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Abstract 2380 RNA technology to regenerate a myocardial infarct through re-activation of a developmental gene network
Abstract   Open access   Peer reviewed

Abstract 2380 RNA technology to regenerate a myocardial infarct through re-activation of a developmental gene network

Brad Amendt, Riley Leonard, Mason Sweat, Steven Eliason and William Kutschke
The Journal of biological chemistry, Vol.302(5 Supplement), 113004
05/2026
DOI: 10.1016/j.jbc.2026.113004
url
https://doi.org/10.1016/j.jbc.2026.113004View
Published (Version of record) Open Access

Abstract

Ischemic injury and adverse post-infarction myocardial remodeling are major causes of heart failure worldwide. Strategies designed to offset cell death with cardiomyocyte regeneration have, to date, not translated to routine clinical practice. We have shown by snRNA multiomics that inhibition of microRNA-200c (PMIS-miR-200c) in mice activates cardiogenic transcription factors (TFs) Tbx5, Gata4, Mef2c and Irx1 to promote cardiomyocyte (CM) maturation. The PMIS-miR-200c transgenic mice have immature, de-differentiated CMs, the first snRNA multiomics analyses of a miR knockdown mouse. PMIS-miR-200c (Plasmid-based microRNA Inhibitor System, PMIS) is a 122nt RNA molecule designed to bind mature miR-200c with a high affinity in vivo. To understand if these immature cardiomyocytes would facilitate heart repair, we preformed ligation of the left anterior descending artery (a severe myocardial infarct, MI) on Wild-Type (WT) and PMIS-miR-200c (PMIS-C) transgenic mice. Echocardiographic left ventricular (LV) ejection fraction (EF) fell from 88.41 ± 1.08% (WT) and 90% ± 1.42% (PMIS-C) (p=NS) to 28% ± 11.55% (WT) and 36% ± 9.35% at 1 day post injury (DPI) (p =NS). At 21 DPI, LVEF was 27% ± 4.31% (WT) and 64% ± 4.25% (PMIS-C) [p ≤ 0.0001]. Post-infarction LV chamber dilation was reversed in PMIS-C mice (1.136 ± 0.19 vs 0.67 ± 0.06 p ≤ 0.004 WT Vol/mass). By 9 WPI, PMIS-C heart function was within normal levels of sham and WT function prior to injury. These results demonstrate that inhibiting miR-200c following ischemic injury can recover cardiac function and prevent LV dilation. Moreover, trichrome stain showed a decrease in fibrosis at 3 WPI (WT: 57% ± 17.46 vs PMIS-C: 12% ± 3.01 p ≤ 0.001). To understand the mechanism causing this phenomenon, we analyzed expression of cardiac progenitor markers. The expression of TFs, Tbx5, Gata4, Mef2c, and Isl1 were increased at 1 and 3 DPI in PMIS-C. At 1 WPI, PMIS-Cborder zone CMs express markers of an immature CM cell state. Conclusions: Inhibiting miR-200c abrogates post-infarction LV remodeling, significantly restores LV function and reduces fibrosis after 3 weeks. Ongoing studies are investigating the therapeutic use of PMIS-miR-200c RNA through delivery in AAV and nanoparticles.
 Mouse models for heart disease Myocardial Infarct repair PEGylated-peptide delivery system for PMIS RNA Plasmid-based microRNA Inhibition System (PMIS) RNA therapeutics

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