A Novel Multi-Lineage Human Intestinal Organoid Screening Platform for Drug Discovery and Preclinical Testing - ABSTRACT The drug development pipeline currently tests drug candidates on simple cell monolayers or animal models; however, 90% of new drugs fail clinical trials, wasting millions of dollars and leaving patients in need. There is an urgent need for better models of human physiology that can accurately mimic the toxicity and efficacy of drug candidates in preclinical drug testing. To address this need, our interdisciplinary team, consisting of Intero Biosystems, Inc. and the University of Michigan, has developed the first stem cell-derived Human Intestinal Organoid (HIO) that contains many of the tissue types found in the native intestine, including the inner lining of the intestine and supporting tissues such as functional smooth muscle that can undergo peristalsis, perfusable blood vessels, and neurons—effectively mimicking the human intestine “in a dish.” In this proposal, we will first validate and optimize the HIO system for use in assays for cell viability and cytotoxicity, which are common in the preclinical space. Next, we will develop a model of intestinal fibrosis for drug efficacy testing. Due to the complexity of this HIO model, it is possible to induce fibrosis with the addition of TGFβ, and a scalable qPCR panel will be developed to assess fibrotic induction. This proposal aims to make significant progress in positioning HIOs as a powerful microphysiological system that could revolutionize preclinical drug testing.
