Storming Immune Monogenic Conditions through Multiomic and Gene Editing Approaches

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The human immune system controls the efficiency to respond to infections and eliminate aberrant cells, such as cancer cells. Immunefunction depends on the balanced contribution of many genes, encoding for receptors, cytokines, cell signalling molecules andtranscription factors and are modulated by a wide range of environmental and epigenetic factors. Monogenic mutations for immunerelated 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 toleukemias (1/1,000-1/5,000). For a given mutated gene, IEI patients can display a wide range of phenotypic expressivity (fromasymptomatic to severely impaired) and different responses to treatments. Therefore, there is an unmet need to address the wideunderlying impact of IEI. Previous EU consortia have not addressed these questions in full. It is therefore needed a new generation ofresearchers, equipped with a complete set of scientific, technological and strategic skills; and a wide vision to face the outstandingchallenges in the IEI field. To this end, the IMMERGE MSCA DN combines the talent of leaders from different clinical and basic researchand biotech environments to train 11 doctoral candidates. Through our research activity and training activities, we will address keychallenges 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 ormodel IEI and develop pre-clinical models. With our strategy, IMMERGE will generate an outstanding network of professionals able todevelop impactful studies that will change the field, generate tools for personalised medicine and generate awareness in the societyand influence policy makers