Gene overdosage and comorbidities during the early lifetime in Down Syndrome

Informazioni relative al progetto

GO-DS21

ID dell’accordo di sovvenzione: 848077

DOI

10.3030/848077

Progetto chiuso

Data della firma CE 22 Novembre 2019

Data di avvio 1 Gennaio 2020

Data di completamento 30 Giugno 2025

Finanziato da

• SOCIETAL CHALLENGES - Health, demographic change and well-being

Costo totale

€ 5 965 967,75

Contributo UE

€ 5 965 967,75

Coordinato da

CENTRE EUROPEEN DE RECHERCHE EN BIOLOGIE ET EN MEDECINE
France

Periodic Reporting for period 4 - GO-DS21 (Gene overdosage and comorbidities during the early lifetime in Down Syndrome)

Periodo di rendicontazione: 2024-07-01 al 2025-06-30

Sintesi del contesto e degli obiettivi generali del progetto

GO-DS21: Advancing Understanding and Care for Comorbidities in Down Syndrome

Down syndrome (DS), caused by an extra copy of chromosome 21, affects approximately 1 in 1,000 births and is often associated with comorbidities such as obesity, intellectual disability (ID), and anxiety. The EU-funded GO-DS21 project aims to better understand the biological and environmental causes of these conditions and to develop new strategies for prevention, diagnosis, and treatment. You can look at a short video explaining the project: https://www.youtube.com/watch?v=zhobkgkWh6A

The project set out to map how comorbidities evolve with age in individuals with DS before the age of 45, while also identifying physiological biomarkers and molecular signatures across human, cellular, and animal models. It explored how environmental factors such as stress, diet, and physical activity influence the development of these comorbidities in preclinical settings. A particular focus was placed on understanding the role of three candidate genen whose overexpression may contribute to the onset of obesity and cognitive impairments. To achieve a comprehensive view, the project integrated multi-level data from patients and experimental models using advanced computational biology and machine learning approaches. Ultimately, GO-DS21 aimed to develop new therapeutic strategies to reduce the severity of comorbidities and to ensure that the knowledge generated would be shared widely with individuals with DS, their families, healthcare professionals, and the broader public.

The project yielded several important outcomes. Clinical studies involving more than 230 individuals with DS revealed specific health trajectories and hormonal profiles, enabling more personalized healthcare strategies. Research using animal models demonstrated that stress significantly worsens obesity and identified genetic loci that contribute to metabolic disorders. Investigations into gene function confirmed that overexpression of DYRK1A and MRAP is linked to both obesity and cognitive deficits, and promising pharmacological treatments targeting DYRK1A were successfully tested in preclinical models. One of the project’s major achievements was the creation of a comprehensive multi-omics dataset—including gene expression, protein levels, metabolites, and gut microbiota—which provided valuable insights into early biomarkers and the biological mechanisms underlying DS comorbidities.

To support data integration and predictive modeling, GO-DS21 developed innovative computational tools such as Cosmonet and GINCCo, which allow researchers to simulate disease mechanisms and forecast health outcomes, paving the way for personalized medicine. The project also tested new therapeutic approaches, including DYRK1A inhibitors, gene therapy strategies, and lifestyle interventions aimed at improving health outcomes in DS. Community engagement was a central pillar of the initiative: the project launched a dedicated website, produced educational videos and brochures, published a children’s book to explain the science in accessible terms, and developed the FoodFall mobile app to promote healthy eating habits. Clinical guidelines for managing obesity in DS were also created and shared with healthcare providers and patient organizations, ensuring that the project’s impact extends well beyond the research community.

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

GO-DS21 A Comprehensive Approach to Understanding DS Comorbidities

GO-DS21 brought together experts in genetics, neuroscience, clinical care, and data science to study comorbidities in DS across multiple levels—from genes and cells to individuals and populations. The project had delivered seven main objectives:

Mapping Health Patterns in People with DS
Over 230 individuals with DS were recruited and assessed for clinical, cognitive, and biological markers. Using electronic health records and biological samples, researchers identified age-related patterns of comorbidities and compared hormone levels to those in the general population. These findings help tailor healthcare strategies to the specific needs of people with DS.

Exploring Environmental Influences
Using mouse and rat models, the project examined how diet, stress, and exercise affect DS-related health issues. The studies revealed that stress worsens obesity and that certain genetic regions contribute to metabolic disorders. These insights are crucial for designing lifestyle-based interventions.

Investigating Key Genes
GO-DS21 focused on three genes—DYRK1A, MRAP, and NRIP1—thought to drive DS comorbidities. Overexpression of DYRK1A and MRAP was shown to cause obesity and cognitive deficits. Promising pharmacological treatments targeting DYRK1A were tested in preclinical models, paving the way for future therapies.

Identifying Biomarkers and Molecular Signatures
Researchers generated one of the most comprehensive datasets on DS to date, analyzing gene expression, proteins, metabolites, and gut microbiota from both human and animal samples. These data help identify early biomarkers and understand the biological mechanisms behind DS comorbidities.

Integrating Data with Advanced Computational Tools
The project developed innovative machine learning and network-based tools to integrate clinical and molecular data. These tools, including Cosmonet and GINCCo, allow researchers to model disease mechanisms and predict health outcomes, supporting personalized medicine approaches.

Developing New Therapies
GO-DS21 tested new compounds, including DYRK1A inhibitors, and explored gene therapy and lifestyle interventions. These strategies aim to reduce the severity of comorbidities in DS and improve quality of life.

Engaging the Community and Sharing Knowledge
A major focus of GO-DS21 was to communicate findings to people with DS, their families, clinicians, and the public. The project website received over 77,000 visits. Educational videos, brochures, and a fairytale book were created to explain the science in accessible ways. A mobile app, FoodFall, was launched to promote healthy eating. Clinical guidelines on managing obesity in DS were developed and shared with healthcare providers and patient associations.

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)

GO-DS21 has made significant contributions to science, healthcare, and society. It has improved our understanding of the complex causes of comorbidities in DS and provided tools and knowledge to support better care. The project’s findings are already influencing clinical practice and will continue to guide future research and innovation.

GO-DS21 Results