Cardiosphere-derived exosomal microRNAs for cardiac repair in pediatric dilated cardiomyopathy: preclinical and safety lead-in phase 1 clinical studies

Introduction Stem cell therapies have been shown to improve cardiac function; however, therapeutic potential of cardiosphere-derived cells (CDCs) in dilated cardiomyopathy (DCM) and the underlying mechanisms of paracrine effectors include CDC-secreted exosomes (CDCex) mediating cardiac repair remain unknown. Purpose- We aimed to evaluate the safety and therapeutic efficacy of CDCs in swine model of DCM and translate the preclinical results into children with DCM. Methods As a preclinical study, female Yorkshire pigs (n=15) were treated by intracoronary administration of microspheres (1.0×104 particles) to develop diffuse cardiac dysfunction and animals were randomly assigned to receive placebo or 9.0×106 CDC injection pretreated by DMSO or exosome inhibitor (EI; GW4869). CDCex-derived microRNAs (miRs) profile was assessed and ventricular ejection fraction (EF) was evaluated before and 1 month after cell infusion. In safety lead-in clinical trial, 5 patients with DCM ( Results Compared with placebo control, DMSO-treated CDC infusion resulted in improved cardiac function with decrease in myocardial fibrosis (18.2±4.1% versus; 9.5±3.6%; P Conclusions Intracoronary delivery of CDCs is safe and improves cardiac function through CDCex-derived miRs secretion in swine model of DCM. The safety lead-in results in patients warrant further assessment of clinical benefits and highlight miR-146a as a major paracrine mediator of CDC's antifibrotic function for clinical therapeutics. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Research Project for Practical Application of Regenerative Medicine (16bk0104052h0001, 17bk0104052h0002, 18bk0104052h0003) by the Japan Agency for Medical Research and Development