular RNAs in heart failure. Eur. J. Heart Fail. 19, 701–709 (2017).

    CAS  PubMed  Google Scholar 

  64. Vausort, M. et al. Myocardial infarction-associated circular RNA predicting left ventricular dysfunction. J. Am. Coll. Cardiol. 68, 1247–1248 (2016).

    PubMed  Google Scholar 

  65. Salgado-Somoza, A., Zhang, L., Vausort, M. & Devaux, Y. The circular RNA MICRA for risk stratification after myocardial infarction. Int. J. Cardiol. Heart Vasc. 17, 33–36 (2017).

    PubMed  PubMed Central  Google Scholar 

  66. Liu, Z. Q. et al. Single-cell transcriptomics reconstructs fate conversion from fibroblast to cardiomyocyte. Nature 551, 100–104 (2017).

    PubMed  PubMed Central  Google Scholar 

  67. Lescroart, F. et al. Defining the earliest step of cardiovascular lineage segregation by single-cell RNA-seq. Science 359, 1177–1181 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Gladka, M. M. et al. Single-cell sequencing of the healthy and diseased heart reveals Ckap4 as a new modulator of fibroblasts activation. Circulation 138, 166–180 (2018).

    CAS  PubMed  Google Scholar 

  69. Blakely, K., Ketela, T. & Moffat, J. Pooled lentiviral shRNA screening for functional genomics in mammalian cells. Methods Mol. Biol. 781, 161–182 (2011).

    CAS  PubMed  Google Scholar 

  70. Zhu, S. et al. Genome-scale deletion screening of human long non-coding RNAs using a paired-guide RNA CRISPR-Cas9 library. Nat. Biotechnol. 34, 1279–1286 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Fei, T. et al. Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. Proc. Natl Acad. Sci. USA 114, E5207–E5215 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Haney, S. A. High-content screening approaches that minimize confounding factors in RNAi, CRISPR, and small molecule screening. Methods Mol. Biol. 1683, 113–130 (2018).

    CAS  PubMed  Google Scholar 

  73. Eulalio, A. et al. Functional screening identifies mi-RNAs inducing cardiac regeneration. Nature 492, 376–381 (2012).

    CAS  PubMed  Google Scholar 

  74. Ucar, A. et al. The miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy. Nat. Commun. 3, 1078 (2012).

    PubMed  Google Scholar 

  75. Fiedler, J. et al. Functional MicroRNA library screening identifies the HypoxaMiR MiR-24 as a potent regulator of smooth muscle cell proliferation and vascularization. Antioxid. Redox Signal. 21, 1167–1176 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Gupta, S. K. et al. Preclinical development of a microRNA-based therapy for elderly patients with myocardial infarction. J. Am. Coll. Cardiol. 68, 1557–1571 (2016).

    CAS  PubMed  Google Scholar 

  77. Krausz, E. High-content siRNA screening. Mol. Biosyst 3, 232–240 (2007).

    CAS  PubMed  Google Scholar 

  78. Jiang, X. et al. A novel EST-derived RNAi screen reveals a critical role for farnesyl diphosphate synthase in beta2-adrenergic receptor internalization and down-regulation. FASEB J. 26, 1995–2007 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Willingham, A. T. et al. A strategy for probing the function of noncoding RNAs finds a repressor of NFAT. Science 309, 1570–1573 (2005).

    CAS  PubMed  Google Scholar 

  80. Beermann, J. et al. A large shRNA library approach identifies lncRNA Ntep as an essential regulator of cell proliferation. Cell Death Differ. 25, 307–318 (2018).

    CAS  PubMed  Google Scholar 

  81. Pfeifer, A. & Verma, I. M. Gene therapy: promises and problems. Annu. Rev. Genom. Hum. Genet. 2, 177–211 (2001).

    CAS  Google Scholar 

  82. French, B. A., Mazur, W., Geske, R. S. & Bolli, R. Feasibility and limitations of direct in-vivo gene-transfer into porcine myocardium using replication-deficient adenoviral vectors. Circulation 90, 517–517 (1994).

    Google Scholar 

  83. Li, X. et al. Loss of AZIN2 splice variant facilitates endogenous cardiac regeneration. Cardiovasc. Res. 114, 1642–1655 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Wang, K. et al. The long noncoding RNA CHRF regulates cardiac hypertrophy by targeting miR-489. Circ. Res. 114, 1377–1388 (2014).

    CAS  PubMed  Google Scholar 

  85. Li, X. R., Zhou, J. & Huang, K. Inhibition of the lncRNA Mirt1 attenuates acute myocardial infarction by suppressing NF-kappa B activation. Cell. Physiol. Biochem. 42, 1153–1164 (2017).

    CAS  PubMed  Google Scholar 

  86. Wang, K. et al. Circular RNA mediates cardiomyocyte death via miRNA-dependent upregulation of MTP18 expression. Cell Death Differ. 24, 1111–1120 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Wang, K. et al. A circular RNA protects the heart from pathological hypertrophy and heart failure by targeting miR-223. Eur. Heart J. 37, 2602–2611 (2016).

    CAS  PubMed  Google Scholar 

  88. Wang, X. H. et al. Increased expression of microRNA-146a decreases myocardial ischaemia/reperfusion injury. Cardiovasc. Res. 97, 432–442 (2013).

    CAS  PubMed  Google Scholar 

  89. Li, Q. L. et al. Overexpression of microRNA-99a attenuates heart remodelling and improves cardiac performance after myocardial infarction. J. Cell. Mol. Med. 18, 919–928 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Nathwani, A. C. et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N. Engl. J. Med. 365, 2357–2365 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Tao, L. et al. Crucial role of miR-433 in regulating cardiac fibrosis. Theranostics 6, 2068–2083 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Long, Q. Q. et al. Long noncoding RNA Kcna2 antisense RNA contributes to ventricular arrhythmias via silencing Kcna2 in rats with congestive heart failure. J. Am. Heart Assoc. 6, e005965 (2017).

    PubMed  PubMed Central  Google Scholar 

  93. Zhang, J. et al. Long noncoding RNA upregulated in hypothermia treated cardiomyocytes protects against myocardial infarction through improving mitochondrial function. Int. J. Cardiol. 266, 213–217 (2018).

    PubMed  Google Scholar 

  94. Bar, C. et al. Telomerase expression confers cardioprotection in the adult mouse heart after acute myocardial infarction. Nat. Commun. 5, 5863 (2014).

    CAS  PubMed  Google Scholar 

  95. Ganesan, J. et al. MiR-378 controls cardiac hypertrophy by combined repression of mitogen-activated protein kinase pathway factors. Circulation 127, 2097–2106 (2013).

    CAS  PubMed  Google Scholar 

  96. Quattrocelli, M. et al. Long-term miR-669a therapy alleviates chronic dilated cardiomyopathy in dystrophic mice. J. Am. Heart Assoc. 2, e000284 (2013).

    PubMed  PubMed Central  Google Scholar 

  97. Wu, Z., Yang, H. & Colosi, P. Effect of genome size on AAV vector packaging. Mol. Ther. 18, 80–86 (2010).

    CAS  PubMed  Google Scholar 

  98. Ferreira, V. et al. Immune responses to intramuscular administration of alipogene tiparvovec (AAV1-LPL(S447X)) in a phase II clinical trial of lipoprotein lipase deficiency gene therapy. Hum. Gene Ther. 25, 180–188 (2014).

    CAS  PubMed  Google Scholar 

  99. Calcedo, R., Vandenberghe, L. H., Gao, G., Lin, J. & Wilson, J. M. Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J. Infect. Dis. 199, 381–390 (2009).

    PubMed  Google Scholar 

  100. Manno, C. S. et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat. Med. 12, 342–347 (2006).

    CAS  PubMed  Google Scholar 

  101. Kormann, M. S. et al. Expression of therapeutic proteins after delivery of chemically modified mRNA in mice. Nat. Biotechnol. 29, 154–157 (2011).

    CAS  PubMed  Google Scholar 

  102. Beermann, J., Piccoli, M. T., Viereck, J. & Thum, T. Non-coding RNAs in development and disease: background, mechanisms, and therapeutic approaches. Physiol. Rev. 96, 1297–1325 (2016).

    CAS  PubMed  Google Scholar 

  103. Sokilde, R., Newie, I., Persson, H., Borg, A. & Rovira, C. Passenger strand loading in overexpression experiments using microRNA mimics. RNA Biol. 12, 787–791 (2015).

    PubMed  PubMed Central  Google Scholar 

  104. Pankratz, F. et al. MicroRNA-100 suppresses chronic vascular inflammation by stimulation of endothelial autophagy. Circ. Res. 122, 417–432 (2018).

    CAS  PubMed  Google Scholar 

  105. Lesizza, P. et al. Single-dose intracardiac injection of pro-regenerative microRNAs improves cardiac function after myocardial infarction. Circ. Res. 120, 1298–1304 (2017).

    CAS  PubMed  Google Scholar 

  106. Yuan, J. et al. MicroRNA-378 suppresses myocardial fibrosis through a paracrine mechanism at the early stage of cardiac hypertrophy following mechanical stress. Theranostics 8, 2565–2582 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Shi, J. et al. miR-17-3p contributes to exercise-induced cardiac growth and protects against myocardial ischemia reperfusion injury. Theranostics 7, 664–676 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Bader, A. G., Brown, D., Stoudemire, J. & Lammers, P. Developing therapeutic microRNAs for cancer. Gene Ther. 18, 1121–1126 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Takeshita, F. et al. Systemic delivery of synthetic microRNA-16 inhibits the growth of metastatic prostate tumors via downregulation of multiple cell-cycle genes. Mol. Ther. 18, 181–187 (2010).

    CAS  PubMed  Google Scholar 

  110. Sanganalmath, S. K. & Bolli, R. Cell therapy for heart failure: a comprehensive overview of experimental and clinical studies, current challenges, and future directions. Circ. Res. 113, 810–834 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Chien, K. R., Zangi, L. & Lui, K. O. Synthetic chemically modified mRNA (modRNA): toward a new technology platform for cardiovascular biology and medicine. Cold Spring Harb. Perspect. Med. 5, a014035 (2014).

    PubMed  Google Scholar 

  112. Zangi, L. et al. Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction. Nat. Biotechnol. 31, 898–907 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Huang, C. L. et al. Synthetic chemically modified mrna-based delivery of cytoprotective factor promotes early cardiomyocyte survival post-acute myocardial infarction. Mol. Pharm. 12, 991–996 (2015).

    CAS  PubMed  Google Scholar 

  114. Rinaldi, C. & Wood, M. J. A. Antisense oligonucleotides: the next frontier for treatment of neurological disorders. Nat. Rev. Neurol. 14, 9–21 (2018).

    CAS  PubMed  Google Scholar 

  115. Evers, M. M., Toonen, L. J. & van Roon-Mom, W. M. Antisense oligonucleotides in therapy for neurodegenerative disorders. Adv. Drug Deliv. Rev. 87, 90–103 (2015).

    CAS  PubMed  Google Scholar 

  116. Singh, J., Kaur, H., Kaushik, A. & Peer, S. A. Review of antisense therapeutic interventions for molecular biological targets in various diseases. Int. J. Pharmacol. 7, 294–315 (2011).

    CAS  Google Scholar 

  117. Graham, M. J. et al. Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides. N. Engl. J. Med. 377, 222–232 (2017).

    CAS  PubMed  Google Scholar 

  118. Krutzfeldt, J. et al. Silencing of microRNAs in vivo with ‘antagomirs’. Nature 438, 685–689 (2005).

    PubMed  Google Scholar 

  119. Czech, M. P. MicroRNAs as therapeutic targets. N. Engl. J. Med. 354, 1194–1195 (2006).

    CAS  PubMed  Google Scholar 

  120. Thum, T. et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456, 980–U983 (2008).

    CAS  PubMed  Google Scholar 

  121. Kaur, H., Arora, A., Wengel, J. & Maiti, S. Thermodynamic, counterion, and hydration effects for the incorporation of locked nucleic acid nucleotides into DNA duplexes. Biochemistry 45, 7347–7355 (2006).

    CAS  PubMed  Google Scholar 

  122. Michalik, K. M. et al. Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth. Circ. Res. 114, 1389–1397 (2014).

    CAS  PubMed  Google Scholar 

  123. Chery, J. RNA therapeutics: RNAi and antisense mechanisms and clinical applications. Postdoc J. 4, 35–50 (2016).

    PubMed  PubMed Central  Google Scholar 

  124. Martinez, E. C. et al. MicroRNA-31 promotes adverse cardiac remodeling and dysfunction in ischemic heart disease. J. Mol. Cell. Cardiol. 112, 27–39 (2017).

    CAS  PubMed  Google Scholar 

  125. Zhou, Q. et al. Inhibition of miR-208b improves cardiac function in titin-based dilated cardiomyopathy. Int. J. Cardiol. 230, 634–641 (2017).

    PubMed  Google Scholar 

  126. Di Gregoli, K. et al. MicroRNA-181b controls atherosclerosis and aneurysms through regulation of TIMP-3 and elastin. Circ. Res. 120, 49–65 (2017).

    PubMed  PubMed Central  Google Scholar 

  127. DeVos, S. L. & Miller, T. M. Antisense oligonucleotides: treating neurodegeneration at the level of RNA. Neurotherapeutics 10, 486–497 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Viereck, J. et al. Long noncoding RNA Chast promotes cardiac remodeling. Sci. Transl Med. 8, 326ra22 (2016).

    PubMed  Google Scholar 

  129. Piccoli, M. T. et al. Inhibition of the cardiac fibroblast-enriched lncRNA Meg3 prevents cardiac fibrosis and diastolic dysfunction. Circ. Res. 121, 575–583 (2017).

    CAS  PubMed  Google Scholar 

  130. Poller, W., Tank, J., Skurk, C. & Gast, M. Cardiovascular RNA interference therapy: the broadening tool and target spectrum. Circ. Res. 113, 588–602 (2013).

    CAS  PubMed  Google Scholar 

  131. Wang, Z. et al. The long noncoding RNA Chaer defines an epigenetic checkpoint in cardiac hypertrophy. Nat. Med. 22, 1131–1139 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Wu, H., Liu, J., Li, W., Liu, G. & Li, Z. LncRNA-HOTAIR promotes TNF-alpha production in cardiomyocytes of LPS-induced sepsis mice by activating NF-kappaB pathway. Biochem. Biophys. Res. Commun. 471, 240–246 (2016).

    CAS  PubMed  Google Scholar 

  133. Du, W. W. et al. Foxo3 circular RNA promotes cardiac senescence by modulating multiple factors associated with stress and senescence responses. Eur. Heart J. 38, 1402–1412 (2017).

    CAS  PubMed  Google Scholar 

  134. Watts, J. K. & Corey, D. R. Silencing disease genes in the laboratory and the clinic. J. Pathol. 226, 365–379 (2012).

    CAS  PubMed  Google Scholar 

  135. Willms, E. et al. Cells release subpopulations of exosomes with distinct molecular and biological properties. Sci. Rep. 6, 22519 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659 (2007).

    CAS  PubMed  Google Scholar 

  137. Ha, D., Yang, N. & Nadithe, V. Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges. Acta Pharm. Sin. B 6, 287–296 (2016).

    PubMed  PubMed Central  Google Scholar 

  138. Tran, T. H., Mattheolabakis, G., Aldawsari, H. & Amiji, M. Exosomes as nanocarriers for immunotherapy of cancer and inflammatory diseases. Clin. Immunol. 160, 46–58 (2015).

    CAS  PubMed  Google Scholar 

  139. Goldie, B. J. et al. Activity-associated miRNA are packaged in Map1b-enriched exosomes released from depolarized neurons. Nucleic Acids Res. 42, 9195–9208 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Sahoo, S. et al. Exosomes from human CD34(+) stem cells mediate their proangiogenic paracrine activity. Circ. Res. 109, 724–728 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Yu, B. et al. Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection. Int. J. Cardiol. 182, 349–360 (2015).

    PubMed  Google Scholar 

  142. Bang, C. et al. Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J. Clin. Invest. 124, 2136–2146 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Ong, S. G. et al. Cross talk of combined gene and cell therapy in ischemic heart disease role of exosomal microRNA transfer. Circulation 130, S60–S69 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Willis, G. R., Kourembanas, S. & Mitsialis, S. A. Toward exosome-based therapeutics: isolation, heterogeneity, and fit-for-purpose potency. Front. Cardiovasc. Med. 4, 63 (2017).

    PubMed  PubMed Central  Google Scholar 

  145. Danhier, F. et al. PLGA-based nanoparticles: an overview of biomedical applications. J. Control. Release 161, 505–522 (2012).

    CAS  PubMed  Google Scholar 

  146. Farokhzad, O. C. & Langer, R. Impact of nanotechnology on drug delivery. ACS Nano 3, 16–20 (2009).

    CAS  PubMed  Google Scholar 

  147. Gadde, S. & Rayner, K. J. Nanomedicine meets microRNA: current advances in RNA-based nanotherapies for atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 36, e73–e79 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Duivenvoorden, R. et al. Nanoimmunotherapy to treat ischaemic heart disease. Nat. Rev. Cardiol. 16, 21–32 (2019).

    CAS  PubMed  Google Scholar 

  149. Hartmann, D. et al. MicroRNA-based therapy of GATA2-deficient vascular disease. Circulation 134, 1973–1990 (2016).

    CAS  PubMed  Google Scholar 

  150. Deng, S. et al. Neonatal heart-enriched miR-708 promotes proliferation and stress resistance of cardiomyocytes in rodents. Theranostics 7, 1953–1965 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Jia, C. et al. Gold nanoparticle-based miR155 antagonist macrophage delivery restores the cardiac function in ovariectomized diabetic mouse model. Int. J. Nanomed. 12, 4963–4979 (2017).

    CAS  Google Scholar 

  152. Zeng, Y. et al. A circular RNA binds to and activates AKT phosphorylation and nuclear localization reducing apoptosis and enhancing cardiac repair. Theranostics 7, 3842–3855 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Leuschner, F. et al. Therapeutic siRNA silencing in inflammatory monocytes in mice. Nat. Biotechnol. 29, 1005–1010 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

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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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