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Cited by 12Cardiac Fibrosis and RemodelingCardiac Ischemia and ReperfusionRNA Interference and Gene Delivery

The DOI matches its Crossref record; 2 of the 2 references it cites were found in a registry or an index.

Augmentation of DNA exonuclease TREX1 in macrophages as a therapy for cardiac ischemic injury

Open access
Ibrahim, Ahmed Gamal-Eldin, Ciullo, Alessandra, Komuro, Hiroaki, Miyamoto, Kazutaka, Jones, Xaviar M., Yamaguchi, Shukuro, Tsi, Kara, Anderson, Jessica, Godoy Coto, Joshua, Kitka, Diana, Liao, Ke, Li, Chang, Rannou, Alice, Nawaz, Asma, Morris, Ashley, Marbán, Cristina H., Lee, Jamie, Manriquez, Nancy, Hong, Yeojin, Naveen Kumar, Arati, Dawkins, James F., Rogers, Russell G., Marbán, Eduardo·2025·Science Translational Medicine
DOI 10.1126/scitranslmed.adp1338PMC PMC11257602

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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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Metadata

Authors
Ibrahim, A. G.-E., Ciullo, A., Komuro, H., Miyamoto, K., Jones, X. M., Yamaguchi, S., Tsi, K., Anderson, J., Godoy Coto, J., Kitka, D., Liao, K., Li, C., Rannou, A., Nawaz, A., Morris, A., Marbán, C. H., Lee, J., Manriquez, N., Hong, Y., Naveen Kumar, A., Dawkins, J. F., Rogers, R. G., & Marbán, E.
Affiliations
  • Cedars-Sinai Medical Center (US)
  • Cedars-Sinai Medical Center, Smidt Heart Institute, Los Angeles, CA 90048, USA.
Corresponding author
Ibrahim, Ahmed Gamal-Eldin
ORCID
Venue
Science Translational Medicine
Publisher
American Association for the Advancement of Science (AAAS)
Published
2025-12-03
Volume
17
Issue
827
Pages
eadp1338-eadp1338
ISSN
  • 1946-6234 (ISSN-L)
  • 1946-6242
DOI
10.1126/scitranslmed.adp1338
PMC
PMC11257602
OpenAlex
W4416965440
Cited by
12
References
2
Citations by year
2026: 8 · 2025: 2
FWCI
6.95
Type
journal article
Language
en
Open access
Locations
  • Science Translational Medicine (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • California Institute for Regenerative Medicine (TRAN1-15317)
  • NIH - NHLBI (R01 HL164588, T32 HL116273, R01 HL142579)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Ischemia and Reperfusion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords
TREX1, Y RNA, myocardial infarction, myocardial ischemia-reperfusion injury, macrophages, extracellular vesicles, cardioprotection, disease-modifying therapy

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