(1357-B) Physiologically Relevant Human Intestinal Organoids for 3D Drug Screening

Abstract: The drug development pipeline currently tests drug candidates in animals before seeking FDA approval for clinical trials, yet 90% of new drugs fail clinical trials, wasting over $1 billion per drug on average. In late 2022, the FDA Modernization Act was signed, allowing alternative methods to replace animal testing in preclinical trials. This legislation will reduce the number of animals sacrificed in research and promote the use of more accurate predictive models to mimic complex drug behavior in humans, with cell-based assays and organoid models as expected alternatives. Organoids are complex “organ-like” 3D cellular structures that mimic aspects of the native organ in vitro, but often lack the ability to mimic many physiologic functions of an organ because they are missing essential cell types such as blood vessels, muscle, neurons, and immune cells.

Here we describe a novel stem cell-derived Human Intestinal Organoid (HIO), the first of its kind to contain many tissue types found in the native intestine, mimicking the human intestine “in a dish”. These HIOs are cultured from a highly tractable and scalable source, human pluripotent stem cells, and grown using our novel method to create complex structures including the inner lining of the intestine known as the epithelium and supporting tissue including smooth muscle, blood vessels, and neurons. These HIOs recapitulate important functions of the human intestine; they spontaneously and rhythmically contract without stimulus, suggesting functional muscle and neuronal connections and they have also been successfully attached to a simulated circulatory system (via microfluidic devices), confirming blood vessel function.

These complex HIOs can aid in disease modeling and drug development. HIOs can be stimulated to mimic intestinal fibrosis, a common complication associated with Inflammatory Bowel Diseases (IBD) like Crohn’s and Ulcerative Colitis, with no treatments available currently. This capability opens new avenues for studying and testing drugs targeting IBD-related complications, providing a valuable tool in the ongoing search for effective drugs to treat these diseases. By moving away from traditional animal testing towards more complex human models of the intestine, we aim to enhance the efficiency of drug development, reduce costs, and contribute to the discovery of safer and more effective pharmaceuticals.