New approach methodologies in Crohn's disease link molecular disease subtypes to clinical outcomes

Current clinical decision-making is hindered by the absence of predictive preclinical models that faithfully bridge molecular diversity to patient outcomes. Here, we apply the principle of abstraction-deriving essential features from human tissues to build next-generation new approach methodologies (NAMs) that transform patient-derived organoids (PDOs) into predictive vehicles for Crohn's disease (CD). From our living biobank of adult stem cell-derived colonic PDOs, we previously defined two molecular CD subtypes: immune-deficient infectious CD (IDICD) and stress and senescence-induced fibrostenotic CD (S2FCD), each defined by unique genomic, transcriptomic, and functional profiles with matched therapeutic vulnerabilities. In this study, we prospectively anchored PDO-derived molecular phenotypes to real-world clinical outcomes, revealing that S2FCD maps to baseline and progressive colonic disease activity, whereas IDICD tracks with prior ileocecal surgery, penetrating disease behavior, as well as baseline and progressive ileal disease activity. By abstracting NAMs from human tissues and cycling insights between small-"n" organoids and Phase 3-sized datasets, this framework recasts PDOs as dynamic, predictive platforms that capture the past, present, and future of disease behavior. Beyond oncology, this work establishes PDOs as vehicles for prospective clinical trial-like studies in inflammatory diseases and highlights colonic immune dysfunction as a potential driver of ileal CD.NEW & NOTEWORTHY In this prospective study, Penrose et al. evaluate a living biobank of genotyped and phenotyped patient-derived organoids (PDOs) as predictive tools in Crohn's disease, demonstrating their ability to faithfully capture past, present, and future disease behavior. By positioning PDOs as new approach methodologies (NAMs), this work extends PDO-informed precision medicine beyond oncology and into complex inflammatory disorders, translating molecular diversity into actionable clinical insights.