There is a growing need to address the high failure rate of drug candidates as they progress through clinical trials. Read how technological advances are enabling the drug development process to more effectively translate results from preclinical experiments to late-stage clinical trials.

The microbiome has been shown to play roles in many different disease processes and is implicated in many more, from infectious and gastrointestinal diseases to autoimmune and neurological disorders. Advanced models of the gut leveraging intestinal and colonic stem cells are enabling the development of more reliable and robust systems for evaluating the impact of changes in the microbiome on gut health and screening potential drug candidates, including small molecules, biologics, and live biotherapeutics.

The ability to grow and expand primary human epithelial cells in vitro has been a significant advancement in the field of gastrointestinal biology. Here, we test human primary intestinal epithelial cells from multiple human donors in the RepliGut Planar system to see if they can recapitulate a similar response and to capture the variability that may occur in humans from a genetically diverse background.

Due to a lack of robust in vivo gut models, animal studies are generally required to evaluate gut toxicity. However, these studies can be lengthy and expensive and may not accurately recapitulate the behavior of the human gastrointestinal tract.  More efficient development of drugs with attractive side effect profiles requires robust, easy-to-use, cost-effective in vitro gut models that are physiologically representative of the human intestinal tract and thus predictive of in vivo behavior.

The variety of normal and diseased human tissues needed to perform comprehensive screening of drug candidates is a key resource for next-generation preclinical models, but obtaining these tissues is challenging. Gene editing enables us to offer a diverse array of human gut models tailored for specific research programs.

Intestinal inflammatory diseases are highly complex, which has thus far prevented development of an effective in vitro disease model. With access to a donor-derived cell biobank and the ability to recapitulate regionspecific environments of the intestine, Altis Biosystems is working toward the development of an in vitro RepliGut model to accurately recapitulate the complex intestinal inflammatory microenvironments.

Advanced microphysiological systems can replicate aspects of intestinal complexity, such as epithelium self-renewal by stem cells in in vitro crypts or the interactions of microbes and intestinal epithelium mediated by a mucus layer. Availability of such models is key to progress in compound screening, disease modeling, and microbiome research.

Gastrointestinal (GI) issues are common side effects of many drugs. Anticipating such side effects before clinical trials is limited by a lack of effective models for evaluating preclinical candidates for their potential to cause diarrhea, nausea, and other gut-related side effects. This article reviews an in vitro human intestinal model is helping develop a system that could help pharma companies identify GI toxicity issues early in the drug development process.

Scott Magness, Chief Scientific Advisor at Altis Biosystems, discusses the impact that RepliGut®- a human stem cell-derived platform that recreates the intestinal epithelium - may have on stem cell research and drug testing.