biostudies-literatureMarban ENHLBI NIH HHS877-885https://www.ebi.ac.uk/biostudies/studies/S-EPMC11469554biostudies-literatureUnknown135(8)All Food and Drug Administration-approved noncoding RNA (ncRNA) drugs (n≈20) target known disease-causing molecular pathways by mechanisms such as antisense. In a fortuitous evolution of work on regenerative medicine, my coworkers and I inverted the RNA drug discovery process: first we identified natural disease-modifying ncRNAs, then used them as templates for new synthetic RNA drugs. Mechanism was probed only after bioactivity had been demonstrated. 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 choCirculation researchDeconstructing Regenerative Medicine: From Mechanistic Studies of Cell Therapy to Novel Bioinspired RNA Drugs.PMC11469554R01 HL155346R01 HL167921R01 HL164588R01 HL142579R01 HL168296Marban EfalseDeconstructing Regenerative Medicine: From Mechanistic Studies of Cell Therapy to Novel Bioinspired RNA Drugs.All Food and Drug Administration-approved noncoding RNA (ncRNA) drugs (n≈20) target known disease-causing molecular pathways by mechanisms such as antisense. In a fortuitous evolution of work on regenerative medicine, my coworkers and I inverted the RNA drug discovery process: first we identified natural disease-modifying ncRNAs, then used them as templates for new synthetic RNA drugs. Mechanism was probed only after bioactivity had been demonstrated. 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 cho2024-01-01T00:00:00Z2024 Sep2026-06-03T20:23:40.007Z2026-05-01T03:10:14.392ZS-EPMC114695543932584710.1161/CIRCRESAHA.124.32305810.1161/circresaha.124.323058