CLINICAL TRANSLATION OF COLON ORGANOID REGENERATIVE MEDICINE (ATORM-C): FROM PRECLINICAL OPTIMIZATION TO FIRST-IN-HUMAN PROOF-OF-CONCEPT IN REFRACTORY INTESTINAL ULCERS

초록

Background & Aims Intestinal organoid transplantation is a promising strategy for mucosal regeneration, yet optimal cellular states and delivery conditions remain undefined. This study investigated whether therapeutic efficacy is governed by culture-induced cellular states and aimed to optimize a clinically applicable transplantation strategy. To facilitate translation to human therapy. a porcine model was employed to refine endoscopic delivery under conditions identical to those used in clinical practice. Methodology Immature Colon Organoids (ICOs) and Mature Colon Organoids (MCOs) were characterized using scRNA-seq and functional assays. Therapeutic efficacy was assessed in DSS-induced colitis mice, while procedural feasibility was validated in a porcine model using clinical-grade endoscopic equipment. Translating these findings, a first-in-human study (n=4) evaluated the safety and preliminary efficacy of endoscopic ICO transplantation in patients with refractory intestinal Behçet’s disease. Results ICOs exhibited a culture-defined regenerative transcriptomic signature lost upon maturation. In DSS-induced colitis mice, ICOs significantly improved survival and histological scores via stable engraftment and paracrine modulation. In a porcine model, autologous transplantation confirmed robust mucosal integration and procedural safety under clinical conditions. Translating these findings, interim analysis of a first-in-human study (n=4) revealed that endoscopic ICO administration was well-tolerated, demonstrating a favorable safety profile with distinct signals of mucosal healing and clinical improvement in refractory intestinal Behçet’s disease. Conclusion Therapeutic efficacy of colon organoids relies on a primed regenerative state of CBCs. ICOs promote mucosal restoration via engraftment and paracrine modulation. Critically, we achieved successful first-in-human transition in intestinal Behçet’s disease. Interim outcomes from four treated patients demonstrate a favorable safety profile and distinct signals of endoscopic improvement. These findings establish ICOs as a clinically actionable cell therapy platform, validating the translational robustness of our defined regenerative organoid strategy.