Storming Immune Monogenic Conditions through Multiomic and Gene Editing Approaches

Informazioni relative al progetto

IMMERGE

ID dell’accordo di sovvenzione: 101119927

DOI

10.3030/101119927

Data della firma CE 11 Luglio 2023

Data di avvio 1 Gennaio 2024

Data di completamento 31 Dicembre 2027

Finanziato da

• Marie Skłodowska-Curie Actions (MSCA)

Costo totale

Nessun dato

Contributo UE

€ 2 591 071,20

Coordinato da

FUNDACIO INSTITUT DE RECERCA CONTRA LA LEUCEMIA JOSEP CARRERAS
Spain

Periodic Reporting for period 1 - IMMERGE (Storming Immune Monogenic Conditions through Multiomic and Gene Editing Approaches)

Periodo di rendicontazione: 2024-01-01 al 2025-12-31

Sintesi del contesto e degli obiettivi generali del progetto

The human immune system is our natural defense against infections and abnormal cells like cancer. It relies on a carefully balanced network of genes that produce receptors, signaling molecules, and transcription factors—all influenced by environmental and epigenetic factors. When a single gene is mutated, as seen in Inborn Errors of Immunity (IEI), this balance is disrupted. Although each IEI is individually rare, together they account for over 400 disorders affecting roughly 1 in 1,000 to 1 in 5,000 people, a prevalence similar to some types of leukemia. Even with the same gene affected, patients can show very different symptoms—from having no noticeable issues to experiencing severe illness—and they respond differently to treatments. This variability underscores a major unmet need: understanding the complex, multi-layered impact of these mutations on immune function.

IMMERGE is an innovative Horizon-MSCA Doctoral Network designed to address this gap. It brings together cutting-edge technologies—such as single-cell and bulk omics, advanced bioinformatics, and state-of-the-art gene editing—to unravel how mutations, especially in crucial pathways like NF-κB and JAK-STAT, disrupt immune cell function. IMMERGE aims to generate new scientific insights that will pave the way for personalized diagnostic and treatment strategies. The project’s integrated approach is not only expected to advance our understanding of immune dysregulation but also to have a broader impact by laying the foundation for improving patient care and shaping evidence-based health policies.

In the political and strategic context, the project supports EU priorities to enhance healthcare innovation, promote precision medicine, and build robust research networks across member states. By training 13 doctoral candidates in a multidisciplinary environment that spans academia, clinical centers, and the biotech industry across six countries, IMMERGE is building a new generation of experts equipped to translate these scientific breakthroughs into tangible societal and economic benefits. The anticipated outcomes include novel diagnostic tools, targeted therapies, and stronger, data-driven policies that can transform patient care and boost the EU's competitiveness in the global biomedical landscape. In summary, IMMERGE sets the stage for a transformative journey—from deep scientific inquiry into the roots of immune disorders to real-world applications that improve lives and shape health policy.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

To date, IMMERGE has made substantial progress in advancing its scientific objectives. The work carried out so far has primarily focused on establishing robust experimental and computational foundations, enabling the generation and analysis of high-quality multi-omics data. Patient cohorts and matched controls have been successfully recruited, providing the basis for systematic investigation of immune-related monogenic conditions. Building on this, a range of advanced methodologies—including single-cell RNA sequencing, chromatin accessibility profiling, and DNA methylation analyses—have been implemented and adapted to the specific challenges of limited patient material.
A key achievement of the project has been the optimisation of experimental protocols for low-input samples, ensuring reliable data generation from rare clinical material. In parallel, several subprojects have developed and validated innovative model systems, notably CRISPR-based gene editing platforms and induced pluripotent stem cell models, which are now being used to investigate the functional impact of disease-associated variants.
These experimental efforts have been closely integrated with the development of bioinformatics pipelines designed to process, integrate, and interpret complex multi-omics datasets. This combined approach is already enabling the identification of candidate regulatory mechanisms and disease-relevant pathways. At the same time, gene editing strategies have advanced from initial design to practical implementation, supporting both the functional validation of genetic variants and the generation of disease models that will underpin subsequent translational work.
Complementing these scientific advances, the project has implemented a structured training programme that plays a central role in achieving its objectives. Through dedicated workshops and hands-on activities, DCs have received advanced training in key areas such as epigenetics and transcriptional regulation, as well as gene editing technologies and their therapeutic applications. This integrated approach ensures that the DCs are not only contributing to the scientific progress of the project but are also acquiring the cutting-edge expertise required to drive future innovation in the field.
Overall, the activities performed during this period have established a solid and scalable framework that positions the project to deliver mechanistic insights and clinically relevant findings in the next phases.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

IMMERGE is generating results that go beyond the current state of the art in several ways.
First, the integration of multi-omics data at single-cell resolution provides unprecedented insights into the cellular and molecular heterogeneity of immune disorders. This approach enables the identification of disease-specific cell states, regulatory networks, and biomarkers that cannot be captured using conventional methods.
Second, the project is advancing the development of innovative bioinformatics frameworks for integrating diverse datasets, facilitating a systems-level understanding of disease mechanisms.
Third, the application of next-generation gene editing technologies, including CRISPR-based approaches and novel nucleases, is enabling precise modelling and correction of genetic defects. These developments open new avenues for therapeutic interventions in IEIs and related conditions.
In addition, the establishment of robust pre-clinical models, including humanized systems and engineered stem cells, represents a significant step forward in translating basic research findings into clinical applications.
Overall, the project is expected to contribute to improve diagnostics, personalized medicine approaches, and innovative treatments for immune-related diseases.