Patient-specific, combinatorial nams for gastrointestinal diseases and drug response prediction

The Department of Health and Human Services National Institutes of Health Office of the Director awarded Cincinnati Children's Hospital Medical Center a $3.24 million Cooperative Agreement on February 9, 2026, under the Trans-NIH Research Support program (CFDA 93.310) to develop combinatorial new approach methodologies (NAMs) for gastrointestinal diseases and drug response prediction.

Cincinnati Children's will establish the Cincinnati Advanced NAM Development and Operational Research Center (CANDOR) to create patient-specific in vitro and in silico NAMs modeling inflammatory bowel disease (IBD), metabolic dysfunction-associated steatotic liver disease (MASLD), and pancreatitis. The in vitro component comprises intestinal, liver, and pancreatic organoids derived from patient-derived pluripotent stem cell banks and patient-derived samples, each populated with immune cells. The in silico component builds computational models based on molecular pathways and cell-cell interactions correlated with patient outcomes and drug response, informed by deeply phenotyped patient cohorts and clinical data. The work addresses a clinical gap: current animal models prove inadequate for these gastrointestinal diseases, and limited drug options exist (none for pancreatitis), making preclinical evaluation a critical bottleneck in drug discovery.

Performance occurs in Cincinnati, Ohio, with a period of performance from the award date through December 31, 2030. The award obligates $3.24 million.

Abstract

Millions of people in the US are impacted by gastrointestinal diseases including inflammatory bowel disease (IBD), metabolic disfunction associated steatotic liver disease (masld) and pancreatitis. There are only a small number of drugs for IBD and masld, and none for pancreatitis, making this a critically significant clinical question. Animal models have proven inadequate surrogates for these diseases and reliance on current preclinical evaluations are considered to be among the most problematic steps in drug discovery. The goal of cincinnati advanced NAM development and operational research center (candor) is to develop combinatorial new approach methodologies (nams) that more accurately model the pathophysiologic complexity and drug responses in patients with these gastrointestinal (GI) diseases. We have established an interdisciplinary team of collaborators of clinicians, scientists, experimental and computational biologists with a history of developing in vitro organoid and in silico nams with a focus on inflammatory diseases of the GI tract. Candor will provide a collaborative pipeline starting with existing cohorts of deeply phenotyped patients with IBD, masld, and pancreatitis. Clinical data and patient samples will be used to build in silico nams, based on molecular pathways and cell-cell interactions that corelate with patient outcome and drug response. Each disease will have a corresponding in vitro NAM comprising intestinal, liver, and pancreatic organoids each with immune cells. Pluripotent stem cell banks have been generated from patients with each of these diseases, and healthy controls, and all organoid platforms are established and benchmarked to human samples. The aims of candor are to establish in vitro nams that accurately model clinical features of IBD, masld, and pancreatitis; to build disease-focused in silico nams that are based on gene regulatory, cell-cell interactions, and pharmacometric models from patients and combine these with data from in vitro nams; and to validate and disseminate combinatorial NAM technologies through training, outreach, and distribution.