Abstract Body: Introduction: In collaboration with University of Arizona biotech spinoff Avery Therapeutics, our laboratory developed a tissue engineered biologic combining human neonatal dermal fibroblasts and human iPSC-derived cardiomyocytes to treat chronic ischemic heart failure. While Guideline Directed Medical Therapy can improve outcomes and slow disease progression in some patients, these treatments fail to address the fundamental cause of disease: fibrosis.
Research Questions/Hypothesis: We hypothesize our biologic will improve structure and function of the chronically infarcted heart via an immunomodulatory mechanism of action (MOA.)
Goals/Aims: Evaluate the safety, efficacy, & MOA of the biologic using immune competent Yucatan mini swine, rats, and mice models.
Methods/Approach: Heart failure was allowed to develop for 3-4 weeks post-infarction prior to treatment. Functional outcomes were assessed through MRI, solid-state micromanometer derived pressure/volume loop analyses, ECG monitoring 24/7, and activity monitor data. Tissue repair and transcriptomic profiles were evaluated using histopathology and Digital Spatial Profiling.
Results/Data: Six months post-treatment with the biologic, there were significant increases in LV contractility (p < 0.05) and improved LV remodeling. No ventricular arrhythmias or changes in LV filling were observed. Histopathological data showed a reduction in fibrosis, with cardiomyocytes replacing scar tissue. We documented an immune modulatory response resulting from the biologic with recruitment of CD45+ immune cells (p=0.003), with a decrease in classically activated M1 macrophages (pro-inflammatory) and an increase in alternatively activated M2 macrophage (reparative) phenotypes.
Conclusion: The biologic demonstrated improvements in LV structure and function, promoting cardiac repair mediated via an immunomodulatory mechanism. These data are particularly exciting as the mechanism is not cardiac specific, suggesting potential applications in other diseases where inflammation and fibrosis result in cell loss.