Periodic Reporting for period 4 - VANGUARD (New Generation Cell Therapy: Bioartificial Pancreas to Cure Type 1 Diabetes)
Período documentado: 2024-01-01 hasta 2025-06-30
Type 1 diabetes (T1D) is a global epidemic, primarily affecting children and young adults and is caused by the autoimmune destruction of insulin-producing β cells. Current treatments, including daily insulin injections and islet transplantation, remain limited. While islet transplantation is the only curative option, it is restricted to a small number of patients due to donor organ scarcity and the need for lifelong immunosuppression.
This project establishes a clear pathway toward a game-changing bioartificial pancreas, providing breakthrough advantages such as potency for single-donor transplantation, improved engraftment and implantation in extrahepatic sites, local immune protection, and graft retrievability. At the same time, it opens new horizons toward unlimited cell-based therapies for T1D, thereby overcoming the constraint of donor organ shortage. By the end of the project, the consortium converged on a clinically oriented design and demonstrated its feasibility across multiple pre-clinical models.
This project establishes a clear pathway toward a game-changing bioartificial pancreas, providing breakthrough advantages such as potency for single-donor transplantation, improved engraftment and implantation in extrahepatic sites, local immune protection, and graft retrievability. At the same time, it opens new horizons toward unlimited cell-based therapies for T1D, thereby overcoming the constraint of donor organ shortage. By the end of the project, the consortium converged on a clinically oriented design and demonstrated its feasibility across multiple pre-clinical models.
Over the project, partners developed and refined each component of the bioartificial pancreas. Early work established pipelines for human amniotic epithelial and mesenchymal stem cells and generated immunomodulatory variants with enhanced HLA-G and PD-L1. In vitro assays showed both native and modified hAMSCs supported β-cell viability and insulin secretion, though with only modest protection against cytotoxic T lymphocytes. Given these results and the regulatory and manufacturing complexity of a third-party allogeneic source, the partners excluded amniotic cells. This ensured the therapeutic effect was attributable to β-cells, endothelial support and Amniogel, while keeping the product clinically feasible and translatable.
Due to streamlined design, organoid generation advanced, markedly improving insulin secretion. Porcine organoids from neonatal porcine islet cells and blood outgrowth endothelial cells (BOECs) reversed diabetes in mice faster than free neonatal islets, demonstrating the advantage of vascularised constructs.
A GMP-compatible process for producing Amniogel established. Batches showed reproducible composition, retaining extracellular matrix proteins, tunable stiffness and pore size, and stable support. Functionally, Amniogel restored cell–matrix interactions, upregulated β1-integrin, reduced apoptosis, and improved insulin secretion. It enhanced β-cell–β-cell and β-cell–endothelial communication, supported by BOEC-driven laminin deposition. In vitro assays also showed Amniogel delayed CD8⁺ T-cell migration and reduced cytotoxicity toward mismatched β-cells, validating its role as both structural and immunological barrier.
These properties enabled vascularised endocrine constructs of intact islets and BOECs in Amniogel. A human BAP was generated with native islets and BOECs, while a porcine BAP combined neonatal porcine islets with BOECs. When transplanted subcutaneously in diabetic mice, both restored normoglycaemia, confirming the importance of ECM support and pre-established vascularisation for extrahepatic sites. Safety studies showed Amniogel supports rodent, human, and porcine islets with excellent biocompatibility. Immune-evasion studies revealed MHC-I down-regulation reduces CD8⁺ T-cell graft destruction without provoking NK rejection, and Amniogel encapsulation can delay, though not fully prevent, graft rejection in humanised mouse models.
The project generated strong dissemination outputs. Results were published in peer-reviewed journals and presented internationally, raising visibility in transplantation, regenerative medicine, and biomaterials. Ethical and legal analyses produced publications and a forthcoming guidance document on responsible development of bioartificial organs. A regulatory roadmap was drafted for BAP classification as an ATMP, and spheroid scalability was demonstrated with the GMP-compliant Sphericalplate 5D platform.
Stakeholder engagement included patient events such as World Diabetes Days, the project website with a patient area, a policy brief, and participation in European Researchers’ Night. These ensured broad dissemination, integrated patient and policymaker feedback, and positioned VANGUARD as a leading contributor to the evolving ATMP landscape.
Due to streamlined design, organoid generation advanced, markedly improving insulin secretion. Porcine organoids from neonatal porcine islet cells and blood outgrowth endothelial cells (BOECs) reversed diabetes in mice faster than free neonatal islets, demonstrating the advantage of vascularised constructs.
A GMP-compatible process for producing Amniogel established. Batches showed reproducible composition, retaining extracellular matrix proteins, tunable stiffness and pore size, and stable support. Functionally, Amniogel restored cell–matrix interactions, upregulated β1-integrin, reduced apoptosis, and improved insulin secretion. It enhanced β-cell–β-cell and β-cell–endothelial communication, supported by BOEC-driven laminin deposition. In vitro assays also showed Amniogel delayed CD8⁺ T-cell migration and reduced cytotoxicity toward mismatched β-cells, validating its role as both structural and immunological barrier.
These properties enabled vascularised endocrine constructs of intact islets and BOECs in Amniogel. A human BAP was generated with native islets and BOECs, while a porcine BAP combined neonatal porcine islets with BOECs. When transplanted subcutaneously in diabetic mice, both restored normoglycaemia, confirming the importance of ECM support and pre-established vascularisation for extrahepatic sites. Safety studies showed Amniogel supports rodent, human, and porcine islets with excellent biocompatibility. Immune-evasion studies revealed MHC-I down-regulation reduces CD8⁺ T-cell graft destruction without provoking NK rejection, and Amniogel encapsulation can delay, though not fully prevent, graft rejection in humanised mouse models.
The project generated strong dissemination outputs. Results were published in peer-reviewed journals and presented internationally, raising visibility in transplantation, regenerative medicine, and biomaterials. Ethical and legal analyses produced publications and a forthcoming guidance document on responsible development of bioartificial organs. A regulatory roadmap was drafted for BAP classification as an ATMP, and spheroid scalability was demonstrated with the GMP-compliant Sphericalplate 5D platform.
Stakeholder engagement included patient events such as World Diabetes Days, the project website with a patient area, a policy brief, and participation in European Researchers’ Night. These ensured broad dissemination, integrated patient and policymaker feedback, and positioned VANGUARD as a leading contributor to the evolving ATMP landscape.
For two decades, cell therapy for type 1 diabetes has relied on donor islet transplantation. While this proved that cell replacement can restore insulin production, it remains limited by donor shortages, low yields, variable graft survival, procedural complexity, and the need for lifelong immunosuppression. These factors have restricted treatment to few patients and prevented wider adoption.
VANGUARD marks a breakthrough, moving from incremental progress to a multi-component therapy designed to overcome these barriers. Unlike simple encapsulation or aggregates, its bioartificial pancreas (BAP) is a vascularised, engineered construct that recreates key features of the native pancreatic niche.
The project advanced the field in several areas:
Scalable cell sources: Porcine neonatal islet organoids assembled with blood outgrowth endothelial cells (BOECs) were validated as reproducible and effective insulin-producing tissue, pointing to an unlimited supply.
Advanced biomaterials: Amniogel, a GMP-compliant hydrogel from human amnion, retains extracellular matrix proteins, restores β-cell–matrix interactions, enhances viability and function, and offers biocompatibility and immunomodulation.
Vascularised constructs: Islets combined with BOECs in Amniogel yielded engineered vascularised constructs that restored normoglycaemia in diabetic mice, even subcutaneously where non-vascularised islets fail. This shows the importance of revascularisation and matrix support.
Immune protection: Amniogel encapsulation delayed rejection of human BAPs in humanised mice, while MHC-I suppression reduced CD8⁺ T-cell destruction without triggering NK attack, laying the groundwork for constructs combining vascularisation with precise immune modulation.
Alongside scientific advances, the project delivered enablers for clinical translation:
Ethical and regulatory frameworks: peer-reviewed publications and a forthcoming guidance document on responsible development of bioartificial organs.
Manufacturing scalability: spheroid upscaling demonstrated on the GMP-compliant Sphericalplate 5D platform.
Stakeholder integration: patient events, policy dialogues, and a project website with a dedicated patient area, ensuring dissemination and user input.
By project end, the consortium refined construct design, validated scalable GMP production, and consolidated regulatory and ethical guidance into a translational roadmap. These achievements position the BAP for large-animal studies and eventual clinical trials.
The potential impacts are significant. A clinically deployable BAP could achieve long-term insulin independence without systemic immunosuppression, transforming diabetes care. Even partial benefits — longer graft survival or reduced insulin needs — would improve quality of life and reduce healthcare costs. At a societal level, VANGUARD has modelled responsible innovation by integrating regulatory foresight, ethics, and patient engagement. This positions Europe as a leader in regenerative medicine and advanced therapies, and a pioneer in embedding societal legitimacy into biotechnology.
VANGUARD marks a breakthrough, moving from incremental progress to a multi-component therapy designed to overcome these barriers. Unlike simple encapsulation or aggregates, its bioartificial pancreas (BAP) is a vascularised, engineered construct that recreates key features of the native pancreatic niche.
The project advanced the field in several areas:
Scalable cell sources: Porcine neonatal islet organoids assembled with blood outgrowth endothelial cells (BOECs) were validated as reproducible and effective insulin-producing tissue, pointing to an unlimited supply.
Advanced biomaterials: Amniogel, a GMP-compliant hydrogel from human amnion, retains extracellular matrix proteins, restores β-cell–matrix interactions, enhances viability and function, and offers biocompatibility and immunomodulation.
Vascularised constructs: Islets combined with BOECs in Amniogel yielded engineered vascularised constructs that restored normoglycaemia in diabetic mice, even subcutaneously where non-vascularised islets fail. This shows the importance of revascularisation and matrix support.
Immune protection: Amniogel encapsulation delayed rejection of human BAPs in humanised mice, while MHC-I suppression reduced CD8⁺ T-cell destruction without triggering NK attack, laying the groundwork for constructs combining vascularisation with precise immune modulation.
Alongside scientific advances, the project delivered enablers for clinical translation:
Ethical and regulatory frameworks: peer-reviewed publications and a forthcoming guidance document on responsible development of bioartificial organs.
Manufacturing scalability: spheroid upscaling demonstrated on the GMP-compliant Sphericalplate 5D platform.
Stakeholder integration: patient events, policy dialogues, and a project website with a dedicated patient area, ensuring dissemination and user input.
By project end, the consortium refined construct design, validated scalable GMP production, and consolidated regulatory and ethical guidance into a translational roadmap. These achievements position the BAP for large-animal studies and eventual clinical trials.
The potential impacts are significant. A clinically deployable BAP could achieve long-term insulin independence without systemic immunosuppression, transforming diabetes care. Even partial benefits — longer graft survival or reduced insulin needs — would improve quality of life and reduce healthcare costs. At a societal level, VANGUARD has modelled responsible innovation by integrating regulatory foresight, ethics, and patient engagement. This positions Europe as a leader in regenerative medicine and advanced therapies, and a pioneer in embedding societal legitimacy into biotechnology.