Research in Multiple sclerosis

Improved and tailored therapies for patients with multiple sclerosis

PI: Kjell-Morten Myhr

Myhr is senior consultant and professor of neurology, and has since 2001 directed the Multiple Sclerosis (MS) Research Group at Haukeland University Hospital and the University of Bergen (https://www.uib.no/fg/kgj-ms). He has previously chaired the first KG Jebsen Centre for Medical Research, focusing on MS-biomarkers (2011-2016), and has since 2019 been the director of the Norwegian Centre for Clinical Treatment Research in Neurology, Neuro-SysMed (https://neuro-sysmed.no/).

The project activities of the Multiple Sclerosis (MS) Research Group aim to support and meet the main objective of Neuro-SysMed to generate improved and tailored treatment strategies for patients with MS. Some projects are a direct result from the NeuroSysMed funding, and others are a part of the longterm commitment of the group for improved therapy and care for MS patients, and thus are important prerequisites for the Neuro-SysMed centre.

The group is currently recruiting patients into four investigator sponsored clinical trials. The RAM-MS study evaluates the safety and efficacy of autologous hematopoietic stem cell transplantation (HSCT) compared to high-efficacy disease modifying therapies (DMT) in relapsing-remitting MS (RRMS) patient with breakthrough disease activity. The OVERLORD-MS study evaluates and compares the efficacy and safety of rituximab and ocrelizumab in newly diagnosed RRMS patients. The COVID-19 vaccine response study evaluates the impact of various DMTs on the vaccination response in MS patients. The SMARTMS study aims to evaluate the regenerative effect of mesenchymal autologous stem cells in progressive MS. This latter study has received approval from the Norwegian Medical Agency and the Ethical Committee, but the start is put on hold due to COVID-19 restrictions for the partner in Ulm, Germany. The group is however pre-screening patients to be ready for the start-up. In addition, they are also national coordinator for three industry sponsored multicentre randomized clinical trials, and recruiting site for another.

In collaboration with the biomarker group, the MS group is currently phenotyping stem cells and immune cells from patients included in the ongoing clinical trials, aiming to identify biomarkers for tailored dosing or patient selection. In other studies, they have evaluated biomarkers of treatment response of natalizumab as well as dimethyl fumarate and teriflunomide. similarly, the use of neurofilament (NFL) and magnetic resonance imaging (MRI) are used to evaluate treatment response and disease progression. The impact of modifiable lifestyle factors are also evaluated, related to treatment efficacy and long-term prognoses, aiming for improved and personalised treatment strategies in MS.

A sensitive and clinical practical screening instrument for early detection of disabling symptoms like cognitive dysfunction is another important research focus with direct impact for the clinical trial efficacy endpoints. Thus, the Norwegian translation of the brief international cognitive assessment for multiple sclerosis (BICAMS) is currently included in the clinical trials.

Registry and epidemiological studies to evaluate possible risk factors and comorbidities have been a long-term commitment for the research group. Recent data on cancer frequency in MS calls or further studies both on the aetiology of the disease, and risk stratification for immunotherapy.

Preclinical studies evaluating effects from vitamin D on remyelination (repair) in animal models, as well as biomarker discovery studies in these animal models and the cerebrospinal fluid from MS patients are other prioritized projects in the group. They also use animal models in feasibility studies of mesenchymal stem cells as a regenerative therapy in progressive MS.

Selected Key Publications

1. Bringeland GH, Blaser N, Myhr KM, Vedeler CA, Gavasso S. Wearing-off at the end of natalizumab dosing intervals is associated with low receptor occupancy. Neurol Neuroimmunol Neuroinflamm. 2020;7:e678. PMID: 32019768
2. Bringeland GH, Myhr KM, Vedeler CA, Gavasso S. Wearing-off at the end of natalizumab dosing interval and risk of MS disease activity: A prospective 1-year follow-up study. J Neurol Sci 2020;415:116880. PMID: 32413799
3. Norborg H, Riise T, Myhr KM, Grytten N, Wergeland S. Real-world discontinuation of teriflunomide and dimethyl fumarate in multiple sclerosis. Mult Scler J Exp Transl Clin 2020/2021 – in press.
4. Varhaug KN, Torkildsen Ø, Myhr KM, Vedeler CA. Neurofilament Light Chain as a Biomarker in Multiple Sclerosis. Front Neurol 2019;10:338. PMID: 31024432
5. Lie IA, Weeda MM, Mattiesing RM, Mol MAE, Pouwels PJW, Barkhof F, Torkildsen Ø, Bø L, Myhr KM, Vrenken H. The relationship between white matter lesions and grey matter atrophy in multiple sclerosis. Neurology 2020/2021, submitted
6. Wesnes K, Myhr KM, Riise T, Kvistad SS, Torkildsen Ø, Wergeland S, Holmøy T, Midgard R, Bru A, Edland A, Eikeland R, Gosal S, Harbo HF, Kleveland G, Sørenes YS, Øksendal N, Bjørnevik K. Low vitamin D, but not tobacco use or high BMI, is associated with long-term disability progression in multiple sclerosis. Mult Scler Relat Disord 2021;50:102801. PMID: 33636616
7. Skorve E, Lundervold AJ, Torkildsen Ø, Myhr KM. A two-year longitudinal follow-up of cognitive performance assessed by BICAMS in newly diagnosed patients with MS. Mult Scler Relat Disord 2020;46:102577. PMID: 33296975
8. Grytten N, Myhr KM, Celius EG, Benjaminsen E, Kampman M, Midgard R, Vatne A, Aarseth JH, Riise T, Torkildsen Ø. Risk of cancer among multiple sclerosis patients, siblings, and population controls: A prospective cohort study. Mult Scler 2020;26:1569-1580. PMID: 31573834
9. Grytten N, Myhr KM, Celius EG, Benjaminsen E, Kampman MT, Midgard R, Vatne A, Aarseth JH, Riise T, Torkildsen Ø. Incidence of cancer in multiple sclerosis before and after the treatment era– a registry- based cohort study. Mult Scler J Exp Transl Clin 2020/2021 – submitted.
10. Nystad AE, Lereim RR, Wergeland S, Oveland E, Myhr KM, Bø L, Torkildsen Ø. Fingolimod downregulates brain sphingosine-1-phosphate receptor 1 levels but does not promote remyelination or neuroprotection in the cuprizone model. J Neuroimmunol 2020;339:577091. PMID: 31739156
11. Oveland E, Ahmad I, Lereim RR, Kroksveen AC, Barsnes H, Guldbrandsen A, Myhr KM, Bø L, Berven FS, Wergeland S. Cuprizone and EAE mouse frontal cortex proteomics revealed proteins altered in multiple sclerosis. Sci Rep 2020/2021 in press
12. Mosleth EF, Vedeler CA, Liland KH, McLeod A, Bringeland GH, Kroondijk L, Berven FS, Lysenko A, Rawlings CJ, Eid KE, Opsahl JA, Gjertsen BT, Myhr KM, Gavasso S. Cerebrospinal fluid proteome shows disrupted neuronal development in multiple sclerosis. Sci Rep 2021;11:4087. PMID: 33602999

Last updated April 16th, 2021 at 11:17 am

Neuroimmunlogy and disease biomarkers

PI: Christian Vedeler

Professor Christian Vedeler is Professor of Neurology and Neuroimmunology at the University of Bergen and Haukeland University Hospital. He is the Director of the Neuroimmunology Laboratory and has for many years developed and established clinically relevant biomarkers for diagnosis and treatment of neurological diseases. Professor Vedeler is an international expert in immune mediated paraneoplastic neurological diseases and his expertise include neuroimmunology, biomarker establishment, autoimmunity and neurodegeneration.

The Biomarker Group currently focuses on translational single cell omics research in two stem cell intervention trials, inspired by the potentially large benefits of the two stem cell clinical trials organized by the MSgroup at Neuro-SysMed. The RAM-MS study seeks to reconstitute the immune system of RRMS patients with a distinct inflammatory component by hematopoietic stem cell transplantation (HSCT). The SMART-MS study seeks to induce the endogenous regenerative potential in the central nervous system (CNS) of MS patients with a distinct neuro-degenerative disease
course, PPMS and SPMS, with mesenchymal stem cells (MSC).

The group is developing quality controlled diagnostic and biomarker assays based on state of the art technologies. They use mass cytometry and flow cytometry for deep immune phenotyping to study the immune response in blood and CSF and the composition of cell products to evaluate treatment safety and response. They develop functional and quantitative assays for antibody based therapy such as receptor occupancy for mass cytometry to monitor drug efficacy in patients. The group further develops and establishes CSF and serum biomarker assays such as neurofilamant (NFL) and IgG bands. Based on quanterix technology, they measure NFL-light chain in serum samples from patients to monitor treatment response and disease progression in neurological diseases. In collaboration with the Department of Medical Biochemistry and Pharmacology, they have established a very sensitive capillary gel electrophoresis method that substantially increased sensitivity and specificity of oligoclonal immunoglobulins in CSF of patients with MS and other neuroinflammatory diseases. Currently, they are establishing a method to test pharmacological
profiles of drugs and anti-drug antibodies of biological medications, such as for anti-CD20 antibodies used to treat patients with MS.

The group contributes with standard operating procedures for laboratory manuals in clinical trials and has optimized standard protocols for biobanking of patient materials in clinical trials at Neuro-SysMed. In addition, the group is working on a set of important proteins, called cerebellar degeneration proteins (CDR1, CDR2, CDR2L), which they have localized to important cell organelles that are essential for neuronal functions, being nuclear speckles, Golgi apparatus and mitochondrial transport. These proteins will be further characterized as potential biomarkers for neurodegenerative diseases. The group further studies the brain microenvironment in post-mortem tissues. They use state of the art imaging mass cytometry to characterize the brain microenvironment at unpresented resolution. They are particularly interested in immunologically competent cells in brain, such as microglia and astrocytes, and study the cell interactions to investigate disease mechanisms and new treatment targets.

Selected Key Publications

Last updated April 16th, 2021 at 11:21 am

Stem-cell derived disease models

PI: Laurence Bindoff

The MMN group performs clinical and basic research primarily focussed on mitochondria and their role in disease. To this end, the group studies primary mitochondrial diseases such as those caused by mutations in POLG and mitochondrial DNA, and mitochondrial dysfunction in other diseases, e.g. Parkinson’s and other neurodegenerative disorders.

Whilst the link between primary mitochondrial defects and disease is clear, multiple lines of evidence link mitochondrial dysfunction and neurodegeneration so that no one mechanism prevails. This suggests that either mitochondrial dysfunction is a “common” final pathway for all forms of neurodegeneration, or that mitochondrial promiscuity, i.e. their involvement in almost any cellular process, means that these changes are secondary, and are either not involved in the disease process or only partly so.

The group has established a robust model system to investigate disease related changes in mitochondrial function. Reprogramming patient fibroblasts to induced pluripotent stem cells (iPSC) provides a substrate from which any cell type/tissue can be generated. For example, the group has generated neuronal lineages including dopaminergic neurones, motor neurones, glial cells such as astrocytes and oligodendrocytes and mesenchymal cells such as cardiomyocytes. MMN’s role in Neuro-SysMed is to provide this expertise in generating stem cell models in appropriate cell lineages (e.g. neuronal or glial). MNN is now extending its work into generating complex structures called organoids. The group has successfully generated cortical organoids (“brains in dish”) from patients with mitochondrial disease and controls.

The group’s studies with stem cell models show that it is possible to replicate findings such as respiratory chain complex I deficiency and mtDNA depletion in neural stem cells (NSC), progenitors committed to the neuronal lineage, but with retained ability to divide. The group published their findings in NSC with POLG mutations in EMBO Molecular Medicine. They have also submitted work showing that astrocytes from POLG patients also manifest a phenotype, but more interestingly, they become toxic for neurones. Astrocyte involvement in neurodegeneration is an exciting new area and these groundbreaking findings suggest that mitochondrial dysfunction may be a common stimulus driving astrocyte conversion from normal to the toxic A1 type that damage and potentially kills neurones. This work is under review. Lastly, the group has been looking at various candidate compounds for treating mitochondrial dysfunction. They found that N-acetylcysteine amide was able to reduce oxidative stress and improve mitochondrial function in iPSC derived dopaminergic neurones. This was published in Experimental Neurology.

The MMN group has also generated cardiomyocytes from iPSC and done this in a 96 well format. This method was published in Scientific Reports. The importance of this work is that it confirms our ability to generate a wide range of differentiated cell types, something that can be important in the future.

The group’s recent clinical work has focussed on greater understanding of POLG related disease and the elaboration of biomarkers with which to diagnose and follow mitochondrial diseases. studies of POLG related disease have used the POLG registry that now contains >180 patients, both living and dead. This unique material has allowed them to generate a simplified classification of POLG related disease, to investigate the impact of gender and pregnancy on disease course and outcome, and to study mental health and quality of life in affected individuals. Intriguingly, they found clear gender differences: males tended to present and die earlier than females and onset and worsening in females was associated with onset of menarche and pregnancy.

The search for biomarkers has focussed on two areas: novel mitochondrial disease markers and studies to investigate how best to use known biomarkers. Neurofilament light chain (NF-L) released by damage to neurones has been used as a marker to follow disease progression in multiple sclerosis. The group asked the question whether it could be useful also in mitochondrial disease, and performed a study comparing it with other known mitochondrial biomarkers, namely FGF21 and GDF15. In their pilot study, they showed that NF-L could be useful in detecting central nervous system involvement in patients with systemic mitochondrial disease. In those with disease restricted to skeletal muscle, FGF21 and GDF15 were more sensitive. They also investigated the detection of mtDNA deletions and showed that urine sediment cells were an appropriate source of DNA, thus obviating the need for muscle biopsy in these patients.

Selected Key Publications

1. Hytönen MK, Sarviaho R, Jackson CB, Syrjä P, Jokinen T, Matiasek K, Rosati M, Quintero I, Arumilli M, Donner J, Anttila M, Bindoff LA, Suomalainen A, Lohi H. In-frame deletion in canine PITRM1 is associated with a severe early-onset epilepsy, mitochondrial dysfunction and neurodegeneration. Hum Genet. Under review. This work is a follow up on the human studies performed with Professor Zeviani (Padua) and confirms that mitochondria are involved in amyloid beta metabolism.
2. Liang KX, Vatne GH, Kristiansen CK, Levglevskyi O, Kondratskaya E, Glover JC, Chen A, Sullivan GJ, Bindoff LA. N-acetylcysteine amide ameliorates mitochondrial dysfunction and reduces oxidative stress in hiPSC-derived dopaminergic neurons with POLG mutation. Exp Neurol. 2020 Nov 29;337:113536. doi: 10.1016/j.expneurol.2020.113536.
3. Balafkan N, Mostafavi S, Schubert M, Siller R, Liang KX, Sullivan G, Bindoff LA. A method for differentiating human induced pluripotent stem cells toward functional cardiomyocytes in 96-well microplates. Sci Reports, 2020 28;10(1):18498. doi: 10.1038/s41598-020-73656-2.
4. Liang KX, Kristiansen CK, Mostafavi S, Vatne GH, Zantingh GA, Kianian A, Tzoulis C, Høyland LE, Ziegler M, Perez RM, Furriol J, Zhang Z, Balafkan N, Hong Y, Siller R, Sullivan GJ, Bindoff LA. Disease-specific phenotypes in iPSC-derived neural stem cells with POLG mutations. EMBO Mol Med 2020 Oct 7;12(10):e12146. doi: 10.15252/emmm.202012146.
5. Lehtonen JM, Auranen M, Darin N, Sofou K, Bindoff LA, Hikmat O, Uusimaa J, Vieira P, Tulinius M, Lönnqvist T, de Coo IF, Suomalainen A, Isohanni P. Diagnostic value of serum biomarkers FGF21 and GDF15 compared to muscle sample in mitochondrial disease. J Inherit Metab Dis. 2020 Aug 28. doi: 10.1002/jimd.1
6. Varhaug, KN, Nido,GS, de Coo I, Isohanni P, Suomalainen A, Tzoulis C, Knappskog P, Bindoff LA. Using urine to diagnose large-scale mtDNA deletions in adult patients. Ann Clin Transl Neurol. 2020 Aug;7(8):1318-1326. doi: 10.1002/acn3.51119.
7. Hikmat O, Naess K, Engvall M, Klingenberg C, Rasmussen M, Tallaksen CM, Brodtkorb E, Ostergaard E, de Coo IFM, PiasPeleteiro L, Isohanni P, Uusimaa J, Darin N, Rahman S, Bindoff LA. Simplifying the clinical classification of polymerase gamma (POLG) disease based on age of onset; studies using a cohort of 155 cases. J Inherit Metab Dis. 2020 Jul;43(4):726-736. doi: 10.1002/jimd.12211.
8. Liang X, Kristiansen, CK, Vatne GH, Hong Y, Bindoff LA. Patient-specific neural progenitor cells derived from induced pluripotent stem cells offer a promise of good models for mitochondrial disease. Cell Tissue Res. 2020 Apr;380(1):15-30.

Registry-based in silico drug screening and epidemiology

PI: Trond Riise

The project aims to develop new and effective treatments for the neurological diseases Parkinson’s disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD). Principal Investigator Trond Riise has a background in mathematics/statistics and works as a professor in epidemiology at the University of Bergen, Norway.

Trond Riise’s research has been related to epidemiological studies of neurological diseases including Parkinson’s disease and multiple sclerosis. The focus has been to identify environmental factors that, by their own or in combinations, significantly change the disease risk. Dr. Riise has an extensive collaboration with researchers at Harvard University, where he previously was a visiting professor. He is also currently a core investigator of the Center for Parkinson Precision Neurology at Brigham and Women’s Hospital and Harvard University. Riise has also been a visiting professor at the Universities of Ferrara and Bologna, Italy. Riise’s international collaborators are key researchers in this Neuro-SysMed project. Dr. Riise is Head of Research of a comprehensive drug-screening project which involves screening of all prescriptions given to all Norwegians since 2004. These prescriptions (about 800 mill) are linked to the incidence of Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). The overall objective of the project is to evaluate whether existing drugs (molecules) can be repurposed as effective treatment of PD, ALS and MS.

The group is introducing an initial screening phase in humans that will form the basis for new hypotheses that in a second phase will be tested and validated in mechanistic experiments using human iPSC-derived neurons and animal models. This approach might be referred to as “inverse translational research” and represents a novel use of Norwegian health registries.

Selected Key Publications

1. Antonazzo IC, Poluzzi E, Forcesi E, Riise T, Bjørnevik K, Baldin E, Muratori L, De Ponti F, Raschi E. Liver injury with drugs used for multiple sclerosis: A contemporary analysis of the FDA Adverse Event Reporting System. Multiple Sclerosis 2019;25:1633-40.
2. Olsen AL, Riise T, Scherzer C. Promise for Parkinson’s: Discovering new benefits from old drugs with big data. Editorial. JAMA Neurology 2018;75(8):917-20.
3. Cortese M, Riise T, Engeland A, Ascherio A, Bjørnevik K. Urate and the risk of Parkinson’s disease in men and women. Parkinsonism and Related Disorders 2018;52:76-82.
4. Mittal S, Bjørnevik K, Im DS, Flierl A, Dong X, Locascio JJ, Abo KM, Long E, Jin M, Xu B, Xiang YK, Rochet JC, Engeland A, Rizzu P, Heutink P, Bartels T, Selkoe DJ, Caldarone BJ , Glicksman MA, Khurana V, Schüle B, Park DS, Riise T, Scherzer CR. β2-Adrenoreceptor is a Regulator of the α-Synuclein Gene Driving Risk of Parkinson’s Disease. Science 2017;357:891-8.

The Philosophy of Neurodegeneration

PI: Jan Reinert Karlsen

Jan Reinert Karlsen is Associate Professor at the Centre for the Study of the Sciences and the Humanities (SVT), an inter-disciplinary and inter-faculty research unit at the University of Bergen. In his affiliation to NeuroSysMed, his project will contribute to a better understanding of philosophical issues in precision medicine in severe chronic neurological diseases. A central issue which will be studied is the concept of suffering. Developing new perspectives on suffering, the group will use this concept as a frame for developing novel interdisciplinary approaches to understanding the characteristics of suffering in patients with severe chronic neurological diseases and how these can be alleviated.

The project will focus on the four diseases studied at Neuro-SysMed: Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). To enable more precise articulations of the philosophical problems to be studied, the aim is to establish and develop collaborations across the various groups and activities at the centre.

The philosophical and methodological issues to be studied are:

Issues related to the nature of severe chronic neurological diseases with a special focus on the problems of heterogeneity and complexity in disease stratification and classification.
Issues related to the limits and goals of the systems / precision medicine paradigm in severe chronic neurological diseases with a special focus on the intersection between data and algorithmic driven science, clinical research, and clinical practice.
Issues related to conceptualization of suffering and the nature and characteristics of suffering in patients with severe chronic neurological diseases, including their co-sufferers, e.g. next of kin.
Issues related to broader societal aspects, expectations, and concerns with regard to precision medicine in severe chronic neurological diseases, including the models for studying these broader aspects (e.g., ethical legal and social aspects (ELSA), responsible research and innovation (RRI), technology assessment (TA), and ethics of science and technology).

The group plans to organize interdisciplinary discussion and reflection fora at Neuro-SysMed that will seek integration across the different groups. Here, topical philosophical, societal, and ethical issues in relation to the centre’s activities will be discussed. The group will contribute to public understanding and debate about these issues.

The activities of the group in 2020 have been restricted by the fact that the PI has been on two consecutive sabbaticals, the first was a research sabbatical committed to a project at SVT during the spring and the second was a parental leave during most of the fall. However, important progress was made at the conclusion of the year in relation to understanding foundational aspects of the concept of suffering, and a new research project was articulated, i.e. “The philosophy of severe chronic neurological diseases”. The PI will continue this work while awaiting the employment of a postdoc to this project. The concept of suffering will serve as a key analytic frame and heuristic entry point of this research project.

During 2020, the group established contact with a recognized international publishing house for writing a book based on this research project. The book proposal will be written in cooperation with the postdoc. Before the March 12th lockdown, Jan Reinert Karlsen contributed to a popular science debate about philosophical aspects of the science of aging organized by The Students’ Society of Bergen. After the lockdown, the Interdisciplinary Seminar about Suffering was reorganized as a ‘peripathetic seminar’ (i.e. walk–think–talk’ seminars) on a weekly basis. These ambulating seminars continued throughout 2020.

Selected Key Publications

1. Karlsen, JR; Solbakk, JH. A waste of time: the problem of common morality in Principles of Biomedical Ethics. Journal of Medical Ethics 2011;37 p. 588-591
2. Karlsen, JR; Solbakk, JH; Holm, S. Ethical Endgames: Broad Consent for Narrow Interests; Open Consent for Closed Minds. Cambridge Quarterly of Healthcare Ethics 2011;20(4) p. 572-583
3. Karlsen, JR; Strand, R. Annexation of Life: The Biopolitics of Industrial Biology. In: Solbakk, JH; Holm, S; Hofmann, B. (eds.) The Ethics of Research Biobanking. Springer 2009 ISBN 978-0-387- 93871-4. p. 315329
4. Karlsen, JR; Solbakk, JH; Strand, R. In the Ruins of Babel: Should Biobank Regulations be Harmonized? In: Solbakk, JH; Holm, S; Hofmann, B. (eds.) The Ethics of Research Biobanking. Springer 2009 ISBN 9780-387- 93871-4. p. 337-349
5. Karlsen, JR; Strand, R. The Ethical Topography of Research Biobanking. In: Ethics, Law and Society Volume IV. Ashgate 2009 ISBN 978-0-7546-7646-1. p. 127-148
6. Karlsen, JR; De Faria, PL; Solbakk, JH. To know the value of everything: a critical commentary to B. Björkman and S.O. Hansson’s ‘Bodily rights and property rights’. Journal of Medical Ethics 2006;(32) p. 21521