Type 1 Diabetes (T1D) in numbers
20.7 million people are affected by T1D worldwide
10 year reduction of life expectancy for people with T1D
2.3 times higher medical expenses than average
4% growth rate of young adults
The Global Burden of Diabetes
Amongst the 415 million people who are affected by diabetes 5% are concerned by T1D. This incurable disease is caused by the autoimmune destruction of the insulin-producing pancreas cells.
Advances in healthcare and increased public awareness resulted in improved management of this disease. However, T1D still requires a daily demanding monitoring and treatment.
A group of European researchers has gathered with the goal of sparing affected people from lifelong insulin therapy, by developing clinical-grade Human Pancreas Organoids (hPOs) for a cell-based therapy.
The LSM4LIFE project is dedicated to develop a process for the mass production of three-dimensional cellular structures of insulin-producing cells (organoids) in the laboratory.
Amongst all the advances in healthcare to overcome the deficient pancreas of patients with T1D, the LSFM4LIFE project is driven by one of the most promising alternatives: stem cell-derived beta cells. The idea is to isolate and to expand adult human pancreas stem cells and to differentiate them into insulin-producing cells.
The stem cell-derived beta cells approach has been made possible by the discovery of the group of Hans Clevers in Utrecht, which succeeded in activating the pancreas ductal cells to express the protein Lgr5, a marker of adult stem cells.
Once isolated and cultured in a 3D gel, the Lgr5- expressing cells form pancreas organoids that can be grown almost limitlessly in culture.
Dr. Meritxell Huch from the Gurdon Institute, a partner of LSFM4LIFE, carried out a study showing that an organoid transplanted into mice differentiates in insulin-producing cells. The final goal of the LSFM4LIFE project is to transfer this technology from mouse to human.
Producing clinical-grade (GMP-compliant) hPOs as a long-term source of pancreas stem cells represent a breakthrough for cellular therapy of T1D. In order to achieve it, LSFM4LIFE partners have several challenges to undertake into different fields: cell-based therapy; 3D scaffolds; mass production of cells; optical technology ; and cell-based assay.
Here are some specific innovation challenges addressed by the LSFM4LIFE project:
LSFM4LIFE work packages
The project starts with an R&D protocol and finishes with a clear strategy for the necessary steps to advance hPO towards clinical trials. During the project, the hPO generation protocols are refined with respect to translation to GMP and in vitro differentiation in two parallel threads that are
Translation of the process of hPO expansion from the R&D level to GMP-level
WP03 & WP07: The generation of undifferentiated hPO from cells extracted from human pancreatic glands provides the starting point for all subsequent activities.
WP04: Based on the initial R&D with undifferentiated organoids, quality criteria for organoid expansion are determined.
WP04, WP05 & WP06: Biomimetic hydrogel and the protocols for expanding the organoids in this hydrogel are optimised until all components are GMP-compliant and the organoids satisfy the quality criteria.
Establishing the differentiation of hPOs in vitro
WP04: Based on comparisons with pancreas islets phenotypic and functional quality criteria for hPO differentiation are established.
WP03 & WP04: The differentiation protocol is optimized until the quality criteria are fulfilled.
WP07: The GMP-compliant undifferentiated organoids as well as the R&D level differentiated organoids are tested in vivo with respect to their safety, long-term survival and functional efficacy.
WP06: All results of the project flow into a strategy for the further development of hPO towards later Clinical Investigations.
The main motivation of LSFM4LIFE is a response to the societal needs for advanced cell-based therapies for the treatment of T1D, improving the quality of life, the health and the life expectancy of the patients affected by T1D.
By intending to produce GMP-level organoids ready for the implementation of the clinical phases, the project is expected to provide an impact on several technological aspects, leading to:
– Expansion of the organoids in chemically well-defined biomimetic hydrogels
– Standardized characterization of the organoids at cellular and molecular level
– The capacity to manufacture the organoids at a therapeutic-relevant quantity under GMP conditions
together a highly competitive group of academic and clinical partners with dynamic high-technology SMEs.