#	Pagina
attuale pagina	/open-h2020/projects/207217/results.html

Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - SYSCID (A Systems medicine approach to chronic inflammatory disease)

Teaser

Summary

Chronic inflammatory diseases (CIDs) comprise a group of incurable disorders of the immune system with a lifetime prevalence of over 10% in the EU and a globally rising incidence in countries adopting the Western industrialized lifestyle. CID are systemic disorders that differ in their main target organ(s), which include the gut (e.g. inflammatory bowel disease - IBD), skin (e.g. psoriasis), lung (e.g. bronchial asthma), vessels/kidney (e.g. systemic lupus erythematosus) and joints (e.g. rheumatoid arthritis). CID show extensive overlap in their genetic risk maps and environmental risk factors, suggesting the existence of a shared underlying disease mechanisms. The diseases usually manifest at a specific time window during adult life and are associated with a significant degree of long-term disability.
SYSCID constitutes an interdisciplinary consortium of researchers from nine European countries with expertise ranging from medical sciences, immunology, genomics, molecular biology, bioinformatics to even computer sciences. The SYSCID network aims to delineate a new molecular stratification for personalized medicine approaches to CID. The consortium focuses on 3 archetypal CIDs: inflammatory bowel disease, rheumatoid arthritis and systemic lupus erythematosus. Patient availability and pre-existing longitudinal multiple OMICs-datasets were the main criteria to select indications for the first level analysis.
SYSCID has set out to tackle several unmet clinical needs in CIDs:
â€¢ A clear diagnosis of disease: Current diagnostic methods are not sufficient to accurately predict early disease manifestation. Time from first symptoms to diagnosis of CID even in Western Europe still suffers from a diagnostic delay of 12-24 months. Diagnostic algorithms employing multimodal marker sets for early and unequivocal detection of disease are thus a major unmet need in CID.
â€¢ Disease progression and comorbidities: Early identification of patients with aggressive disease behavior or prediction of complications such as malignancies, are decisive elements for a future individualized clinical treatment. First promising results have demonstrated that an exhaustion signature of specific immune cells may predict complicated disease behavior across several CID.
â€¢ Therapy Response: Several different targeted therapies neutralizing specific factors of the immune system (so called â€œbiologicalsâ€, e.g. antibodies to TNF or IL6) have been approved. Such therapies are cost-intensive and suffer from significant primary and secondary non-response rates. So far on the individual patient level, a molecular rationale (biomarker) for employing a specific compound in an indication situation is missing. SYSCID will follow different layers of molecular information in individual patients over time in order to develop systems-based decision support to select the right therapy at the right time.
The consortium employs a variety of patient sample types derived from peripheral blood: whole blood and sorted blood immune cell types to single cell analysis. The project also comprises experimental strategies to develop epigenome editing therapies to reprogram specific cell types e.g. macrophage polarization defects.

Work performed

In its first 18 months, SYSCID has successfully commenced its scientific work programme and has established a fully functional consortial structure with all positions filled after month 6. As the project still is in an early phase, by definition a lot of the work in the reporting period has to be considered preparatory for the large-scale analytical tasks ahead. A kick-off meeting was held in Kiel in month 4. Communication has been established early on and project progress is monitored bi-weekly by structured web-based (video)conference, where data are shared and discussed. A second general assembly has been held in April, 2018 on Crete, where the first data production and analysis results were presented and discussed in detail.
Results:
Patient selection and sample ascertainment: We have successfully selected patient and control populations for several large scale experiments aiming to address predictors and mechanisms of (1) disease severity and outcome across CID (1022 patients and 303 controls) and (2) response to targeted therapies (anti-TNF, anti-integrin, Anti-Blys) with >170 newly treated patients with up to 8 timepoints for longitudinal multi-Omics analysis. Several additional smaller cohorts (early arthritis prediction, disease liability in â€œhealthyâ€ control cohorts, purified subsets of cells from IBD, RA and SLE) are underway. Clinical data and scoring systems have been harmonized between participating clinicians and a data/metadata matrix has been implemented with the central data management project.
Quality control and protocol harmonization: The production centers (USAAR, UNIGE, CAU, UCAM, ULG, UBO) have implemented SOP-like protocols for cell purification, sample extraction, quality controls and production of molecular data (RNA, DNA methylation, 16S rDNA, IgG glycome. Selected samples: Metagenome, Genome, single cell RNA assessment and single cell chromatin (ATAC)). A pipeline for uploading to the central data repository has been set up. The QC steps include inter-lab variation testing and extraction controls.
Production: Using this harmonized production pipeline, the consortium partners have already extracted, prepared and analysed >2300 samples by RNA sequencing, >1400 samples by EPIC array (DNA methylation), the data is currently assembled for integrative analysis in the respective tasks and work packages. Pilot analyses have successfully been finished and have led to joint publications, e.g on prediction of response to anti-integrin therapy by transcriptomal signatures (Zeissig et al., Gut 2018) or on an interferon-responsive gene signature predicting anti-TNF success in IBD.
Outreach: The consortium has presented its aims and first results at several outreach occasions on international conferences (e.g. United European Gastroenterology Week, UEGW, IHEC). SYSCID has become an official partner of IHEC and is part of an EU systems medicine initiative â€œSTANDS4PMâ€ for harmonizing data sets and models. The scientific concepts of SYSCID have been put down in several white papers, which are now published (Schultze et al., Immunity 2018 and Sommer et al., Nat Rev Microbiol 2017).

Final results

SYSCID aims to contribute to the development of precision medicine by identifying a new molecular taxonomy of CID, which will provide a rationale for clinical decision support, e.g. which patient has a predicted complicated course and which therapy should be selected? Results from the first 18 months have shown predictive potential from integrated Omics signatures for anti-Integrin and anti-TNF therapies in IBD. Using innovative technologies such as single cell sequencing and IgG glycomics, SYSCID will generate an integrated understanding to identify outcome predictor patterns. Insights from well-characterized patient cohorts with longitudinal molecular and clinical data will help to define meaningful, molecularly defined subphenotypes that will enable efficient patient stratification for future care of CID patients.