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Hirai, Kenta Department of Pediatric Cardiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
Ousaka, Daiki Department of Cardiovascular Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
Fukushima, Yosuke Department of Pediatric Cardiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
Kondo, Maiko Department of Pediatric Cardiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
Eitoku, Takahiro Department of Pediatric Cardiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
Shigemitsu, Yusuke Department of Pediatric Cardiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
Hara, Mayuko Department of Pediatric Cardiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
Baba, Kenji Department of Pediatric Cardiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences ORCID Kaken ID
Iwasaki, Tatsuo Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kaken ID publons
Kasahara, Shingo Department of Cardiovascular Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kaken ID publons
Ohtsuki, Shinichi Department of Pediatric Cardiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
Oh, Hidemasa Department of Regenerative Medicine, Center for Innovative Clinical Medicine, Okayama University Hospital ORCID Kaken ID researchmap
Abstract
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.
Note
This is the author's version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Translational Medicine on 573(12), 2020, DOI: 10.1126/scitranslmed.abb3336.
Published Date
2020-12-09
Publication Title
Science Translational Medicine
Volume
volume12
Issue
issue573
Publisher
American Association for the Advancement of Science
Start Page
eabb3336
ISSN
1946-6234
NCID
AA12519139
Content Type
Journal Article
language
英語
OAI-PMH Set
岡山大学
Copyright Holders
© The Authors
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PubMed ID
DOI
Web of Science KeyUT
Related Url
isVersionOf https://doi.org/10.1126/scitranslmed.abb3336
Funder Name
Japan Agency for Medical Research and Development
助成番号
19H03738