Periodic Reporting for period 4 - ISLET (Advancing Innovative Stem Cell-based Therapy for Diabetes in Europe)
Reporting period: 2024-03-01 to 2025-08-31
Diabetes is marked by high levels of blood glucose, which can lead to serious health issues. Both type 1 diabetes (T1D) and type 2 diabetes (T2D) are related to insulin levels, the hormone produced by the pancreas that allows blood sugar to enter cells for energy use. However, in T2D, the pancreas does not produce enough insulin, or the insulin produced does not function properly. The EU-funded ISLET project's innovative program uses stem-cell-derived human pancreatic islet cells and develops quality-control assays to enable rapid commercialisation of a game-changing therapy for T1D.
Objectives
T1D is one of the main health challenges, affecting 6 million European citizens. Today, T1D places a significant economic burden on healthcare and the labour force. To bring advanced therapy for type T1D patients, a scalable source of pancreatic islets for transplantation is needed. The objective of the ISLET project is to build and implement a new and innovative program for the production and marketing of human pluripotent stem cell (hPSC)-derived advanced therapy medicinal products (ATMPs) for the treatment of EU citizens with T1D. To achieve this, ISLET gathers a constellation of experts to establish a transferable GMP-compliant manufacturing program based on improved and standardized protocols for the generation and characterization of future ATMPs. Furthermore, to make a product closer to the "golden standard" human pancreatic islet, ISLET will develop islet-like clusters composed of isolated hPSC-derived alpha and beta-like cells and will implement advanced strategies for safe, up-scaled production and a quantitative go/no-go assessment of therapeutic quality.
Specifically, to overcome the lack of robust qualitative and quantitative assays to assess islet function, ISLET will introduce a novel quality control concept to predict therapeutic efficacy using quantitative proteomics and lipidomics as part of the ATMP development chain—a concept that will be widely applicable. Additionally, a commercial route for exploiting hESC-derived ATMPs for T1D treatment with the EU will be developed. Finally, a professionally supported dual plan for public engagement in stem cell therapy and diabetes is rounding out the project.
Objectives
T1D is one of the main health challenges, affecting 6 million European citizens. Today, T1D places a significant economic burden on healthcare and the labour force. To bring advanced therapy for type T1D patients, a scalable source of pancreatic islets for transplantation is needed. The objective of the ISLET project is to build and implement a new and innovative program for the production and marketing of human pluripotent stem cell (hPSC)-derived advanced therapy medicinal products (ATMPs) for the treatment of EU citizens with T1D. To achieve this, ISLET gathers a constellation of experts to establish a transferable GMP-compliant manufacturing program based on improved and standardized protocols for the generation and characterization of future ATMPs. Furthermore, to make a product closer to the "golden standard" human pancreatic islet, ISLET will develop islet-like clusters composed of isolated hPSC-derived alpha and beta-like cells and will implement advanced strategies for safe, up-scaled production and a quantitative go/no-go assessment of therapeutic quality.
Specifically, to overcome the lack of robust qualitative and quantitative assays to assess islet function, ISLET will introduce a novel quality control concept to predict therapeutic efficacy using quantitative proteomics and lipidomics as part of the ATMP development chain—a concept that will be widely applicable. Additionally, a commercial route for exploiting hESC-derived ATMPs for T1D treatment with the EU will be developed. Finally, a professionally supported dual plan for public engagement in stem cell therapy and diabetes is rounding out the project.
The ISLET project, now in its fourth year, has achieved significant progress in developing the 1st-generation stem cell-derived islet product for T1D. Key milestones include finalizing the product’s composition and administration route, addressing critical scientific and methodological questions for the second-generation product, and publishing several impactful findings.
A major achievement has been the establishment of a GMP-compliant protocol for producing cell banks and the first-generation ISLET product. This includes generating master and working cell banks and locking a robust differentiation process to derive insulin-producing β cells from the H9 human embryonic stem cell line. These β cells will undergo preclinical testing in diabetic rats via hepatic portal vein administration, simulating the intended clinical route.
Another breakthrough was the discovery that apical-basal polarity regulates endocrine progenitor fate. Polarized progenitors preferentially differentiate into β cells through the cAMP/PKA-CREB-EGR1 pathway, while loss of polarity promotes α cell formation via ARX expression. This patented finding provides a novel strategy to enhance β cell differentiation efficiency for improvement of future products. During RP4, the challenge of off-target cell types in SC-islets was addressed through multiple strategies. Using CRISPR-engineered cell lines, researchers identified aptamers and antibodies targeting the insulin-HLA class I complex. Additionally, CD133 and CD49a were validated as markers for β cell enrichment, improving purity and safety. Optimized SC-islet compositions demonstrated improved β cell maturation and identified off-target gene markers for quality control.
Advances in proteomics and lipidomics workflows were also achieved to assess cell maturation and health. Lipidomic profiling revealed biomarkers of β cell maturation and stress, supporting new quality control assays for transplant viability.
Finally, public engagement was strengthened through collaborations with the IDF Youth Forum and EuroGCT, delivering educational resources, lab visits, and video interviews. Training initiatives, including media skills and participation in the European Summer School for Stem Cells and Regenerative Medicine, further enhanced outreach and capacity building across the consortium.
A major achievement has been the establishment of a GMP-compliant protocol for producing cell banks and the first-generation ISLET product. This includes generating master and working cell banks and locking a robust differentiation process to derive insulin-producing β cells from the H9 human embryonic stem cell line. These β cells will undergo preclinical testing in diabetic rats via hepatic portal vein administration, simulating the intended clinical route.
Another breakthrough was the discovery that apical-basal polarity regulates endocrine progenitor fate. Polarized progenitors preferentially differentiate into β cells through the cAMP/PKA-CREB-EGR1 pathway, while loss of polarity promotes α cell formation via ARX expression. This patented finding provides a novel strategy to enhance β cell differentiation efficiency for improvement of future products. During RP4, the challenge of off-target cell types in SC-islets was addressed through multiple strategies. Using CRISPR-engineered cell lines, researchers identified aptamers and antibodies targeting the insulin-HLA class I complex. Additionally, CD133 and CD49a were validated as markers for β cell enrichment, improving purity and safety. Optimized SC-islet compositions demonstrated improved β cell maturation and identified off-target gene markers for quality control.
Advances in proteomics and lipidomics workflows were also achieved to assess cell maturation and health. Lipidomic profiling revealed biomarkers of β cell maturation and stress, supporting new quality control assays for transplant viability.
Finally, public engagement was strengthened through collaborations with the IDF Youth Forum and EuroGCT, delivering educational resources, lab visits, and video interviews. Training initiatives, including media skills and participation in the European Summer School for Stem Cells and Regenerative Medicine, further enhanced outreach and capacity building across the consortium.
Expected impact 1; Identification of potential regenerative therapies to address unmet clinical needs of large patient groups.
T1D places a significant burden on daily life and healthcare systems. ISLET aims to address this unmet clinical need by establishing a long-term program for continuous improvement of ATMPs. Preclinical studies have demonstrated the feasibility of generating functional β cells from human pluripotent stem cells (hPSCs) in diabetic animal models, paving the way for scalable production of β cells for large patient populations. To achieve this, ISLET will develop a transferable platform and implement a robust pipeline for manufacturing and testing stem cell-derived islet products.
Expected impact 2: Strengthening of Europe's position in translational regenerative medicine.
Currently, ATMP development is dominated by the USA, primarily driven by large pharmaceutical and biotech companies. In diabetes, where existing treatments generate substantial revenue, ATMP-based approaches offer limited short-term financial incentives for industry investment. ISLET will serve as a model for collaborative innovation, integrating basic and clinical research within Europe’s regulatory and legal framework for hPSC-based ATMP development. By coordinating the entire value chain from discovery to commercialization. ISLET will ensure that new therapies meet regulatory standards and are commercially viable, ultimately bringing advanced treatments for T1D to market
Expected impact 3: New therapies for major human diseases and conditions and new approaches for therapy taken further in the development pipeline.
Stem cell researchers across disease areas face challenges in generating fully mature, therapeutically active cell types and scaling differentiation protocols under GMP conditions. ISLET addresses these bottlenecks through a unique expansion, differentiation, and purification strategy, enabling scalable manufacturing of hESC-based medicinal products in full compliance with clinical regulations In addition, the consortium will complement traditional in vitro and in vivo assays for quality control by developing new beyond-state-of-the-art predictive measures using proteomic and lipidomic profiling. Therefore, providing a novel quantitative readout more potent than existing methods for assessing manufacturing quality.
T1D places a significant burden on daily life and healthcare systems. ISLET aims to address this unmet clinical need by establishing a long-term program for continuous improvement of ATMPs. Preclinical studies have demonstrated the feasibility of generating functional β cells from human pluripotent stem cells (hPSCs) in diabetic animal models, paving the way for scalable production of β cells for large patient populations. To achieve this, ISLET will develop a transferable platform and implement a robust pipeline for manufacturing and testing stem cell-derived islet products.
Expected impact 2: Strengthening of Europe's position in translational regenerative medicine.
Currently, ATMP development is dominated by the USA, primarily driven by large pharmaceutical and biotech companies. In diabetes, where existing treatments generate substantial revenue, ATMP-based approaches offer limited short-term financial incentives for industry investment. ISLET will serve as a model for collaborative innovation, integrating basic and clinical research within Europe’s regulatory and legal framework for hPSC-based ATMP development. By coordinating the entire value chain from discovery to commercialization. ISLET will ensure that new therapies meet regulatory standards and are commercially viable, ultimately bringing advanced treatments for T1D to market
Expected impact 3: New therapies for major human diseases and conditions and new approaches for therapy taken further in the development pipeline.
Stem cell researchers across disease areas face challenges in generating fully mature, therapeutically active cell types and scaling differentiation protocols under GMP conditions. ISLET addresses these bottlenecks through a unique expansion, differentiation, and purification strategy, enabling scalable manufacturing of hESC-based medicinal products in full compliance with clinical regulations In addition, the consortium will complement traditional in vitro and in vivo assays for quality control by developing new beyond-state-of-the-art predictive measures using proteomic and lipidomic profiling. Therefore, providing a novel quantitative readout more potent than existing methods for assessing manufacturing quality.