Project: Nucleosome Biomarkers as predictors of inflammatory response
This project has five goals_x000D_1) Identification of epigenetic biomarkers of early inflammation/rejection in an ex-vivo model _x000D_2) Multivariate clustering analysis to derive potential signatures of Graft Vs Host Disease (GvHD) as a model for early inflammation and rejection response_x000D_3) Evaluation of epigenetic signatures as indicators of response to immunosuppressants_x000D_4) Validation of novel biomarkers in clinical samples from haematopoetic cell transplant recipients_x000D_5) Evaluation as biomarkers of organ transplant rejection_x000D__x000D_A strong, internationally diverse team has been assembled to bring the necessary range of ex-vivo tissue model, biomarker discovery expertise, bioinformatics and clinical access required to successfully complete this challenging industrial research programme._x000D__x000D_The consortium leader, Volition, is a Belgian diagnostics company based in Wallonia. Volition's innovative, proprietary technology platform, Nucleosomics®, allows simple access to epigenetic information (non-DNA sequence based factors affecting gene expression). Nucleosomes compact DNA inside the nucleus and consist of DNA looped around a core of 8 histone proteins. The proteins have chemical modifications, variations in protein sequence and chemical modifications to the DNA (e.g. methylation) which all serve to activate or repress the expression of particular genes. Nucleosomes can form complexes with other proteins and are released by dying cells into the blood in diseases including cancer, infectious disease, autoimmune disease, inflammation and organ rejection (References in Appendix A). Volition's range of simple NuQ® immunoassays allow rapid quantification of these epigenetic changes in-vitro and in biofluids (blood, serum, urine etc.). NuQ® markers can be used alone, in combination or as ratios to generate profiles related to specific conditions. Volition has a strong IP position with a range of granted and filed patents protecting the Nucleosomics® technology. Whilst the company's CO focus is currently cancer diagnostics, prognostics and efficacy monitoring, initial work has shown that NuQ® profiles vary in inflammatory and autoimmune conditions (Crohn's and Inflammatory Bowel Disease). Volition has 16 validated assays available for research use with additional assays under development and expected to be ready for the start of this program. _x000D__x000D_Alcyomics was established from the Institute of Cellular Medicine at Newcastle University, UK. The patented unique human Skin Explant technology (Skimune™) was developed for prediction of early GvHD (80% positive correlation with acute GvHD depending on degree of prophylaxis used). The model can also predict late (chronic) GvHD in conjunction with additional biomarkers such as heat shock protein 70 (References in Appendix A). This unique, non-artificial, human in-vitro assay technology is patented as a diagnostic tool to test drugs and compounds for potential allergic or hypersensitivity reactions i.e. safety, potency and toxicity. Skimune™ has also been used to test the efficacy of immunomodulatory therapies for use in autoimmune disease e.g. arthritis and inflammatory conditions (See Appendix A). In addition, the Skimune™ technology can assess the immunomodulatory properties of stem cells e.g. mesenchymal stem cells and cellular therapies. Importantly, the histopathological analyses of the ex-vivo Skimune™ assay has been shown to be 100% specific and 95% sensitive in comparison with animal data and has excellent reproducibility. _x000D__x000D_Critical aspects to this approach include; identification of putative NuQ® biomarkers of immune response (and monitoring therapeutic modulation of the response) using the Skimune™ system ; bioinformatics - clustering - analysis of the novel biomarkers to enhance the diagnostic and prognostic power (sensitivity and specificity); and access to clinical samples from transplant recipients for validation._x000D__x000D_Newcastle University will be subcontracted to provide the clinical expertise and samples required in the final phase. Newcastle benefits from 16 large biobanks with Research Tissue Bank status with a wealth of clinical expertise. In particular, the new Institute of Transplantation offers the only UK center performing all solid organ transplants on one site which, coupled with track a record of national and international collaborations will ensure that clinical material to complement local resources can be easily accessed._x000D__x000D_The primary market is acute/chronic transplant rejection (bone marrow, stem cell, islet cell transplants and solid organs). Volition will CE mark lead diagnostic/prognostic biomarkers for clinical applications within Europe followed by application to the FDA in the US. There is a significant unmet need for improved safety and efficacy of immunosuppressants, with GvHD still a major cause of mortality. There are opportunities for service to developers of novel immunosuppressants and personalized approaches to immune modulation.
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Acronym
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NuQ®
(Reference Number: 8245)
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Duration
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01/12/2013 - 31/05/2016
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Project Topic
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Graft versus Host Disease (GvHD) can complicate haematopoietic stem cell transplantation. Its immunobiology is similar to solid organ graft rejection. We propose a rational ex vivo approach to identify novel epigenetic GvHD biomarkers as indicators of early inflammation and rejection responses.
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Network
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Eurostars
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Call
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Eurostars Cut-Off 10
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Project partner
