More than 300 million people worldwide are suffering from more than 6000 rare diseases. Nearly all of these rare diseases are caused by a single inherited mutation and cannot be treated effectively. Repair of the defective gene by gene editing is the only possible curative therapy. However, only for very few rare diseases such gene editing therapy has reached the clinic. The “Gene therapy of Rare Diseases” (GetRadi) consortium aims now to contribute strongly to the establishment of more gene therapies for rare diseases. This will be accomplished by training of future leaders in gene therapy of rare diseases preforming ambitious research projects, with the following objectives: (i) Improving transfer of genome editing tools to target cells, (ii) improving gene editing efficiency, and (iii) improving safety of gene therapy. Strong participation of the pharmaceutical industry to research projects and training, development of novel in vitro and in vivo models for rare diseases to test gene therapies in relevant settings, and application of several unique genome editing tools developed by the applicants to the treatment of rare diseases are hallmarks of the network. GetRadi brings together strong industrial beneficiaries (AstraZeneca, Miltenyi Biotec) supervising 3 ESR, highly innovative academic beneficiaries supervising 7 ESR, 3 additional industrial partners, and 4 student enrolling universities. Professional outreach training with access to widely used social media channels will be provided by the partner “European Consortium for Communicating Gene and Cell Therapy Information”. Complementary unique expertise that is spread efficiently by network-wide training and secondments, excellent quality of supervision and intersectoral interactions, innovative transferable skill training, and efficient consortium management will result in an exceptional training of future leaders in gene therapy of rare diseases.

Antigen-stimulated naïve CD8+ T cells proliferate and differentiate into effector and memory cells. Whereas effector T cells remove infected or cancerous cells, memory T cells protect the organism from re-infections. Despite decades of research, the challenging central questions of how naïve T cells form diverse progeny and what drives the differential response of naïve and memory T cells to infection remain unanswered, largely because of lacking experimental tools. The goal of this project is to generate a comprehensive model of cell-fate choices of naïve and memory CD8+ T cells in vivo. We will achieve this by addressing three complementary specific objectives: 1) To understand the early and late fate choices in naïve T cells. 2) To uncover differences between naïve and memory T-cell responses and fates. 3) To identify the role of proximal protein kinases LCK and FYN in T-cell fate choices. We will pursue these aims using a combination of experimental immunology and systems biology. We used the synergy between novel genetic models and single cell atlases (i) to characterize an unprecedented transient stage of activated T cells, (ii) to determine the early gene expression signatures and fate choices of in vivo activated naïve and memory T cells, and (iii) to observe that LCK secures memory T-cell formation. These tools and findings offer us novel perspectives to tackle the challenging objective in its full complexity. We will develop additional unique experimental models coupled with innovative in-silico techniques to uncover the cellular and molecular mechanisms underlying diverse fate choices of particular T-cell subsets and to narrow the gap between mouse and human immunology. Overall, this project has the ambition to resolve long-standing fundamental questions in immunology to open new avenues for targeting and modulating T-cell fates in vivo for efficient vaccine design and for promoting beneficial cytotoxic responses to chronic infections and cancer.

Mutations within coding genes have traditionally been considered the major genetic cause of human disease. However, it is becoming increasingly clear that the genetic, structural and/or epigenetic disruption of enhancers and enhancer landscapes represent major etiological factors in numerous human diseases (i.e. enhanceropathies), ranging from rare congenital disorders to common diseases associated with ageing (e.g. cancer, diabetes). Although changes in enhancer activity are predicted to have broad pathological and therapeutic implications, we currently have a limited mechanistic understanding of human enhanceropathies. This reflects, at least partly, our still primitive and partial understanding of the mechanisms whereby enhancers can control gene expression. We hypothesize that enhancers are a diverse group of regulatory sequences that can utilize different mechanisms to control gene expression at the transcriptional and/or post-transcriptional level. Consequently, human enhanceropathies are likely to display an equally diverse molecular basis that, we believe, can only be uncovered using highly multidisciplinary systems biology approaches. Chiefly, elucidating the molecular basis of human enhanceropathies has far reaching translational implications, especially considering the pandemic proportions that some of these disorders are acquiring in recent years. Therefore, the major goal of the ENHPATHY network is to provide early-stage researchers with a multidisciplinary training in which cutting-edge genomic and genetic engineering approaches are ombined with various in vitro and in vivo disease models. Moreover, together with our private partners we aim at translating our molecular findings into new diagnostic and therapeutic strategies.

In response to the HORIZON-INFRA-2023-DEV-01-03 call, INFRAPLUS aims to expand INFRAFRONTIER's capacity for human disease modelling, refine its service portfolio by reducing animal usage and developing alternative cellular models, and optimise the use of resources. INFRAPLUS seeks to achieve several objectives: Developing national node capacities and expertise for providing innovative in vivo, in vitro and preclinical services, developing novel model systems and services to meet the demands of existing and novel user communities, and reducing environmental impact. To achieve these objectives, INFRAPLUS will focus on launching pilot services, refining new technologies, emphasising alternate cellular models, designing and implementing special training programmes and optimising resources for the entire consortium. The project includes a defined service development strategy supported by a strong IT and data management backbone and is built upon the needs of the scientific community. Ultimately, INFRAPLUS will enhance and evolve INFRAFRONTIER's capacity for modelling human diseases and enable breakthrough research by providing researchers cutting-edge tools and services to respond to global biomedical challenges.