Forty million individuals worldwide suffer from type 1 diabetes. This disease is managed by insulin therapy in a vast majority of patients because of the limited accessibility of beta cell replacement therapies (pancreas or islet of Langerhans transplantation). There is an urgent need for the development of a beta cell replacement therapy that will be available to larger numbers of type 1 diabetic patients. The VANGUARD project aims to deliver an Advanced Therapeutic Medicinal Product (ATMP) of high translational potential, with properties of increased functionality and implantability and protection from immune destruction. We will construct a bioartificial pancreas by assembling insulin- producing organoids, composed of islet cells, human amniotic epithelial cells (hAEC) and blood outgrowth endothelial cells (BOECs), into an amniotic membrane-derived hydrogel. Components of the amniotic membrane will provide extracellular matrix and mechanical protection and confer their well-defined anti-inflammatory and immunomodulatory properties to the constructs. hAECs will be genome-edited to overexpress and locally release immunomodulatory molecules (HLA-G, HLA-E, CD47 and PD-L1) and endothelial cells will enhance graft revascularization. Functionality, biocompatibility, potency and safety of the bioartificial pancreas will be assessed in vitro and in vivo by implantation in mice reconstituted with a human immune system as pre-clinical model. The consortium consists of 5 academic institutions with leading scientists in their field, 2 SMEs and 1 NGO with expertise in ethical and social aspects of transplantation. The ATMP delivered upon completion of the project will provide a model for rapid development of a bioartificial pancreas, utilizing “infinite” sources of insulin-producing cells (stem cell-derived, xenogeneic), and available to all type 1 diabetic patients before they develop the devastating chronic complications of the disease.

Liver transplantation (LT) is a life-saving procedure for decompensated cirrhosis (DC) and hepato-cellular carcinoma (HCC). Its efficacy is hampered by the risk of death/drop-out on the Wait List (WL). This risk is driven by organ shortage and is mitigated by organ offering schemes. According to a sickest first policy, offering schemes prioritize LT candidates with the highest risk of dying, as assessed by predictive models. To drive allocation, Organ Sharing Organizations (OSOs) use a 20-year-old model, the MELD, predicting mortality in DC but not in HCC. Because of a dramatic increase in % of HCC candidates (40% against 10% in early 20ties), MELD schemes are increasingly inaccurate, with persisting 15 to 30% mortality in countries with low/medium donation rate. This scenario, together with advances in prognosis in DC and HCC candidates and statistics, prompts LT community to look for up-dated algorithms to refine offering schemes. To address this issue, key European LT stakeholders including OSOs, experts in LT, Statisticians, Research Labs and SME joined LEOPARD. Building on an innovative, harmonized OSOs pre-LT dataset and advances in modeling, LEOPARD propose to design and validate 1) an AI-based LEOPARD predictive algorithm outperforming current allocation models by better stratifying patients on the risk of mortality, to be proposed OSOs to drive allocation; 2) DC & HCC LEOPARD calculators available for professional for assistance in complex decision-making processes; 3) OMICs/radiomics predictive signatures integrated in a prototype 3rd-generation exploratory model. We expect to generate computational tools improving candidates’ outcomes, with more patients transplanted on time. Adoption of these tools should result in harmonization of European heterogeneous prioritization schemes, and in a signification reduction in disparities of access to LT, a major objective pointed out by EC. LEOPARD should place Europe in leading position for organ offering schemes.

Rejection is the major cause of allograft failure with dramatic consequences in terms of mortality, morbidity and increased cost for the society. The field of transplantation lacks a robust assessment of risk stratification. Thus, it impairs the development of relevant clinical trials to address graft and patient outcomes. We formed the EU-TRAIN project by gathering reference kidney transplant centres in a fully operating European network including 12 partners. Our ambitious but realistic goals are: to provide clinicians with innovative and accessible tools for early prediction of individual risk of allograft rejection and transplant loss; to personalise clinical management and treatment and; to improve allograft outcomes. This project will engineer a risk stratification system applied to kidney transplant patients by analysing the integration of several layers of data (clinical, histological, immunological data as well as gene expression and novel biomarkers) - the TRAnsplant Comprehensive Evaluator of Risk (EU-TRACER). EU-TRACER will be generated and validated in 2 dedicated studies including a randomised control trial. Translation to patients will be achieved by delivering: 1) A multiplex non-invasive biomarker system for the stratification and immune monitoring of low and high risk kidney recipients; 2) A prognostic system for individual risk stratification for allograft rejection and failure that will assist decision making via an interactive web interface. The EU-TRACER, developed with our 3 industrial partners, will define a new standard of care in transplantation. The EU-TRACER will have the potential for a large implementation and diffusion in other centres in Europe and will be suitable for industrial collaboration.

Solid organ transplantation (SOT) is the treatment of choice for end-stage organ failure but the immunosuppressive drugs used to prevent graft rejection expose to an increased risk of opportunistic infections among which CMV disease leads to the most frequent morbidity and even mortality. HORUS project gathers solid-organ transplantation experts, computational data scientists, virologists and immunologists in a fully operating European network including 25 partners. HORUS ambitious but realistic goals is to improve our understanding of CMV/host interactions in the context of immunosuppression, with a particular focus on i) the characterization of signatures associated with the control of CMV replication after transplantation, ii) the characterization of signatures associated with the evolution toward a difficult-to-treat CMV disease and poor outcome during CMV replication, iii) the discovery of new specific immunomodulatory molecules promoting CMV control while maintaining prevention of acute rejection. HORUS includes the constitution of the first European SOT recipient longitudinal cohort. In a sub- “HORUS-exploratory cohort”, we will perform a deep investigation of viral, clinical and immunological characteristics. Combining those parameters will provide a signature early after transplantation to predict the risk of developing CMV infection and a signature at day 0 of infection to predict the risk of CMV disease severity. This signature will next be validated retrospectively on the whole cohort and prospectively in a “proof-of-concept" study. Moreover, HORUS will include functional in vitro and mice models to understand the mechanisms of lymphocyte response to CMV and provide innovative methods to increase CMV-specific immunity. Altogether, HORUS will lead to personalized clinical prevention and treatment of CMV disease and to improvement of patient outcomes.