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

Reporting period: 2020-11-01 to 2021-10-31

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 6 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.

After major efforts at the start of INNODIA focusing on standardization of sampling protocols and ethical approvals, all clinical partners (WP 1) have speedily recruited participants into the natural history study. Our clinical network has expanded, with new partners joining INNODIA and satellites of established INNODIA partners now present in 6 countries. All clinical centers are accredited and have been trained for use of the INNODIA eCRF. 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 being prepared.

In WP2 we have made major progress in 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 a first version of manuscript has been drafted. Similar work on the ‘First 100 unaffected family members’ is ongoing.
Six Immune Hubs or Sub-Hubs are installed and active to evaluate the immunome of the ND cohort from the Natural History Study, but also from the MELD-ATG clinical trial.

WP3 aims to gain better insight in the way beta-cells are destroyed in T1D. Despite being forced to homework for many researchers due to COVID-19, our collaborative research has progressed well in this period, with many publications and collaborations as a result. Important achievements were the following: 1. The characterization of the insulin granules as major sources of autoimmune epitotopes targeted by pathogenic CD8+ T cells; 2. The identification of CD8+ T cell reactivity patterns against native and citrullinated epitopes, showing adaptability of the thymus for post-translational modifications; 3. A case report showing that evolution of T1D may be characterized by autoimmune flares followed by remission and eventual relapses; 4. The discovery that target tissues of autoimmune diseases, i.e. T1D, rheumatoid arthritis, lupus and multiple sclerosis show similar gene expression signatures, with a key role for type I interferons; 5. The demonstration of the systemic bioavailability of an oral PPI-Fc vaccine, presently being optimized for the prevention of diabetes in mouse models; 6. Confirmation of the presence of the SARS-COV-2 receptor ACE2 in human -cells and the finding that TYK2 and JAK inhibitors prevent expression of this receptor and may protect -cells during COVID-19 infection; 7. Validation of a new in vitro protocol that enables full differentiation of human stem cells into adult islet-like cells; 8. Development of a novel mouse model of T1D, the YES-RIP-hB7.1 mouse.; 9. Ongoing testing of combination therapies aiming to revert established diabetes in mouse models for subsequent clinical testing.

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 progressed more rapidly than foreseen and are already running the first clinical trial. To streamline our efforts, we have taken several steps: 1) Accreditation of clinical centers. All centers have been accredited in 2017/2018 and are being followed up for quality in recruitment. New centers were accredited in 2020, and re-accreditation is ongoing; 2) Establishment of a Masterprotocol on the backbone of which clinical trials run and that allows adaptive and novel trial design. This has been finalized and obtained positive advice in February 2020; 3) Establishment of a Clinical Trial Prioritization Committee (ICTPC) that handles prioritization of offered trials to INNODIA; 4) Establishment of the Clinical Coordination Centre to oversee the activities related to the clinical trials running in INNODIA. In 2020, the first INNODIA trial MELD-ATG (KU Leuven as sponsor, UCAM as co-coordinator and Sanofi providing study drug) has been initiated in September 2020 with first participant recruited on 15 December 2020. One year later several clinical sites are open for recruitment of trial participants, and 17 patients are in follow-up already.

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 in 2021 to communication on the aspects related to the COVID-19 pandemic and increasing visibility of INNODIA branding. Moreover, expansion (in budget, partners and projects), long term sustainability and dealing with Brexit were prioritized. We stepped up communication to partners and increased the use of external communication channels to promote our work.
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 growing and delivering. We are now ready for important next steps: further branding of INNODIA and looking towards the future, with harvesting on everything we built in INNODIA. This will include exploring of new collaboration opportunities outside of the consortium, seeking for strategic partnership for future expansion of the network with new partners, all in close harmony with our patient advisory committee (PAC), representing people living with T1D and their families.
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