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The journey began with the development of cardiosphere-derived cells (CDCs) for cardiac regeneration. While testing CDCs in a first-in-human trial, we discovered they worked indirectly: ncRNAs within CDC-secreted extracellular vesicles mediate the therapeutic benefits. The vast majority of such ncRNAs are fragments of unknown function. We chose several abundant ncRNA species from CDC-secreted extracellular vesicles, synthesized and screened each of them in vitro and in vivo. Those with exceptional disease-modifying bioactivity inspired new chemical entities that conform to the structural conventions of the Food and Drug Administration\u2013approved ncRNA armamentarium. This discovery arc\u2014Cell-Derived RNA from Extracellular vesicles for bioinspired Drug develOpment, or CREDO\u2014has yielded various promising lead compounds, each of which works via a unique, and often novel, mechanism. The process relies on emergent insights to shape therapeutic development. The initial focus of our inquiry\u2014CDCs\u2014are now themselves in phase 3 testing for Duchenne muscular dystrophy and its associated cardiomyopathy. But the intravenous delivery strategy and the repetitive dosing protocol for CDCs, which have proven key to clinical success, both arose from systematic mechanistic inquiry. Meanwhile, emergent insights have led to multiple cell-free therapeutic candidates: CDC-secreted extracellular vesicles are in preclinical development for ventricular arrhythmias, while the CREDO-conceived RNA drugs are in translation for diseases ranging from myocarditis to scleroderma.<\/jats:p>","DOI":"10.1161\/circresaha.124.323058","type":"journal-article","created":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T14:00:35Z","timestamp":1727359235000},"page":"877-885","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":12,"title":["Deconstructing Regenerative Medicine: From Mechanistic Studies of Cell Therapy to Novel Bioinspired RNA Drugs"],"prefix":"10.1161","volume":"135","author":[{"given":"Eduardo","family":"Marb\u00e1n","sequence":"first","affiliation":[{"name":"Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000151313.18547.A2"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.655209"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehr172"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0007195"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mayocp.2014.02.014"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.310253"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtcvs.2015.06.076"},{"key":"e_1_3_3_9_2","unstructured":"Naofumi Takehara TO Nakata M Kami D Nakamura T Matoba S Gojo S Sawada T Yaku H Matsubara H Kyoto Prefectual University of Medicine Kyoto Japan. 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