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.
