The research within our LUMC departments is conducted within departmental research programmes. The research programme below is embedded within the department of Neurology.
- Research programme: Neurological Motor Disorders
- Department: Neurology
- Programme leader: Prof. Dr. J.J.G.M. Verschuuren
- Principal investigators: Prof. Dr. R.A.C. Roos, Prof. Dr. J.J. van Hilten, Dr. E.H. Niks, Dr. J.J. Plomp
- Biomedical research profile: Translational Neuroscience
- Generic research profile: Biomedical Imaging
Aim and focus
The “Neurological Motor Disorders (NMDs)” is a collaborative effort of our clinical team supported by basic science research groups focusing on chronic conditions of the motor system from muscle to cortex.
- Peripheral motor disorders, including myasthenia gravis (MG), Duchenne and Becker muscular dystrophies (DMD/BMD), Facioscapulohumeral muscular dystrophy (FSHD), oculopharyngeal muscular dystrophy (OPMD), and Inclusion Body Myositis (IBM)
- Central motor disorders, including Huntington’s disease (HD) and Parkinson’s disease (PD)
The aim of the programme is to conduct innovative research on clinical profiling, disease course, quality of life, clinical and radiological biomarkers, pathophysiology and development of new treatments. This is supported by detailed and innovative, national and international patient registries and the development of new clinical, biological or radiological outcome measures to support clinical research and trial readiness in close collaboration with our basic science research partners.
The research lines within the Neurological Motor Disorders programme have several project specific aims:
- To unravel the natural history and disease modifiers, e.g. international natural history study in DMD and HD, quantification of motor and non-motor deficits of PD and HD.
- To unravel the pathophysiology of the diseases, e.g. role of MuSK antibodies in MuSK MG, muscle MRI in DMD
- To unravel genotype – phenotype relationships, e.g. muscle or brain MRI studies in DMD, or MRI studies and genetic studies in HD
- To decipher the best outcome measures covering various aspects and stages of the disease, e.g. outcome scale research in DMD, MG, HD and PD.
- To identify biomarkers that reflect disease severity or determine the progression and generalisation of the disease, e.g. serum biomarkers in DMD
- To identify and validate treatment targets, e.g. improve the diagnosis and clinical care of patients with HD and PD
- To test novel treatment modalities, e.g. clinical trials in DMD or MG.
Position in international context
The research lines have a high standing in the international communities. The LUMC has top positions in the development of the antisense therapy for Duchenne muscular dystrophy (DMD), on research of Becker muscular dystrophy (BMD), of myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), Huntington’s disease (HD) and Parkinson’s disease (PD) in close collaboration with many internationally renowned experts, consortia and industry partners (BioMarin, Genentech, ArgenX, Alnylam, TECAN-IBL). This international collaboration with scientific and clinical researchers includes University of Barcelona; Skirball Institute at New York; Institute of Molecular Medicine, John Radcliffe Hospital, Oxford; Queens Square Centre for neuromuscular diseases and movement disorders, London; George Huntington Institute Muenster, University of London; University of Leuven; Hopital Salpêtrière Paris, GHI Munster, PET Centre Stockholm, Max Planck Institute for Molecular Biomedicine Münster, Germany. LUMC is member of the international TREAT-NMD consortium, and has a long lasting collaboration with the John Walton Muscular Dystrophy Research Centre at Newcastle University, UCL Institute of Child Health in London, the Neuromuscular Reference Centre at University Hospitals Leuven and the institute de Myologie in Paris on DMD research. In the last 5 years, nine international therapeutical clinical trials have been performed in DMD. Important memberships included three FP7 EU-funded projects on Duchenne muscular dystrophy and autoimmune MG, participation in the neuromuscular European Reference Network EURO-NMD, the Cure Huntington Disease Initiative (CHDI) foundation, the European Huntington Disease Network (EHDN), the International Parkinson’s Disease Genomic Consortium, the “Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)” in Tübingen, Neurogenomics Lab and Parkinson Personalized Medicine Program, Harvard Medical School and Brigham & Women’s Hospital, Cambridge (MA), USA.
Our group provided members for scientific panels or advisory boards, the chair of the Scientific Neuroimmunology Panel of the European Association of Neurology, of the Oversight Committee for the worldwide Duchenne patient registries (TGDOC) of the TREAT-NMD Alliance, and of the Huntington research committee in the World Federation of Neurology, and provided members of the Scales Development Committee and Parkinson’s Disease Subtypes Committee of the International Parkinson’s Disease and Movement Disorders Society.
Our research group has (inter)national invitations for keynote lectures and reviews, grants from national and international bodies like NWO, ZonMw, NIH, EU, national awards, and papers in high impact journals.
Content / highlights / achievements
- First-in-human, successful clinical trial with antisense oligonucleotides for Duchenne muscular dystrophy (N Engl J Med 2007;357:2677; N Engl J Med. 2011;364:1513), and with idebenone (Lancet 2015;385:1748)
- First description of morphological brain abnormalities in DMD (Ann Neurol 2014;76:403), of cerebral dystrophin isoforms throughout human development (Sci Rep. 2017 Oct 3;7(1):12575), and the first description of reduced cerebral perfusion in DMD (Neuromuscul Disord. 2017 Jan;27(1):29-37
- Serum MMP-9 as predictive biomarker for therapy in Duchenne (Sci Rep , 2017)
- Unravelling of the pathogenesis of MuSK MG, role of tumour in LEMS, and internationally recognized top referral centre for MG and LEMS (J Clin Oncol. 2008+2009+2011; Lancet Neurology 2011;10:1098; Brain 2012;135:1081; Ann Neurol. 2012;72:927; Proc Natl Acad Sci U S A. 2013;110:20783)
- Three FP7 projects, two on DMD and one on MG, with the LUMC as a major partner were obtained in 2013.
- Establishment of a clinical trial unit for national and international studies on therapy and national history in DMD, BMD and MG.
- Set-up one of the most extensively characterized cohorts of PD patients worldwide (the PROPARK-cohort), and of MuSK MG, LEMS, and the DMD/BMD patient registry with the highest coverage (>70%) worldwide.
- Leading role in the European Huntington Disease Network as the largest clinical centre for Huntington Disease in Europe.
- Leading role in the development of clinical rating scales for PD (i.e., SCOPA scales / SENS-PD), which have been used in over 200 studies and are available in up to 14 languages.
- Leading role in prognostic research in PD as Member of Taskforce Subtype PD of the Movement Disorder Society. (Lancet Neurol 2017;16:620)
- Parelsnoer (www.parelsnoer.org) for Parkinson and for DMD. LUMC initiative to start DMD as a new Parel for national coordination of biobanking and collection of standardized clinical data.
- Participation in international panel discussion around stakeholder cooperation to overcome challenges in orphan medicine development in DMD (EH Niks, Lancet Neurol. 2016;15:882)
- Clinical and genetic characterization of a new brain and muscle disorder (EH Niks, Nat Genet. 2014;46(2):188-93)
Future themesPeripheral motor disorders
- The participation in international or investigator-initiated trials is increasing. Our research is moving towards detailed natural history studies and development and validation of serological, urinal or radiological biomarkers and outcome measures, supported by a biobank of several materials, among which skin-derived fibroblasts and post-mortem material. Studies to improve care (medication and non-medication) in several of the disease in our cluster
- Continue the drug development for DMD, including mutation specific exon skipping studies in DMD, and other drugs targeting general muscle pathology in DMD, like a myostatin inhibitor, histon deacetylase inhibitor, mitochondrial electron flux facilitor, and an anti-inflammatory compound
- Continue an international natural history studies on DMD and complete a national natural history study on BMD using the Leiden DMD/BMD ProMISe patient registry
- Coordination of Parelsnoer initiative on DMD/BMD. Coordinate standardized clinical follow-up and biomarker studies in blood and urine of all DMD and BMD patients in the Netherlands as part of a Parelsnoer Institute initiative
- Extend MRI studies on muscle and brain in DMD and BMD
- Develop outcome measures in the late non-ambulant stage of DMD in collaboration with the TIM movement lab
- Use the Leiden web-based MG/LEMS national ProMISe patient registry to collect clinical data, serum markers and DNA and extend the number to 1000 patients
- Continue the pathophysiological and experimental therapeutic studies in MG models and FSHD models
- To explore the role of the immune system in MG, FSHD, and IBM
- To explore the use of iPS cells and muscle-on-a-chip techniques for muscle research , in collaboration with the other neurology research line PaCD and the dept of HG
- Development of antisense oligonucleotides for HD
- Natural history study and search for new imaging parameters in HD and PD
- Development of iPS cells for PD and HD.
- The ”Personalized Therapeutics for Parkinson’s disease” consortium, which will be headed by our group and will start in 2018, with a focus on improving personalized medicine for patients with PD
- Improvement of strategies for patient selection for deep brain stimulation in PD
- Extend genotype-phenotype translational studies on disease progression in PD, using advanced computational modelling based on gene-expression data of the Allen Brain Institute
- Further development of the Technology In Motion (TIM) lab as a centre for research and care of neurological and other motor disorders
Cohesion within LUMC
“Neurological Motor Disorders (NMD)” and “Paroxysmal Cerebral Disorders (PaCD)” together form the LUMC Priority Research Theme “Translational Neuroscience/Leiden Centre for Translational Neuroscience (LCTN)”. Both NMD and PaCD are also well embedded within the University Priority Profiles “Brain function and dysfunction over the lifespan” and “The Leiden Centre for Translational Drug Discovery & Development (LCTD3)”, and participate in the generic research profile “Biomedical Imaging” (BI). TN has its own, well-attended yearly symposium, which in 2017 attracted 80 abstracts from within the LUMC.
There are many excellent, and often longstanding, clinical and scientific collaborations with other LUMC departments, including (in alphabetical order): Anaesthesiology, Bioinformatics, Blood bank, Cardiology, Clinical Genetics, Clinical Chemistry, Endocrinology, Human Genetics, Immunohematology and Blood Transfusion, Infectious diseases, Medical Microbiology, Medical Statistics and Leiden Institute of Advanced Computer Science, Medical Psychology, Molecular Cell Biology, Neurosurgey, Parasitology (Biomolecular Mass Spectrometry Unit), Pathology, Pediatrics, Pharmacy, Public Health and primary care, Psychiatry, Radiology, Rehabilitation, and Rheumatology and Ethics & Law, which forms a section of the Neurology department.
NMD is well embedded within LUMC. There is a unique clinical expertise and very active translational research collaboration for several important neuromuscular diseases, DMD/BMD, MG, LEMS, FSHD, OPMD, IBM, within the LUMC. This group of neuromuscular diseases has been selected as national clinical referral centre (TRF) by the LUMC.
Care and research on PD and HD are firmly embedded within the LUMC. Unique clinical expertise is available and solid collaborations, in particular with the departments of radiology and human genetics and the Leiden Network for Personalized Therapeutics have been established. The LUMC also is national clinical referral centre for movement disorders, including PD and HD, and is one of the six national referral centres for selection of PD patients for deep brain stimulation.
In addition, for neuromuscular diseases and HD, they also have been selected as national expertise centres for Rare Disorders by the NFU.