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Multi-omics Interdisciplinary Research Integration to Address DEmentia diagnosis

Periodic Reporting for period 1 - MIRIADE (Multi-omics Interdisciplinary Research Integration to Address DEmentia diagnosis)

Reporting period: 2019-11-01 to 2021-10-31

Dementia is a threatening disease due to its increasing incidence in the aging population, bulging costs and inhumane clinical course, while no cure is currently available. An estimated 40 million individuals suffer from dementia worldwide, 8.8 million in Europe, a number expected to double every 20 years. Dementia is diagnosed based on cognitive decline, while pathology starts 10-20 years before symptom onset. To make progress in the development of effective drugs for dementia, there is an urgent need for body fluid biomarkers to enable precision health for dementia: for an early and specific diagnosis for each dementia type and objective monitoring of disease progression. To accelerate development of such tools, radically novel approaches are needed, conceptualised by scientists with unprecedented skills. The aim of MIRIADE is to train a new generation of scientists able to optimise and accelerate development of novel body fluid biomarkers for dementia. To reach this aim, we address the following objectives:
- To equip 15 scientists with unique skills and strategies to target biomarker development (WP6).
- To establish a roadmap for strong stakeholder interactions to accelerate the biomarker development process (WP1-5,7).
- To develop an open integrated data platform for biomarker development in dementia (WP1).
- To develop computational tools for rational prediction of biomarker states in CSF and blood (WP1,2).
- To develop novel biomarker assays for specific types of dementia and validate these in shared biobank samples (WP1-3).
- To facilitate clinical implementation of biomarker assays by preparing market entry (WP4).
WP1: The goal of WP1 is to integrate existing –omics data for identification of pathways and candidate biomarkers for differential dementia diagnosis. For selection, we have performed data-integration of existing biomarker discovery datasets of available data entries in CSF, tissue and blood of dementia patients and controls. For each dementia type, the 3-5 most promising candidates have been prioritized for development in WP2 and 3 as described by each early-stage researcher (ESR), below. In addition, we developed protein-protein interaction prediction tools, to understand the protein interaction in different biofluids, and to improve the rationale behind antibody-development. This will further improve selection of proteins and reagents for assay development.

WP2: Biomarker assays in CSF and blood are developed using state-of-the-art protein technologies. The same biomarkers are developed on different technologies, for optimal synergism and comparison of the efficacies of each strategy to build a roadmap for optimised development in WP5. There is continuous interaction of WP2 with WP1 and among the ESRs in WP2 for selection of biomarkers and reagents (e.g. antibody prediction evaluation, use antibodies to increase SRM sensitivity). As such ESRs are currently developing both SRM and ELISA based assays for 3 AD markers, 5 FTD markers, 6 DLB markers and 6 markers for all dementias.

In WP3, we will clinically validate candidate biomarkers that are developed in WP1/2. We have identified several biomarkers for which assay development was successful for at least one assay type, to the level of clinical proof of concept.

The aim of WP4 is to further develop biomarker assays that have proven clinical use into biomarker assays available on the market. So far, several relevant actions for market introduction have been started for the biomarker neurofilament light (NfL), i.e. the application of EMA approval, development of reference methods and reference calibrators and standard operation procedures for blood processing, and the development of alternative assay modalities, such point of care set-ups and alternative reagents for NfL and pTau assays. In addition, NPTX2 and VAMP-2 are evaluated for their market viability.

The aim of WP5 is to provide a roadmap for innovation of the biomarker development process. This will be done by studying the different assay development strategies in WP1-4. So far, literature studies have been performed and data are being collected by performing interviews and observations of interactions between MIRIADE partners, defining the framework for the Roadmap.

Education and training (WP6) are an inherent component of the MIRIADE project. The first network-wide training week included training on biomarkers for dementia, bioinformatics, assay development, business innovation, patient perspective, entrepreneurship, and research integrity. The content of the second training week focused on the progress reports of the ESRs, reproducibility in science, dissemination of data, ethics and privacy regulations and biostatistics. In addition, the training week contained three open lectures aiming to reach scientists/interested people also outside of the MIRIADE network. In addition, our ESRs followed 70 individual courses on a wide range of topics, such as general or specific scientific project content related topics and transferable skills.

WP7, 8 and 9: Dissemination, Project management and Ethics. Our website was launched and there are 3 active social media accounts run by our ESRs: Twitter (@MIRIADE10), LinkedIn (MIRIADE E.U.) and Instagram (miriade.eu). We’ve also had media exposure through articles on our partners’ Alzheimer Europe website and newsletter and via Italian newspapers and a TV interview. MIRIADE is proud to already have published 14 open access publications with an average impact factor of 15.29. Overall project management has been efficient, coherently, and timely, despite the covid-19 pandemic. Due to the pandemic, ESR9 recruitment was moved to another beneficiary within the consortium and finalized in December 2021. As part of the ethics requirements, we have submitted 4 deliverables on human cells and tissues, protection of personal data, non-EU countries and environmental protection and safety.
Within MIRIADE, we will train 15 ESRs with excellent scientific skills who are able to apply the most advanced protein technologies combined with entrepreneurial mind-sets to successfully bring biomarkers to the clinic. Our strong network of academic and industry experts and patient organizations will accelerate the development and implementation of clinically relevant biomarkers for patients with dementia. Our blood and CSF biomarker tools allow for precision medicine with early and specific diagnosis of different types of dementia and treatment monitoring of disease progression. Proteomics datasets will be integrated and result in an unprecedented big data integration platform for candidate biomarker identification. With the platform, we will develop a comprehensive representation of disease mechanisms at the level of molecular processes: a Dementia Disease Map. Additionally, we will generate tools for protein predictions, as well as templates for data-integration and –sharing to enable efficient search for biomarkers. Early detection of dementia –even before clinical symptoms arise- will have a major impact on the diagnosis and treatment of (future) dementia patients, and thus on the socio-economic impact associated with dementia and it’s treatment in Europe and beyond. Timely accurate diagnosis reduces the costs and uncertainty of the diagnostic process, and allows for early intervention leading to better quality of life and less societal costs.
Overview of the MIRIADE workflow targeting innovative ESR training in biomarker development