Cardiosphere-derived exosomal microRNAs for myocardial repair in pediatric dilated cardiomyopathy

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Science Translational Medicine  09 Dec 2020:
Vol. 12, Issue 573, eabb3336
DOI: 10.1126/scitranslmed.abb3336

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Curbing cardiomyopathy

Stem cells and exosomes have been investigated as potential treatments for cardiovascular applications with varying degrees of success. Here, Hirai et al. treated a porcine model of dilated cardiomyopathy with cardiosphere-derived cells (CDCs) or CDCs pretreated to prevent release of their exosomes. Cardiac repair was achieved with injection of CDCs, but blocking exosome release abrogated functional recovery—even when exosomes were coinjected with cells. Moving into the clinic, they safely treated five pediatric patients with dilated cardiomyopathy with CDCs. Analysis of patients’ CDC-derived exosomes implicated miR-146a-5p in inhibiting inflammatory cytokine expression. Results demonstrate the safety of CDC treatment and highlight a potential mechanism of therapeutic efficacy.


Although cardiosphere-derived cells (CDCs) improve cardiac function and outcomes in patients with single ventricle physiology, little is known about their safety and therapeutic benefit in children with dilated cardiomyopathy (DCM). We aimed to determine the safety and efficacy of CDCs in a porcine model of DCM and translate the preclinical results into this patient population. A swine model of DCM using intracoronary injection of microspheres created cardiac dysfunction. Forty pigs were randomized as preclinical validation of the delivery method and CDC doses, and CDC-secreted exosome (CDCex)–mediated cardiac repair was analyzed. A phase 1 safety cohort enrolled five pediatric patients with DCM and reduced ejection fraction to receive CDC infusion. The primary endpoint was to assess safety, and the secondary outcome measure was change in cardiac function. Improved cardiac function and reduced myocardial fibrosis were noted in animals treated with CDCs compared with placebo. These functional benefits were mediated via CDCex that were highly enriched with proangiogenic and cardioprotective microRNAs (miRNAs), whereas isolated CDCex did not recapitulate these reparative effects. One-year follow-up of safety lead-in stage was completed with favorable profile and preliminary efficacy outcomes. Increased CDCex-derived miR-146a-5p expression was associated with the reduction in myocardial fibrosis via suppression of proinflammatory cytokines and transcripts. Collectively, intracoronary CDC administration is safe and improves cardiac function through CDCex in a porcine model of DCM. The safety lead-in results in patients provide a translational framework for further studies of randomized trials and CDCex-derived miRNAs as potential paracrine mediators underlying this therapeutic strategy.

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