Towards enhanced translational colon-specific in vitro tissue models for assessment of drug disposition, metabolism and safety

The overarching goal of this Ph.D. project is to generate and in-depth characterize suitable colon-specific in vitro models to accurately examine colonic drug disposition, metabolism and assess the safety profile of selected compounds in the colon, with specific focus on reproducibility and scalability for pharmaceutical use. Research activities will include: (1) establishing and characterizing 1 to 2 enhanced translational colon-specific in vitro models in their capability to precisely assess colonic drug disposition, metabolism and toxicity; (2) producing a comparative data set of translational intestinal (colonic and/or small intestinal) in vitro models tackling drug disposition, metabolism and toxicity; (3) distinguishing the strengths and drawbacks of each model; (4) identifying the best suitable model(s) for in-house use at Janssen Pharmaceuticals. The main models to be used will be: (a) Primary Human Organoids (Hubrecht Organoid Technology, HUB; Utrecht, the Netherlands); (b) Human 3D Colon Microtissues (small intestinal and colonic; MatTek Life Sciences, Ashland, MA, US); (c) Caco-2 cell monolayers (human colorectal adenocarcinoma cell line), the in vitro gold standard. These models will be the basis for the studies of drug disposition, metabolism and safety, which are intended to be carried out throughout the course of the Ph.D. project. A secondment of 4 months will take place at the University of Parma (advisor: Prof. Dr. Simona Bertoni), in the 26th month of the project, for additional 4, and its specific goal is to perform absorption studies with an in vitro diseased colonoid model (e.g. Inflammatory Bowel Disease, IBD, colonoid model).