Intestinal organoids: roadmap to the clinic

Abstract

Recent advances in intestinal organoid research, along with encouraging preclinical proof-of-concept studies, have revealed significant therapeutic potential for induced pluripotent stem cell (iPSC) derived organoids in the healing and replacement of severely injured or diseased bowel [1-3]. To fully realize the tremendous promise of stem cell organoid-based therapies, careful planning aligned with significant resources and efforts must be devoted demonstrating their safety and efficacy to meet critical regulatory requirements. Early recognition of the inherent preclinical and clinical obstacles that occur with the novel use of pluripotent stem cell derived products will accelerate their bench to bedside translation [4-6]. To overcome many of these hurdles, a close and effective collaboration is needed between experts from various disciplines, including basic and clinical research, product development & manufacturing, quality assurance & control, and regulatory affairs. Therefore, the purpose of this article is to outline the critical areas and challenges that must be addressed when transitioning laboratory-based discovery, through an Investigational New Drug (IND) application to first-in-human clinical trial, and to encourage investigators to consider the required regulatory steps from the earliest stage of the translational process. The ultimate goal is to provide readers with a draft roadmap which they could use while navigating this exciting regenerative medicine therapeutic space.

Molecular Effects of Chronic Exposure to Palmitate in Intestinal Organoids: A New Model to Study Obesity and Diabetes

“…Our study provides a snapshot of the chronic hyperlipidemia effect on intestinal cell differentiation by using small intestinal organoid platforms. Organoids allow for the investigation of how biologically active intestinal cells interact in the gut, how TFs regulating gut cell differentiation interact with each other, and how nutritional changes causing metabolic diseases could impair these aspects [ 16 , 28 , 29 ]. In addition, our 3D platform could represent a starting point for the development of on-chip model in order to obtain an enhancement of the understanding of physiopathological alterations that could lead to an improvement in the prevention and treatment of complex chronic diseases such as obesity and diabetes.…”

Engineered Synthetic Matrices for Human Intestinal Organoid Culture and Therapeutic Delivery

“…One major hurdle with this approach lies in identifying a delivery method that supports cell survival, engraftment, and retention at the site of administration. [49] A proof-of-concept study demonstrating that organoids engraft into injured tissue was reported by Yui et al [5] They transplanted LGR5+ mouse colonic organoids to the colon in a DSS-induced colitis murine model. To test the regenerative capacity of the intestinal organoids, they prepared a single cell suspension with ≈500 organoids and delivered these via an intracolonic infusion.…”

“…When considered for in vivo intestinal regenerative therapy and clinical translation, both iPSC‐ and ASC‐derived are promising candidates, however, manufacturing practices, time and costs, autologous versus allogeneic tissue source, and availability of tissues should be considered. [ 49 ]…”

“…For intestinal organoid therapy, it is important to consider scale-up processes and regulatory aspects to increase the relevance and clinical translation. [49,155] In this section, we discuss current work in engineering new intestinal organoid therapies employing regenerative medicine principles.…”

Applications of human organoids in the personalized treatment for digestive diseases

“…In the past decade, the generation of intestinal organoids has provided a rich reference for understanding intestinal pathology. 97 – 99 Organoid models can effectively mimic the state of intestinal diseases, including motility disorders, malabsorptive diarrhea, inflammation, infection, and cancer. 40 , 75 , 95 , 100 Microvillus inclusion disease (MVID) is a congenital disease of the intestinal epithelium that causes malnutrition and is characterized by diffuse villus atrophy or absence of apical microvilli.…”