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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - GlySign (Exploitation of Glycosylation Signatures for Precision Medicine)

Teaser

Summary

During the progression of many chronic diseases including various inflammatory conditions and cancer complex, distinctive changes occur in the carbohydrates (glycans) that are attached to various proteins. These changes can be observed when measuring the glycomics profiles or â€“ Glycan Signatures â€“ of human glycoproteins by using appropriate analytical platforms. GlySign is a research training network that aims at developing disease glycomic markers together with the suitable analytical technology for clinical translation in the context of Precision Medicine (PM). The three beneficiaries of the GlySign Consortium have been instrumental in contributing to knowledge in this field through development of glycomics technology and discovery of clinically important novel glycan biomarkers in a variety of diseases.
Glycan signatures have great potential for adding useful diagnostic and prognostic information in PM. However, advancement of this field is slow because (a) glycans have immense structural complexity resulting in major technical challenges for their analysis and (b) there is a lack of experts with required glycoanalytical skills. GlySign addresses this gap by training six early stage researchers (ESRs) within an innovative training-by-research programme with high industrial-academic mobility to eventually push forward the translation of novel glycomics-based diagnostic tools and markers into clinical practice. This is being achieved by developing a range of selective and sensitive glycomics technologies for the analysis of samples from patients and healthy controls in close collaboration between industry/academia as well as clinical chemists and clinicians who will be the end users of GlySignâ€™s final products. To this end, we focus the training on clinical glycomics applied to different model diseases implicating changes in the glycosylation of circulating proteins specific to disease progression or subtype: auto- and alloimmune diseases, e.g. rheumatoid arthritis (Work Package 1, ESRs 1-3), and diabetes and prostate cancer (Work Package 2, ESRs 4-6). All three host beneficiaries host an ESR involved in both scientific Work Packages enabling and enhancing the research interactions between the partners to accomplish shared goals. Due to the consortiumâ€™s strong industrial and translational focus, GlySign will fill a current gap on the healthcare market by establishing new in-vitro diagnostic platforms for clinical exploitation of glycomic biomarkers for PM.
Currently, the glycomics workflows and platforms appropriate for the different disease groups addressed in Work Packages 1 and 2 have been established by the six ESRs. This includes the development of prototype assays suitable for future implementation in the clinical routine laboratory. The established methodologies have either already been applied on samples from clinical cohorts (ESRs 2, 4, 5, 6) or will be applied soon (ESRs 1 and 3).
GlySign provides all 6 ESRs with valuable training in clinical glycomics technology and expertise in clinical translation of molecular biomarkers. It impacts the involved SMEs by contributing to the development of their business portfolios in the fields of clinical glycomics and characterization of biopharmaceuticals.
More information on the project and scientists in charge as well as descriptions of individual ESR projects can be found on: glysign.eu/.

Work performed

The ESRs involved in WP1 Auto- and alloimmune diseases are establishing multi-platform diagnostic assays for IgG-based patient stratification. ESR 1 has set up a middle-up approach with orthogonal techniques to simultaneously analyse IgG N-glycosylation and other post-translational modifications in patient samples with rheumatoid arthritis. ESR 2 has applied two different techniques for IgG glycosylation analysis on two cohorts of patients suffering from i) the autoimmune disease ANCA-Associated Vasculitis (AAV) and ii) Clostridium difficile infection. The longitudinal and pre- and post-treatment design of these studies will allow the (i) validation and (ii) discovery of predictive IgG glycobiomarkers. A ready-to-use microtitre-plate enzyme-based method panel for robust quantitation of IgG glycosylation has been developed by ESR 3.
The focus of WP2 is the development of enhanced assays for diabetes and prostate cancer patient stratification. ESR 4 has developed an ultrahigh sensitivity mass spectrometry assay detecting different glyco- and other isoforms of prostate specific antigen (PSA) from serum or urine. Two orthogonal methods for the analysis of antennary fucosylation of plasma N-glycans have been developed by ESR 5 and have been applied to a clinical cohort including Maturity-Onset Diabetes of the Young (MODY) and other diabetes patients. The data are being analysed to validate findings from literature and to assess additional, novel glycomic markers to distinguish the different diabetes types. ESR 5 and 6 are finalizing method development for specific plasma protein glycosylation analysis, i.e. apolipoprotein C3 and IgG, respectively. The assays will soon be applied on a large type 2 diabetes cohort for glycobiomarker development to improve the management of diabetic complications. ESR 6 has, moreover, measured a large diabetes cohort, the results of which were recently published in a peer-reviewed journal.
All six ESRs presented and disseminated their work, GlySign objectives and results, at multiple scientific conferences, such as MSACL Europe 2018 or GlycoCOM 2018. In that way, they interacted with researchers from academia and healthcare industry as well as clinicians. Moreover, the ESRs were active in communicating their research to the general public by, for example, creating and posting on their GlySign Facebook page.

Final results

Since the proposal phase of the project, the consortiumâ€™s attention has been focused on the impact of its activities on research excellence, on the exploitation of research results for the benefit of the patients as well as for increasing the innovation capacity of the European scientific community, and finally, on the training of its ESRs to provide them with the necessary skills for their future career prospects.
The GlySign project is focused on developing analytical and commercially complete glycomic and glycoproteomic services and kits for rapid, highâ€throughput patient stratification methods for complex diseases, which will ultimately help in matching therapies to patient populations, paving the way towards tailor-made therapeutically successful outcomes. This requires the training of experts in this field who are able to grasp the technological potential and understand the implicit and explicit needs for patient stratification and to develop suitable approaches.
Within the GlySign programme, great attention is given to ensuring intersectorial and multidisciplinary training including business skills, expected to enhance the ESRsâ€™ career perspectives and employability. To achieve this, next to providing them with network-wide training events that were tailor-made according to their needs, all ESRs have been guaranteed a minimum industrial placement of 18 months, with one industrial and one academic supervisor. With experience in diverse research and commercial areas, e.g. biopharmaceutical services and kits, and translation of clinical markers, the involved SMEs significantly contribute to research training and career perspectives.