Editor’s summary

Noncoding RNAs (ncRNAs) have been shown to attenuate DNA damage and inflammatory signaling after myocardial infarction, but optimization of these treatments for the clinic remains a challenge. Ibrahim et al. design a synthetic RNA [therapeutic Y RNA 1 (TY1)] on the basis of cardioprotective biological ncRNA sequences. They demonstrate that TY1 reduced inflammation and DNA damage, in part through increased three-prime DNA exonuclease 1 (TREX1). TY1 treatment limited cardiac injury in rat and pig models of ischemia-reperfusion. Macrophages contributed to TY1 cardioprotection, and extracellular vesicles isolated from macrophages also reduced injury in rats. These results suggest that attenuating DNA damage may be an effective strategy for treating cardiac injury and other inflammatory disorders. —Allison Williams

Abstract

Noncoding RNAs (ncRNAs) are increasingly recognized as promising therapeutic candidates. Here, we report the development of therapeutic Y RNA 1 (TY1), a synthetic ncRNA bioinspired by a naturally occurring human small Y RNA with immunomodulatory properties. TY1 up-regulates three-prime DNA exonuclease 1 (TREX1), an exonuclease that rapidly degrades cytosolic DNA. In preclinical models of myocardial infarction (MI) induced by ischemia-reperfusion, TY1 reduced scar size. The cardioprotective effect of TY1 was abrogated by prior depletion of macrophages and mimicked by adoptive transfer of macrophages exposed to either TY1 or Trex1 overexpression. Inhibition of Trex1 in macrophages blocked TY1 cardioprotection. Consistent with a central role for Trex1, TY1 attenuated DNA damage in the post-MI heart. The key beneficial effects appear to be mediated by extracellular vesicles secreted by TY1-conditioned macrophages. This previously undescribed mechanism—pharmacological up-regulation of Trex1 in macrophages—establishes TY1 as the prototype for a new class of ncRNA drugs with disease-modifying bioactivity. We refer to this potential new class of ncRNA drugs as exomers because of the identification of their parent molecules in extracellular vesicles.

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REFERENCES AND NOTES

1

M. Algoet, S. Janssens, U. Himmelreich, W. Gsell, M. Pusovnik, J. Van den Eynde, W. Oosterlinck, Myocardial ischemia-reperfusion injury and the influence of inflammation. Trends Cardiovasc. Med. 33, 357–366 (2023).

2

S. Frantz, M. J. Hundertmark, J. Schulz-Menger, F. M. Bengel, J. Bauersachs, Left ventricular remodelling post-myocardial infarction: Pathophysiology, imaging, and novel therapies. Eur. Heart J. 43, 2549–2561 (2022).

3

N. Dicks, K. Gutierrez, M. Michalak, V. Bordignon, L. B. Agellon, Endoplasmic reticulum stress, genome damage, and cancer. Front. Oncol. 5, 11 (2015).

4

S. J. Forrester, D. S. Kikuchi, M. S. Hernandes, Q. Xu, K. K. Griendling, Reactive oxygen species in metabolic and inflammatory signaling. Circ. Res. 122, 877–902 (2018).

5

P. Zheng, Q. Chen, X. Tian, N. Qian, P. Chai, B. Liu, J. Hu, C. Blackstone, D. Zhu, J. Teng, J. Chen, DNA damage triggers tubular endoplasmic reticulum extension to promote apoptosis by facilitating ER-mitochondria signaling. Cell Res. 28, 833–854 (2018).

6

A. Decout, J. D. Katz, S. Venkatraman, A. Ablasser, The cGAS-STING pathway as a therapeutic target in inflammatory diseases. Nat. Rev. Immunol. 21, 548–569 (2021).

7

D. J. Cao, G. G. Schiattarella, E. Villalobos, N. Jiang, H. I. May, T. Li, Z. J. Chen, T. G. Gillette, J. A. Hill, Cytosolic DNA sensing promotes macrophage transformation and governs myocardial ischemic injury. Circulation 137, 2613–2634 (2018).

8

K. Hamidzadeh, S. M. Christensen, E. Dalby, P. Chandrasekaran, D. M. Mosser, Macrophages and the recovery from acute and chronic inflammation. Annu. Rev. Physiol. 79, 567–592 (2017).

9

S. Pereira-Lopes, T. Celhar, G. Sans-Fons, M. Serra, A. M. Fairhurst, J. Lloberas, A. Celada, The exonuclease Trex1 restrains macrophage proinflammatory activation. J. Immunol. 191, 6128–6135 (2013).

10

K. Peschke, M. Achleitner, K. Frenzel, A. Gerbaulet, S. R. Ada, N. Zeller, S. Lienenklaus, M. Lesche, C. Poulet, R. Naumann, A. Dahl, U. Ravens, C. Gunther, W. Muller, K. P. Knobeloch, M. Prinz, A. Roers, R. Behrendt, Loss of Trex1 in dendritic cells is sufficient to trigger systemic autoimmunity. J. Immunol. 197, 2157–2166 (2016).

11

N. Yan, Immune diseases associated with TREX1 and STING dysfunction. J. Interferon Cytokine Res. 37, 198–206 (2017).

12

H. Du, N. Xiao, S. Zhang, X. Zhou, Y. Zhang, Z. Lu, Y. Fu, M. Huang, S. Xu, Q. Chen, Suppression of TREX1 deficiency-induced cellular senescence and interferonopathies by inhibition of DNA damage response. iScience 26, 107090 (2023).

13

M. A. Matter, F. Paneni, P. Libby, S. Frantz, B. E. Stahli, C. Templin, A. Mengozzi, Y. J. Wang, T. M. Kundig, L. Raber, F. Ruschitzka, C. M. Matter, Inflammation in acute myocardial infarction: The good, the bad and the ugly. Eur. Heart J. 45, 89–103 (2024).

14

E. Marban, A mechanistic roadmap for the clinical application of cardiac cell therapies. Nat. Biomed. Eng. 2, 353–361 (2018).

15

A. G. Ibrahim, K. Cheng, E. Marban, Exosomes as critical agents of cardiac regeneration triggered by cell therapy. Stem Cell Rep. 2, 606–619 (2014).

16

G. de Couto, R. Gallet, L. Cambier, E. Jaghatspanyan, N. Makkar, J. F. Dawkins, B. P. Berman, E. Marban, Exosomal microRNA transfer into macrophages mediates cellular postconditioning. Circulation 136, 200–214 (2017).

17

R. Gallet, J. Dawkins, J. Valle, E. Simsolo, G. de Couto, R. Middleton, E. Tseliou, D. Luthringer, M. Kreke, R. R. Smith, L. Marban, B. Ghaleh, E. Marban, Exosomes secreted by cardiosphere-derived cells reduce scarring, attenuate adverse remodelling, and improve function in acute and chronic porcine myocardial infarction. Eur. Heart J. 38, 201–211 (2017).

18

R. G. Rogers, M. Fournier, L. Sanchez, A. G. Ibrahim, M. A. Aminzadeh, M. I. Lewis, E. Marbán, Disease-modifying bioactivity of intravenous cardiosphere-derived cells and exosomes in mdx mice. JCI Insight 4, e125754 (2019).

19

G. de Couto, E. Jaghatspanyan, M. DeBerge, W. Liu, K. Luther, Y. Wang, J. Tang, E. B. Thorp, E. Marban, Mechanism of enhanced MerTK-dependent macrophage efferocytosis by extracellular vesicles. Arterioscler. Thromb. Vasc. Biol. 39, 2082–2096 (2019).

20

J. F. Dawkins, A. Ehdaie, R. Rogers, D. Soetkamp, J. Valle, K. Holm, L. Sanchez, I. Tremmel, A. Nawaz, M. Shehata, X. Wang, A. Prakosa, J. Yu, J. E. Van Eyk, N. Trayanova, E. Marban, E. Cingolani, Biological substrate modification suppresses ventricular arrhythmias in a porcine model of chronic ischaemic cardiomyopathy. Eur. Heart J. 43, 2139–2156 (2022).

21

L. Cambier, G. de Couto, A. Ibrahim, A. K. Echavez, J. Valle, W. Liu, M. Kreke, R. R. Smith, L. Marban, E. Marban, Y RNA fragment in extracellular vesicles confers cardioprotection via modulation of IL-10 expression and secretion. EMBO Mol. Med. 9, 337–352 (2017).

22

L. Cambier, J. F. Giani, W. Liu, T. Ijichi, A. K. Echavez, J. Valle, E. Marban, Angiotensin II-induced end-organ damage in mice is attenuated by human exosomes and by an exosomal Y RNA fragment. Hypertension 72, 370–380 (2018).

23

F. Huang, N. Na, T. Ijichi, X. Wu, K. Miyamoto, A. Ciullo, M. Tran, L. Li, A. Ibrahim, E. Marban, G. de Couto, Exosomally derived Y RNA fragment alleviates hypertrophic cardiomyopathy in transgenic mice. Mol. Ther. Nucleic Acids 24, 951–960 (2021).

24

M. Winkle, S. M. El-Daly, M. Fabbri, G. A. Calin, Noncoding RNA therapeutics—Challenges and potential solutions. Nat. Rev. Drug Discov. 20, 629–651 (2021).

25

A. Ciullo, C. Li, L. Li, K. C. Ungerleider, K. Peck, E. Marban, A. G. E. Ibrahim, Biodistribution of unmodified cardiosphere-derived cell extracellular vesicles using single RNA tracing. J. Extracell. Vesicles 11, e12178 (2022).

26

K. S. Schmidt, S. Borkowski, J. Kurreck, A. W. Stephens, R. Bald, M. Hecht, M. Friebe, L. Dinkelborg, V. A. Erdmann, Application of locked nucleic acids to improve aptamer in vivo stability and targeting function. Nucleic Acids Res. 32, 5757–5765 (2004).

27

A.-M. Yu, Y. H. Choi, M.-J. Tu, RNA drugs and RNA targets for small molecules: Principles, progress, and challenges. Pharmacol. Rev. 72, 862–898 (2020).

28

H. Abou Assi, A. K. Rangadurai, H. Shi, B. Liu, M. C. Clay, K. Erharter, C. Kreutz, C. L. Holley, H. M. Al-Hashimi, 2’-O-Methylation can increase the abundance and lifetime of alternative RNA conformational states. Nucleic Acids Res. 48, 12365–12379 (2020).

29

C. Z. Chung, L. E. Seidl, M. R. Mann, I. U. Heinemann, Tipping the balance of RNA stability by 3′ editing of the transcriptome. Biochim. Biophys. Acta Gen. Subj. 1861, 2971–2979 (2017).

30

A. R. Gruber, R. Lorenz, S. H. Bernhart, R. Neubock, I. L. Hofacker, The Vienna RNA websuite. Nucleic Acids Res. 36, W70–W74 (2008).

31

J. Houseley, D. Tollervey, The many pathways of RNA degradation. Cell 136, 763–776 (2009).

32

M. Ghildiyal, P. D. Zamore, Small silencing RNAs: An expanding universe. Nat. Rev. Genet. 10, 94–108 (2009).

33

L. J. Ji, X. M. Chen, Regulation of small RNA stability: Methylation and beyond. Cell Res. 22, 624–636 (2012).

34

A. Ciullo, K. Peck, X. Jones, S. Yamaguchi, A. A. Morris, A. N. Kumar, L. Li, J. Lee, R. M. dos Santos, E. Cingolani, A. G. Ibrahim, TDO2-augmented fibroblasts secrete EVs enriched in immunomodulatory Y-derived small RNA. J. Extracell. Biol. 2, e73 (2023).

35

J. Deng, X. Bai, H. Tang, S. Pang, DNA damage promotes ER stress resistance through elevation of unsaturated phosphatidylcholine in Caenorhabditis elegans. J. Biol. Chem. 296, 100095 (2021).

36

M. Gonzalez-Quiroz, A. Blondel, A. Sagredo, C. Hetz, E. Chevet, R. Pedeux, When endoplasmic reticulum proteostasis meets the DNA damage response. Trends Cell Biol. 30, 881–891 (2020).

37

J. A. Johnston, C. L. Ward, R. R. Kopito, Aggresomes: A cellular response to misfolded proteins. J. Cell Biol. 143, 1883–1898 (1998).

38

S. Nishtala, Y. Neelamraju, S. C. Janga, Dissecting the expression relationships between RNA-binding proteins and their cognate targets in eukaryotic post-transcriptional regulatory networks. Sci. Rep. 6, 25711 (2016).

39

S. Vasudevan, Y. C. Tong, J. A. Steitz, Switching from repression to activation: MicroRNAs can up-regulate translation. Science 318, 1931–1934 (2007).

40

L. Jia, Y. Mao, Q. Ji, D. Dersh, J. W. Yewdell, S.-B. Qian, Decoding mRNA translatability and stability from the 5′ UTR. Nat. Struct. Mol. Biol. 27, 814–821 (2020).

41

K. Leppek, R. Das, M. Barna, Author correction: Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them. Nat. Rev. Mol. Cell Biol. 19, 673 (2018).

42

F. Mignone, C. Gissi, S. Liuni, G. Pesole, Untranslated regions of mRNAs. Genome Biol. 3, reviews0004.1 (2002).

43

Y. Lim, S. Arora, S. L. Schuster, L. Corey, M. Fitzgibbon, C. L. Wladyka, X. Wu, I. M. Coleman, J. J. Delrow, E. Corey, L. D. True, P. S. Nelson, G. Ha, A. C. Hsieh, Multiplexed functional genomic analysis of 5′ untranslated region mutations across the spectrum of prostate cancer. Nat. Commun. 12, 4217 (2021).

44

A. Chow, B. D. Brown, M. Merad, Studying the mononuclear phagocyte system in the molecular age. Nat. Rev. Immunol. 11, 788–798 (2011).

45

Y. Xing, X. Sun, Y. Dou, M. Wang, Y. Zhao, Q. Yang, Y. Zhao, The immuno-modulation effect of macrophage-derived extracellular vesicles in chronic inflammatory diseases. Front. Immunol. 12, 785728 (2021).

46

J. A. Welsh, D. C. I. Goberdhan, L. O’Driscoll, E. I. Buzas, C. Blenkiron, B. Bussolati, H. Cai, D. Di Vizio, T. A. P. Driedonks, U. Erdbrugger, J. M. Falcon-Perez, Q. L. Fu, A. F. Hill, M. Lenassi, S. K. Lim, M. G. Mahoney, S. Mohanty, A. Moller, R. Nieuwland, T. Ochiya, S. Sahoo, A. C. Torrecilhas, L. Zheng, A. Zijlstra, S. Abuelreich, R. Bagabas, P. Bergese, E. M. Bridges, M. Brucale, D. Burger, R. P. Carney, E. Cocucci, R. Crescitelli, E. Hanser, A. L. Harris, N. J. Haughey, A. Hendrix, A. R. Ivanov, T. Jovanovic-Talisman, N. A. Kruh-Garcia, V. Ku’ulei-Lyn Faustino, D. Kyburz, C. Lasser, K. M. Lennon, J. Lotvall, A. L. Maddox, E. S. Martens-Uzunova, R. R. Mizenko, L. A. Newman, A. Ridolfi, E. Rohde, T. Rojalin, A. Rowland, A. Saftics, U. S. Sandau, J. A. Saugstad, F. Shekari, S. Swift, D. Ter-Ovanesyan, J. P. Tosar, Z. Useckaite, F. Valle, Z. Varga, E. van der Pol, M. J. C. van Herwijnen, M. H. M. Wauben, A. M. Wehman, S. Williams, A. Zendrini, A. J. Zimmerman, M. Consortium, C. Thery, K. W. Witwer, Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches. J. Extracell. Vesicles 13, e12404 (2024).

47

A. A. Shamseddine, M. V. Airola, Y. A. Hannun, Roles and regulation of neutral sphingomyelinase-2 in cellular and pathological processes. Adv. Biol. Regul. 57, 24–41 (2015).

48

S. Nikfarjam, K. K. Singh, DNA damage response signaling: A common link between cancer and cardiovascular diseases. Cancer Med. 12, 4380–4404 (2023).

49

B. Schumacher, J. Pothof, J. Vijg, J. H. J. Hoeijmakers, The central role of DNA damage in the ageing process. Nature 592, 695–703 (2021).

50

G. Robert, J. R. Wagner, ROS-induced DNA damage as an underlying cause of aging. Adv. Geriatr. Med. Res. 2, e200024 (2020).

51

M. Motwani, S. Pesiridis, K. A. Fitzgerald, DNA sensing by the cGAS-STING pathway in health and disease. Nat. Rev. Genet. 20, 657–674 (2019).

52

Y. G. Yang, T. Lindahl, D. E. Barnes, Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell 131, 873–886 (2007).

53

J. L. Grieves, J. M. Fye, S. Harvey, J. M. Grayson, T. Hollis, F. W. Perrino, Exonuclease TREX1 degrades double-stranded DNA to prevent spontaneous lupus-like inflammatory disease. Proc. Natl. Acad. Sci. U.S.A. 112, 5117–5122 (2015).

54

E. Tseliou, J. Fouad, H. Reich, L. Slipczuk, G. de Couto, M. Aminzadeh, R. Middleton, J. Valle, L. Weixin, E. Marban, Fibroblasts rendered antifibrotic, antiapoptotic, and angiogenic by priming with cardiosphere-derived extracellular membrane vesicles. J. Am. Coll. Cardiol. 66, 599–611 (2015).

55

G. de Couto, W. Liu, E. Tseliou, B. Sun, N. Makkar, H. Kanazawa, M. Arditi, E. Marban, Macrophages mediate cardioprotective cellular postconditioning in acute myocardial infarction. J. Clin. Invest. 125, 3147–3162 (2015).

56

K. I. Mentkowski, A. Mursleen, J. D. Snitzer, L. M. Euscher, J. K. Lang, CDC-derived extracellular vesicles reprogram inflammatory macrophages to an arginase 1-dependent proangiogenic phenotype. Am. J. Physiol. Heart Circ. Physiol. 318, H1447–H1460 (2020).

57

E. Marban, Deconstructing regenerative medicine: From mechanistic studies of cell therapy to novel bioinspired RNA drugs. Circ. Res. 135, 877–885 (2024).

58

N. Salari, F. Morddarvanjoghi, A. Abdolmaleki, S. Rasoulpoor, A. A. Khaleghi, L. A. Hezarkhani, S. Shohaimi, M. Mohammadi, The global prevalence of myocardial infarction: A systematic review and meta-analysis. BMC Cardiovasc. Disord. 23, 206 (2023).

59

L. Gross, L. Blum, G. Silverman, Experimental attempts to increase the blood supply to the dog’s heart by means of coronary sinus occlusion. J. Exp. Med. 65, 91–108 (1937).

60

D. J. Lefer, E. Marban, Is cardioprotection dead? Circulation 136, 98–109 (2017).

61

K. Miyamoto, X. M. Jones, S. Yamaguchi, A. Ciullo, C. Li, J. G. Coto, K. Tsi, J. Anderson, A. Morris, E. Marbán, A. G.-E. Ibrahim, Intravenous and oral administration of the synthetic RNA drug, TY1, reverses heart failure with preserved ejection fraction in mice. Basic Res. Cardiol. 120, 363–371 (2025).

62

X. M. Jones, A. Ciullo, T. Mesquita, M. Fournier, W. Liu, L. Li, A. G. Ibrahim, E. Marban, Abstract 14651: Noncoding RNA drug, TY1, attenuates cardiac fibrosis in two mouse models of systemic sclerosis. Circulation 148, 10.1161/circ.148.suppl_1.14651 (2023).

63

R. Phillips, Targeting the DNA damage response attenuates SLE-associated B cell characteristics. Nat. Rev. Rheumatol. 19, 2 (2023).

64

T. Manolakou, D. Nikolopoulos, D. Gkikas, A. Filia, M. Samiotaki, G. Stamatakis, A. Fanouriakis, P. Politis, A. Banos, T. Alissafi, P. Verginis, D. T. Boumpas, ATR-mediated DNA damage responses underlie aberrant B cell activity in systemic lupus erythematosus. Sci. Adv. 8, eabo5840 (2022).

65

E. D. Tichy, N. Y. Ma, D. Sidibe, E. Loro, J. Kocan, D. Z. Chen, T. S. Khurana, P. Hasty, F. Mourkioti, Persistent NF-κB activation in muscle stem cells induces proliferation-independent telomere shortening. Cell Rep. 35, 109098 (2021).

66

A. C. Y. Chang, A. C. H. Chang, A. Kirillova, K. Sasagawa, W. Su, G. Weber, J. Lin, V. Termglinchan, I. Karakikes, T. Seeger, A. M. Dainis, J. T. Hinson, J. Seidman, C. E. Seidman, J. W. Day, E. Ashley, J. C. Wu, H. M. Blau, Telomere shortening is a hallmark of genetic cardiomyopathies. Proc. Natl. Acad. Sci. U.S.A. 115, 9276–9281 (2018).

67

S. Yamaguchi, K. Miyamoto, X. M. Jones, A. Ciullo, A. Morris, K. Tsi, E. Marban, A. G. E. Ibrahim, Oral bioavailability of a noncoding RNA drug, TY1, that acts on macrophages. bioRxiv 591474 (2024); https://doi.org/10.1101/2024.04.27.591474.

68

M. Hoss, P. Robins, T. J. Naven, D. J. Pappin, J. Sgouros, T. Lindahl, A human DNA editing enzyme homologous to the Escherichia coli DnaQ/MutD protein. EMBO J. 18, 3868–3875 (1999).

69

S. R. Margolis, S. C. Wilson, R. E. Vance, Evolutionary origins of cGAS-STING signaling. Trends Immunol. 38, 733–743 (2017).