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Translational approaches to disease modifying therapy of type 1 diabetes: an innovative approach towards understanding and arresting type 1 diabetes – Sofia ref.: 115797

Periodic Reporting for period 7 - INNODIA (Translational approaches to disease modifying therapy of type 1 diabetes: an innovative approach towards understanding and arresting type 1 diabetes – Sofia ref.: 115797)

Okres sprawozdawczy: 2021-11-01 do 2022-10-31

The overall objective of INNODIA is to advance in a decisive way how we predict, stage, evaluate and prevent type 1 diabetes (T1D). We are achieving this by creating novel tools, such as biomarkers, disease models and clinical trial paradigms. The establishment of a clinical platform in Europe, allowing the running of clinical trials in a standardized way is one of the main goals towards finding cures in a faster way.
Year 7 was crucial for INNODIA, with several key milestones reached, the major ones being: 1) reaching the target number of participants in the Natural History Study and 2) finalizing biomarker study in cohort of people with newly diagnosed T1D (ND) through omics analysis with publication drafted, and 3) the creation of a sustainable INNODIA non-profit organization.

After major efforts at the start of INNODIA focusing on standardization of sampling protocols and ethical approvals, all clinical partners (WP1) have speedily recruited participants into the natural history study. During the past year the recruitment targets in the Natural History Study have been reached, and samples are available for biomarker research purposes. First steps have been made to recruit from now on also AAb+ participants coming from general population screenings, and a ‘lighter’ follow-up of these at risk people is now ongoing.

In WP2 we have finalized the studies on ‘Omics platforms’ on a cohort of 100 subjects with ND T1D on whom clinical progression data are also available, with the goal of understanding heterogeneity of disease progression. An integrated analysis has been performed and manuscript is currently under review. In addition, work has continued to address the major unmet need around biomarkers, as well as on a validation cohort (approximately 157 subjects matching the 1st 100, for which samples are now being tested) as well as organizing an equivalent study in unaffected family members.

WP3 aims to gain better insight in the way beta-cells are destroyed in T1D. Some of the important achievements were the following: 1. Work done elucidating mRNA splice and secretory granule antigens are also targeted by CD4+ T cells, including those infiltrating the islets of T1D patients; 2. IFNg doesn’t freely diffuse into the islet and alpha and delta cells are as sensitive as beta cells to IFNg; 3. Detection of MDA5-positive/hormone-negative endocrine islet-like clusters in T1D donors, exclusively in donors with recent disease onset and not in autoantibody-positive nondiabetic donors or donors with long-standing T1D; 4. Further characterization of endotypes based on proinsulin processing and CD47 expression ongoing.; 5. The response of β-cells to IFNs is regulated both temporally and quantitatively to achieve effective signal integration; 6; CRTC1 plays a role in the apoptosis-protective mechanism exerted by miR-184-3p inhibition in β-cells under inflammatory stress; 7. Identified central role of ADAR1 in beta cells during inflammation; 8. Identified an aberrant Tgm2 expression in NOD mice, which may contribute to the loss of tolerance.

WP4 is devoted to the establishment of an integrative systems biology platform and in silico modelling for T1D. A crucial role for WP4 in this period has been the work in the biomarker identification effort on ‘the first 100’ ND cohort. The support of the data collection and in-silico analysis infrastructure has been additionally geared towards establishing clinical trials and defining sub-cohorts of interest. WP4 has also done essential work in adapting the eCRF system for clinical trials, complying with the necessary regulatory requirements.

As INNODIA moved to the next level (clinical trial initiation and execution), the role of WP5 grows. We have continued to maintain the necessary quality standards and to accredit newly joined centers of the INNODIA Clinical Trial Network (CTN). The INNODIA Clinical Trial Prioritisation Committee (ICTPC) has given green light to three additional studies that may run within the INNODIA network in the future. In addition, the creation of an automated statistical computer code for interim analysis with adaptive decision making was completed. The Trial Platform for combination therapy was also approved by the CHMP. With regard to the novel innovative implemented phase II clinical trial MELD-ATG, 72 patients have been screened, of which 53 have been randomized and 52 treated. The MELD-ATG study is currently running in 9 countries and 13 clinical sites.

WP6 groups all the work of managing and running INNODIA. As INNODIA is growing in collaborations, scientific output, clinical output, potential interests in new trials, we are stepping up the management of INNODIA. Next to overall project management, specific attention has been dedicated to boosting of INNODIA branding. An important milestone was achieved with the creation of a sustainable INNODIA non-profit organization!
All activities have progressed well, although some deliverables and milestones encountered delays for which new delivery dates have been proposed. This was mainly due to COVID which affected our work, but overall the network is now back to speed and delivering. Important new steps have been taken: further branding of INNODIA and looking towards the future, with harvesting on everything we built in INNODIA. We are proud on the successful creation of an INNODIA non-profit association, through which the important building blocks that have been created during the INNODIA project will continue to shine!
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