Skip to main content

Multiple manifestations of genetic and non-genetic factors in Multiple Sclerosis disentangled with a multi-omics approach to accelerate personalised medicine

Periodic Reporting for period 3 - MultipleMS (Multiple manifestations of genetic and non-genetic factors in Multiple Sclerosis disentangled with a multi-omics approach to accelerate personalised medicine)

Reporting period: 2020-01-01 to 2020-12-31

Multiple Sclerosis (MS) is an immune-mediated disease and a leading cause of non-traumatic disability in young adults in Europe, affecting ~2.3 million persons worldwide. It is a lifelong disease that strikes individuals, predominantly women, in their most productive years with an unpredictable and progressive disability that affects all areas of life and includes physical disability, cognitive impairment and fatigue. The complex interactions between genetic and non-genetic factors produce heterogeneities in patients as reflected in the diversity of pathophysiology, clinical manifestations, response to therapies, disease development and progression. MS cannot be cured but there are several available disease modifying treatments (DMTs) that can reduce disease activity in RRMS patients. However, the majority of RRMS patients eventually convert to a secondary progressive form of MS (SPMS) for which there is no approved treatment today.

The overall annual cost for MS is estimated to be € 15.5 billion in Europe including direct medical costs (pharmaceutical and non-pharmaceutical), direct non-medical costs (such as informal care, devices and adaptations), and finally indirect costs (such as productivity losses due to sick leave, incapacity to work and early retirement). The cost of MS increases with increasing disability reaching an annual cost of € 60.000 for patients who have reached progressive stage of disease, with the largest part being indirect costs. Hence, MS is one of the most expensive chronic diseases even compared to many diseases with higher prevalence.

The aim of MultipleMS is to develop novel personalised medicine approaches for MS patients. To this end we will identify a combination of evidence-based selection of clinical, biological, and lifestyle features that can predict the clinical course, stratify patients based on their risk and the therapeutic response to the existing DMTs in a real-world setting, and to gain in-depth knowledge of distinct pathogenic pathways to allow identification of targets for novel treatments.

The overall objectives of MultipleMS are:
• To stratify MS patients according to differential disease etiology, disease severity and progression, and DMT response.
• To identify and validate novel biomarkers to guide stratification of patients according to disease etiology, disease severity and progression and DMT response.
• To identify targets and interventions for new precise therapies.
• To develop guidelines for a new precision medicine using biomarker guided DMT placement and monitoring in clinical settings.
• To exploit and disseminate resulting biomarkers, guidelines and therapeutic targets.
Considerable effort have been put into establishing the project as fully compliant with GDPR. This has involved establishing novel data and material transfer agreements and it is also permeating the handling of data in the whole consortium.

Two database solutions have been established for both exiting retrospective and new prospective cohort data, with secured authentication system. All partners have supplied clinical and genetic data from retrospective cohort. For genetic data and clinical phenotypes harmonization and quality control is completed. For lifestyle data harmonization is started. Analysis identifying heterogeneity based on MS risk variants and lifestyle exposures have been initiated. Cell-specific pathway analysis have been performed and individual scores have been computed. MRI images have been processed in a harmonized way and resulting metrics have been uploaded in the database. Further analyses methods have been developed and implemented by several MultipleMS partners. Genetic associations to EDSS based severity scores for MS have been performed. Local genetic analyses for cerebrospinal fluid biomarkers and MRI metrics have also been carried out. Plasma neurofilament has been determined for a large number of MS cases and it has been shown that it can be used as a prognostic marker of response to treatment as well as disability progression. Significant method developments both regarding laboratory procedures, especially with regard to novel classes of biomarkers as well as immunophenotyping, and data analyses have been performed. Development of open tools for patient stratification has been initiated.

The prospective study is running at all clinical centers in 8 EU countries. Baseline recruitment is completed with 505 patients included. 374 (74%) have had their 12 month follow up visit and 103 (25%) their 24 month visit. DNA and RNA has been extracted from the baseline samples. Immunophenotyping of baseline samples is ongoing.

A systematic reviews of published MS guidelines regarding use of biomarkers in clinical practice has been performed and manuscripts have been written. A survey has been distributed to MS neurologists across Europe to understand differences and similarities of clinical practice across Europe and willingness to use biomarkers in every day clinical practice, results have been presented at international conference.

We have established communication and dissemination channels, e.g. an official MultipleMS website, Facebook-page and Twitter account, which are available to all MultipleMS members and open for the public. A Stakeholder Forum was developed containing contact information of relevant stakeholders, such as pharmaceutical companies, (clinical) research associations, governmental bodies, non-governmental organisations, patient organisations and health professionals. Stakeholders are informed about the project’s development and can provide feedback to the consortium. A Stakeholder workshop was arranged in London in May 2018 with participants from 18 different key organizations/companies, where the aim was to inform about the objectives and progress of MultipleMS and to consult them on their expectations of MultipleMS to allow for the best translation of project results. A stakeholder meeting was also held at the ECTRIMS conference in Berlin in 2018. A PhD/Postdoc student challenge, supported by Novartis, was organized in Copenhagen 2017. Each attendee presented their vision on how to best involve and reach patients in the development and implementation of project results.
To create strategic global synergies, MultipleMS includes 22 partners and covers not only the necessary clinical, biological, and computational expertise, but also includes six industry partners ensuring dissemination and exploitation of the methods and clinical decision support system. Moreover, the pharmaceutical industry partners provide expertise to ensure optimal selection and validation of clinically relevant biomarkers and new targets. Our conceptual personalized approach can readily be adapted to other immune-mediated diseases with a complex gene- lifestyle background and broad clinical spectrum with heterogeneity in treatment response. MultipleMS therefore has a potential implication on European policies, healthcare systems, innovation in translating big data and basic research into evidence-based personalized clinical applications.

The project has already resulted in several new collaborations including EU-STANDS4PM and IMSGC and initiated collaborations with other consortia active in the MS field such as MAGNIMS.
MultipleMS approach