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

Year: 2025

Type: article

Abstract: Noncoding RNAs (ncRNAs) are increasingly recognized as bioactive. Here we report the development of TY1, a synthetic ncRNA bioinspired by a naturally-occurring human small Y RNA with immunomodulatory properties. TY1 upregulates 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 either to TY1 or TREX1. Inhibition of TREX1 in macrophages blocked TY1 cardioprotection. Consistent with a central role for TREX1, TY1 attenuated DNA damage in the post-MI heart. This novel mechanism—pharmacologic upregulation of TREX1 in macrophages—establishes TY1 as the prototype for a new class of ncRNA drugs with disease-modifying bioactivity. One Sentence Summary Upregulation of three prime exonuclease, TREX1, in macrophages enhances tissue repair post myocardial infarction.

Source: Science Translational Medicine

DOI: 10.1126/scitranslmed.adp1338

Institutions: Cedars-Sinai Medical Center, Cedars-Sinai Smidt Heart Institute

Language: English

Topic: Cardiac Fibrosis and Remodeling

Subfield: Cardiology and Cardiovascular Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: California Institute for Regenerative Medicine, Cedars-Sinai Medical Center, National Institutes of Health, National Heart, Lung, and Blood Institute

Awards: G6518805075, Noncoding RNA drug TY1 as a therapeutic candidate for scleroderma and systemic sclerosis, Macrophages as effectors of cell therapy for heart failure, Biological substrate modification to suppress ventricular arrhythmias in a porcine model of chronic ischemic cardiomyopathy, Training in Advanced Heart Disease Research

OpenAlex ID: W4416965440