Storming Immune Monogenic Conditions through Multiomic and Gene Editing Approaches

The human immune system controls the efficiency to respond to infections and eliminate aberrant cells, such as cancer cells. Immune function depends on the balanced contribution of many genes, encoding for receptors, cytokines, cell signalling molecules and transcription factors and are modulated by a wide range of environmental and epigenetic factors. Monogenic mutations for immune-related genes, also known as Inborn Errors of Immunity (IEI), provide unique examples for understanding immune fitness. IEI, individually considered as rare diseases, constitute a group of >400 immune disorders with a combined prevalence similar to leukemias (1/1,000-1/5,000). For a given mutated gene, IEI patients can display a wide range of phenotypic expressivity (from asymptomatic to severely impaired) and different responses to treatments. Therefore, there is an unmet need to address the wide underlying impact of IEI. Previous EU consortia have not addressed these questions in full. It is therefore needed a new generation of researchers, equipped with a complete set of scientific, technological and strategic skills; and a wide vision to face the outstanding challenges in the IEI field. To this end, the IMMERGE MSCA DN combines the talent of leaders from different clinical and basic research and biotech environments to train 11 doctoral candidates. Through our research activity and training activities, we will address key challenges in the field: 1) To assess the functional impact of IEI in different immune cell types through single cell and bulk multiomics. 2) To develop computational tools for dissecting the altered cellular pathways underlying specific IEI. 3) To genetically correct or model IEI and develop pre-clinical models. With our strategy, IMMERGE will generate an outstanding network of professionals able to develop impactful studies that will change the field, generate tools for personalised medicine and generate awareness in the society and influence policy makers.