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The next generation epigenetic medicine for inflammation

Periodic Reporting for period 2 - EPIMAC (The next generation epigenetic medicine for inflammation)

Reporting period: 2017-01-01 to 2019-06-30

Background and context of the project results.
Epigenetic marks regulate DNA availability for transcription, and accessibility for chromatin, and are as such critical in regulating gene expression, and allow cells to differentiate and respond to environmental stimuli. The importance of these epigenetic marks in inflammation and cancer is evident, and molecules have been newly developed to intervene with these marks (Nicodeme et al, Nature 2011; Kruidenier et al, Nature 2012; Ntziachristos et al, Nature 2014). Such compounds turn out to have extremely anti-inflammatory effects in macrophages, dendritic cells and monocytes, as well as in their target cells (Nicodeme et al, Nature 2010; Kruidenier et al, Nature 2012). Epigenetic mechanisms fundamentally control cell function in health and disease, for instance in cells dividing and their potential to remain self-renewable. Epigenetic medicines show great promise in cancer clinical trials. In the current project we develop a number of projects to show the efficacy of epigenetic medicines to treat inflammation and inflammatory disease.
In several immune-mediated inflammatory diseases (IMID) inhibitors of epigenetic modifications, such as histone deacetylases, are effective in treating inflammatory gut disorders and juvenile arthritis. However, an incomplete understanding of the contributions of specific epigenetic modifiers to immune cell function, and the poor availability of selective tool compounds that target them, currently restricts further development in the clinic. The private partner GSK has an extensive drug discovery program aimed at intervening in epigenetic modifications. These compounds will allow the consortium to map how epigenetic processes in innate immune cells can be targeted to control IMIDs.

The project.
Epimac is an EU funded Training Network for young researchers, focusing on new medicine development in the area of epigenetics. We do this in unprecedented interaction with the researchers from the pharmaceutical industry partner GlaxoSmithKline. This provides the trained investigators the unique opportunity to be trained in academic and big pharma settings, so they learn the process of basic science, drug development, modelling, and clinical application, within their research.
Summary of the work performed.
In this project we established the repertoire of epigenetic marks in inflammatory cells, identify the epigenetic landscape in inflammatory cells of the inflamed colon mucosa and intervene with these marks to reduce inflammation in inflammatory bowel disease (IBD) and chronic inflammatory diseases such as RA. The goal has been to gain better insight into how epigenetic modifications regulate innate immune cell differentiation and function, particularly in the case of IMIDs.

Implementation of novel technology.
Each project partner has expertise in specific IMIDs (inflammatory bowel disease, atherosclerosis) in which aberrant innate immune cell function contributes profoundly to pathology. For this, we used a technique called Chromatine immune precipitation, which ESRs were able to learn and implement in GSK premises. We have focused on a new class of medicine to be developed for immune cells that gotten out of control, such as seen in IBD. In several immune-mediated inflammatory diseases inhibitors of epigenetic modifications, such as histone deacetylases, or BET inhibitors are effective in treating inflammatory gut disorders and juvenile arthritis. However, an incomplete understanding of the contributions of specific epigenetic modifiers to immune cell function, and the poor availability of selective tool compounds that target them, currently restricts further development in the clinic.
To gain better insight into how epigenetic modifications regulate innate immune cell differentiation and function in in vivo models, we employed a technique called ESM-targeting, making use of special chemistry to target HDAC and BET inhibitor molecules into the cells of interest.
In terms of the impact on training of ESRs, and established synergy with private sector. Secundments and interaction with private partner GSK-EpiNova are fulfilled. All ESRs have spent their research time at AMC and GSK working on common projects. Hence, this project provided ESRs academic-industrial partnership, and a unique overview of the whole drug development cycle. This will enrich ESRs career perspectives by preparing them for research possibilities in both academic and private sectors.

Training
We look at general IMIDs (inflammatory bowel disease, rheumatoid arthritis, atherosclerosis,) but focus on IBD, in which aberrant innate immune cell function contributes profoundly to pathology. Training aspects and graduate school curricula were followed zooming in on: technology, business and entrepreneurship, drug development, disease pathology and clinical regulatory aspects. Altogether, the Epimac program has fulfilled the wish to deliver 5 well-trained ESRs familiar with academic and industry perspective of science.
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