Functional Genomics of Muscle, Nerve and Brain Disorders

The research within our LUMC departments is conducted within departmental research programmes. The research programme below is embedded within the department of Human Genetics.

Aim and focus

The common focus of this program is to elucidate genetic, genomic and epigenetic modifiers in neuromuscular, neurogenetic, myodegenerative and neurodegenerative disorders. Depending on the knowledge about the genetic factors involved, the strategy varies from gene identification in patient material to immunological, genetic, molecular, electrophysiological, and biochemical approaches to understand the underlying pathology and to identify targets for therapeutic interventions. Our mission is to elucidate molecular changes in the disease with the perspectives to develop new, reliable and feasible techniques for accurate clinical diagnostics; to refine prognostic precision; to study normal and abnormal gene products by reverse genetics and functional genomics; and to generate and use cellular and animal model systems to understand disease pathology, for therapy development and biomarker discovery, and ultimately to improve prevention.

Position in international context

Long-standing top positions have been achieved in the fields of DMD, FSHD, MG and migraine. Our work yields papers in high-impact journals, patents on therapeutic approaches, invitations for keynote lectures and reviews, awards at international and national conferences, international grants from e.g. the EU, NIH, MDA, AFM and major national funding from NWO, ZonMw and disease-specific funding mechanisms (DPP, PBS, SVS, Dutch Brain Foundation). Our mouse model research has amongst others yielded mouse models for migraine and associated disorders, mouse models for FSHD, OPMD and DMD. All of these models are in great demand for human therapy development. This research line has contributed significantly to the high profile of LUMC in public private partnerships.      

Content / highlights / achievements

  • Successful, worldwide first human DMD exon-skip clinical trial with basic, clinical and industrial consortium, with Biomarin Leiden, showing first clinical benefit (two NEJM papers). Biomarin has sublicensed this approach to Sarepta Therapeutics, which has an approved drug in the USA.
  • Discovery of a uniform (epi)genetic mechanism in FSHD (Science and NY Times front page, Nat Genet, Am J Hum Genet).
  • Functional insights in migraine from unique migraine mouse models.
  • Identifications of tens of common variants for migraine (multiple Nat Genet papers).
  • Demonstration that OPMD is a paradigm for muscle ageing, development of biomarkers for OPMD, functional insights in OPMD pathogenesis from a novel OPMD mouse model, and new therapeutic options for OPMD & sarcopenia (including patent). 
  • In vivo demonstration that MuSK-MG is an autoimmune disease caused by IgG4 autoantibodies.
  • The IgG4 autoimmune paradigm: demonstration that MuSK IgG4 autoimmune antibodies functionally interfere with neuromuscular junction signalling in the absence of complement activation.
  • Disease gene and modifier gene discoveries by next sequencing technology, e.g. focal epilepsy, HCHWA-D and FSHD2.
  • Establishment of a neuronal differentiation induced pluripotent stem cell lab for the study of neurological disease mechanisms and therapy development.
  • Biosemantics technologies applied to further the understanding of disease mechanisms in HD, as part of a multidisciplinary e-Science approach developed between the CAG-repeat research group and the biosemantics group.
  • Patented inventions of therapeutic methodology in DMD, CADASIL, HD, SCA, HCHWA-D, FSHD, and OPMD, that led to collaborations on (preclinical) therapy development with industrial partners as Biomarin, ProQR, Amylon, IBL International, ArgenX, Facio Therapies and Ionis Pharmaceuticals.
  • Generation of a humanised DMD mouse model allowing pre-clinical optimization of human exon skipping drugs.
  • Key involvement in academic, regulatory and patient organisation stakeholder collaborations for therapy development for rare neuromuscular disorders (two Lancet Neurology papers)
  • Participation in European Reference Networks for rare diseases, including Neuromuscular Diseases (EURO-NMD) & GO-FAIR Rare diseases.

Future themes

  • Maintain the general multidisciplinary approach, while avoiding further diversification. Increase the deployment of sequencing and other high-throughput technologies to obtain more complete pictures of disease processes and their potential remedies, both in rare and common disease. The field of human genetics has progressed increasingly from finding genes and primary mutational causes towards elucidating mechanisms, improving genotype/phenotype correlations, achieving more reliable prognosis, and designing the first mechanistic therapies, in close concert with other HG research lines.
  • Pursue translational opportunities with high priority, expanding RNA therapies into new disease areas, both in areas of own expertise and in collaboration with other groups with proper disease expertise for other fields as well as patient organisations and regulatory agencies. To design therapeutic and eventually preventive interventions remains the ultimate aim. Expand collaborations with Leiden University (beta-faculties) and pharmaceutical industries.  
  • Continue strengthening national and international interactions in the biobanking area (in close collaboration with clinical departments at LUMC, for DMD and FSHD this work is facilitated by funding from ‘Spieren voor Spieren’ to set up the Duchenne and FSHD Centers of Expertise in the Netherlands, part of which involves generating a comprehensive biobank for patients. This change in emphasis is in step with the political and societal climate, requiring scientists to move beyond rare monogenic disorders, toward more frequent multifactorial ones.
  • Continue to implement and develop novel technological opportunities ensuring that our research lines will be highly competitive in the near and more distant future. To this end we continue to invest in our genomics facility (www.LGTC.nl), muscle physiology test systems, state-of-the-art integration of electrophysiology on various platforms (both in slices and in intact (awake) animals) with optogenetics to measure and modulate neuronal activity, advanced in vivo imaging technologies, and neuro- and myo-iPS cell and organ facilities, which will also contribute to reduce the number of animals used for biomedical science experiments.
  • Nonetheless, we see our broad monogenic disease expertise as invaluable, as this offers well-defined 'human disease models’, besides animal ones, for the focused development of mechanistic interventions. It is our conviction that this stepwise, targeted approach will ultimately also greatly benefit mechanistic intervention in complex multifactorial diseases.
  • Develop a systems-level approach that combines -omics and semantic analysis for neurodegenerative disorders via automated workflows and semantic databases. We therefore define a shared strategy between the neuromuscular and CAG-research group and the biosemantics group for integrating state-of-the-art computational knowledge discovery methods into routine biological research practice. The shared strategy provides a basis for participation in grant proposals.

Cohesion within LUMC

This research line is well-embedded in the LUMC’s medical research profile Translational Neuroscience (Van der Maarel is co-chair of Translational Neuroscience). Studies of neuromuscular, neurodegenerative and neurogenetic (episodic) diseases, such as DMD, FSHD, MG, OPMD, HD, HCHWA-D, migraine and CADASIL, are performed in collaboration with e.g. the departments of Neurology, Radiology, Clinical Genetics, Orthopedics, Neurophysiology, Psychiatry, and Anatomy. All our human disease studies and animal models will derive great utility from high-resolution molecular interaction detection in collaboration with Center for Molecular Imaging and Center for Biomolecular Mass Spectrometry, the Leiden Institute for Chemistry, and the Leiden Academic Centre for Drug Research. The research line is participating heavily in bachelor and master education of biomedical sciences and medicine. The research line is also involved in the Leiden Network for Personalised Therapeutics (LNPT); Aartsma-Rus is on the board of directors of this network.