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Emulating diabetes for drug discovery
SCHLIEREN, Switzerland & CAMBRIDGE, U.K.—With a £750,000 grant from EU-based Eurostars, InSphero AG, which develops three-dimensional culture models, and DefiniGEN, which engages in stem cell-derived human cell production and metabolic disease modeling, are collaborating to develop a drug-screening platform based on human pancreatic beta-like cells derived from iPSCs. The collaboration is designed to support the need for human in-vitro model systems for diabetes drug discovery and safety testing.
Diabetes is a growing, global public health concern that affects more than 415 million people worldwide—a number that is predicted to increase to 642 million by 2040. Because the lack of robust models to support drug discovery and development is slowing progress of new therapeutic options to the clinic, the two companies are developing a portfolio of scalable, patient-derived diabetes models.
As explained by Dr. Joan Mir Col, scientist and lead project manager, and Dr. Burcak Yesildag, head of Islet Solutions Group at InSphero, the islets of Langerhans, micro-organs of the pancreas, regulate blood glucose levels by secreting multiple hormones, most importantly insulin and glucagon. Because of the inherent variability and short lifespan of human islets outside of the body, traditional methods of diabetes research and drug discovery using primary human islets are challenging. Because islets vary in size and cellular composition, multiple islets need to be pooled for each experimental condition, requiring tedious hand-picking for hours under a microscope. Moreover, insulin secretory function can be influenced by exocrine tissue contamination or viability of the donor material. This means high batch-to-batch variations need to be considered when planning each experiment.
InSphero’s proprietary islet dissociation and reaggregation process controls the size of the newly formed spheroids (3D islet microtissues) and excludes the impurities from exocrine tissue and non-viable cells to ensure long-term, robust islet functionality, while reducing variability and ensuring data reproducibility. The 3D InSight Diabetes Platform is a comprehensive 3D in-vitro solution that includes pancreatic islet microtissue models, specialized cell culture media, scalable and automation-compatible Akura plate technology, 3D-optimized assay protocols, and support from application scientists.
Since InSphero’s in-vitro solutions cannot resolve the scarcity of donor islets for research or the biological variation among the specimens isolated from different donors, InSphero is collaborating with DefiniGEN to explore new avenues for the development of a pancreatic islet testing platform. It uses pluripotent stem cells, which could provide an unlimited source of uniform, highly functional insulin-producing cells with direct positive implications for diabetes drug discovery. DefiniGEN, which has a powerful platform technology for optimal differentiation of iPSCs into beta-like cells, provides iPSC-derived functional human-like cells including hepatocytes, pancreatic beta cells and intestinal organoids, explained Filipa Soares, director of strategic R&D at DefiniGEN.
Combining the technologies of both companies, InSphero will develop iPSC-derived 3D pancreatic islet models with improved maturity and function using automation compatible 384-multiwell plate formats for high-throughput screening and downstream drug evaluation for diabetes research. DefiniGEN will provide iPSC-derived pancreatic endocrine cells. Using the Akura plate technology platform, InSphero will aim to develop the optimal methodologies for aggregation of these cells into 3D spheroids, to further improve the maturation and the insulin secretory function of iPSC derived beta cells. In parallel, DefiniGEN will generate complementary CRISPR gene-edited disease models for the most relevant genes associated with type 2 diabetes in genome-wide association studies. The ultimate focus will be the formation of 3D microtissues with these gene-edited endocrine cells to enable a new disease-relevant, high-throughput, compatible drug discovery platform for diabetes.
This project is funded by Eurostars, a joint program between EUREKA and the European Commission. It is co-funded by the national budgets of 36 Eurostars participating states and partner countries and by the European Union through Horizon 2020. It is intended to support development of rapidly marketable innovative products, processes and services that help improve lives of people around the world.
“We expect to have an iPSC-derived 3D pancreatic islet model on the market in 2022, which will be followed by the launch of the CRISPR gene-edited models within the next year,” Yesildag said. “However, during 2021, we plan to conduct a ring-trial with interested industrial parties to collect user experience data on platform performance. InSphero will train ring test participants on the features of the iPSC-derived platform, handling of Akura plate technology and assay performance. DefiniGEN will provide the iPSC-derived pancreatic endocrine cells to InSphero for the production of 3D microtissues. Then, beta testers will receive samples of 3D InSight islet microtissues produced from primary human tissue along with a pancreatic benchmark toolkit to compare the performance of the new iPSC-derived system to an already-established model. After the ring test, we will apply feedback from industrial users to refine the final product before the official launch.”