Current orthopaedic treatments permit spontaneous bone regeneration to unite and heal 90% bone injuries. Non-union associates pain and disability, often requiring biological enhancement. Regenerative medicine research suggests to the general public that alternative treatments based on advanced therapy medicinal products (ATMP) are already available. However, early clinical trials only explore its potential benefit. Underreported results and absence of early trial confirmation in adequately powered prospective randomized clinical trials (RCT) indicate that evidence is not available to transfer any technique into routine clinical application. This ORTHOUNION Project was developed from FP7-Project (REBORNE). Its results confirmed 92% bone healing rate (Gómez-Barrena et al, 2016 submitted manuscript) with an autologous ATMP of GMP expanded bone marrow derived human MSC in non-unions, where the reported bone healing rate after surgery with standard bone autograft is 74%. Any further development requires adequately powered prospective RCTs. This will be the main aim of ORTHOUNION: to assess clinically relevant efficacy of an autologous ATMP with GMP multicentric production in a well-designed, randomized, controlled, three-arm clinical trial under GCP, versus bone autograft, gold-standard in fracture non-unions. A non-inferiority analysis will evaluate if cell dose can be lowered. ATMP has been authorized by the National Competent Authorities of the participating countries in 3 previous trials (REBORNE) and will be monitored by ECRIN-ERIC to ensure quality and credibility of RCT results. Secondary aims include innovative strategies to increase manufacturing capacity and lower costs to pave translation into routine clinical treatments, biomaterial refinement to facilitate surgery, personalized medicine supportive instruments for patient selection and monitoring, and health economic evaluation. Results in this project may help define the future of bone regenerative medicin

The objective of the project is to develop novel curative concepts for chronic hepatitis B (CHB). Specific aims will be to: 1) improve the rate of functional cure of CHB by boosting innate immunity with immune modulators and stimulating adaptive immune responses with a novel therapeutic vaccine; ii) characterize immune and viral biomarker signatures for patient stratification and treatment response monitoring; iii) integrate biological and clinical data to model the best combination treatment for future trials; iv) model the effectiveness of novel curative therapies with respect to disease spectrum, patient heterogeneity, and constraints of National Health Systems. The project organization will combine: i) a Proof of Concept clinical trial of a combination of 2 novel compounds stimulating innate immunity; ii) a preclinical immune therapy platform in humanized mice combining immune-modulatory strategies to stimulate innate immunity, rescue exhausted HBV-specific T cells and generate anti-HBV adaptive responses; iii) extensive virologic and immune profiling to identify correlates of cure in patients, iv) the integration of large biological and clinical datasets, v) a cost-effectiveness modelling of new therapeutic interventions, vi) project management, vii) results exploitation and dissemination. The proposal responds to the work program by: i) including the evaluation of emerging concepts in drug and vaccine development to discover a curative strategy for CHB, a major public health concern for Europe, ii) capitalizing on knowledge of host-pathogen interactions to develop novel immune-based therapies, iii) considering age, gender and viral genetic variations, iv) comprising a clinical trial and a pre-clinical platform for the discovery of novel immune interventions, and selection of relevant biomarkers for validation in established clinical cohorts, v) addressing conditions for effective uptake of the new curative interventions by National Health Systems.

Alcohol-related hepatocellular carcinoma (ALD-HCC) is, in Europe, the leading cause of liver cancer (2nd most common cause of cancer-related death worldwide, affecting both men and women). ALD-HCC has a median 5-year survival rate of 15%. Yet, the prognosis is driven by the tumour stage, with curative options providing a 5-year survival exceeding 70% for early-stage HCC (<20% of cases). Therefore, interventions aiming to improve prevention and early detection are key. ALD-HCC results from the interplay between environmental determinants and genetic variations. A comprehensive characterisation of environmental factors (e.g. diet, lifestyle) linked to ALD-HCC is still lacking. We recently performed the 1st genome-wide association study of ALD-HCC and identified predisposing genetic variations. However, their role on alcohol-related liver carcinogenesis needs clarification and the genetic architecture of ALD-HCC remains mostly unknown. GENIAL brings together partners with unique expertise in clinical hepatology, single-cell and spatial multi-omics, artificial intelligence (AI) and communication and dissemination capacities. Our aim is to 1) portray genetic and environmental determinants promoting ALD-HCC; 2) evaluate how they interact at cellular level in human samples and preclinical models to get novel insights into liver carcinogenesis, and identify chemopreventive targets; and 3) assess how these determinants modulate the ALD-HCC risk in prospective cohorts of patients included in HCC surveillance programs. Environmental factors will be comprehensively characterised in an ongoing clinical trial designed to evaluate alternative methods for early-stage HCC detection. Finally, AI models, reaching the minimal viable product stage by the end of GENIAL, will be used to integrate genetic and non-genetic information (including digital imaging) to develop novel cost-effective strategies towards prevention and early-stage detection of ALD-HCC in at-risk individuals. This action is part of the Cancer Mission cluster of projects on ‘‘Understanding’.