Augmentation of DNA exonuclease TREX1 in macrophages as a therapy for cardiac ischemic injury
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 <i>Trex1</i> overexpression. Inhibition of <i>Trex1</i> in macrophages blocked TY1 cardioprotection. Consistent with a central role for <i>Trex1</i>, 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 <i>Trex1</i> 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.
Authors
- Xaviar M Jones (ORCID: https://orcid.org/0000-0003-1815-4166)
- Jamie Lee (ORCID: https://orcid.org/0009-0001-3516-6380)
- Joshua Godoy Coto (ORCID: https://orcid.org/0009-0006-9510-4209)
- Alice Rannou (ORCID: https://orcid.org/0000-0002-7683-7523)
- Russell G. Rogers (ORCID: https://orcid.org/0000-0003-2438-7433)
- Eduardo Marbán (ORCID: https://orcid.org/0000-0002-3863-280X)
- Jessica Anderson (ORCID: https://orcid.org/0009-0006-2016-7109)
- James Dawkins (ORCID: https://orcid.org/0000-0002-2387-1488)
- Ke Liao (ORCID: https://orcid.org/0000-0002-3475-9598)
- Hiroaki Komuro (ORCID: https://orcid.org/0000-0002-8249-6761)
- Alessandra Ciullo (ORCID: https://orcid.org/0000-0002-8681-3883)
- Arati Naveen Kumar (ORCID: https://orcid.org/0000-0002-9877-5239)
- Yeojin Hong
- Diána Kitka (ORCID: https://orcid.org/0000-0002-8319-5960)
- Ashley Morris (ORCID: https://orcid.org/0009-0006-8094-3560)
- Kara Tsi (ORCID: https://orcid.org/0009-0003-8593-7037)
- Cristina H. Marbán
- Nancy Manriquez (ORCID: https://orcid.org/0009-0002-9429-1824)
- Kazutaka Miyamoto (ORCID: https://orcid.org/0009-0005-8220-1205)
- Shukuro Yamaguchi (ORCID: https://orcid.org/0000-0002-5320-6366)
- Ahmed Ibrahim (ORCID: https://orcid.org/0000-0002-1657-7432)
- Chang Li (ORCID: https://orcid.org/0009-0003-1662-2795)
- Asma Nawaz
Institutions
- Cedars-Sinai Medical Center (US)
- Cedars-Sinai Smidt Heart Institute (US)
Publication Details
- Journal
- Science Translational Medicine
- Published
- 2025-12-03
- DOI
- https://doi.org/10.1126/scitranslmed.adp1338
- Citations
- 1
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.80