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

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Publication Year:
2025
Authors:
Ahmed Gamal-Eldin Ibrahim, Alessandra Ciullo, Hiroaki Komuro, Kazutaka Miyamoto, Xaviar M Jones, Shukuro Yamaguchi, Kara Tsi, Jessica Anderson, Joshua Godoy Coto, Diana Kitka, Ke Liao, Chang Li, Alice Rannou, Asma Nawaz, Ashley Morris, Cristina H Marban, Jamie Lee, Nancy Manriquez, Yeojin Hong, Arati Naveen Kumar, James F Dawkins, Russell G Rogers, Eduardo Marban
PubMed ID:
41337545
Funding Grants:
Public Summary:
Scientists have developed a new, biologically inspired RNA drug called TY1 that shows significant promise in healing the heart after a heart attack. The drug works by boosting a specific enzyme that cleans up stray, damaged DNA inside cells. Rather than acting on the heart directly, TY1 targets the body's immune cells (macrophages), prompting them to release tiny healing packages that travel to the heart and successfully reduce scarring. Because this drug relies on these naturally secreted packages to deliver its healing effects, researchers have dubbed TY1 the very first of a brand-new class of medicines called "exomers," which opens up a completely novel approach to repairing damaged tissue.
Scientific 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.