LUMC is the leader for work package 8.2 (Optimization of systemic delivery and improvement of quality and safety standards for treatment of patients with muscular dystrophies and spinal muscular atrophy). Main objectives of WP8.2 involve genotoxicity and in vivo toxicology studies, optimization of delivery methods, dose and treatment regimens and determination of the delivery efficiency required for therapeutic effect in animal models (improvement of muscle function and endurance).

The work performed by LUMC for this work package, mainly focuses on the development of a systemic delivery method for antisense oligonucleotides (AONs) as tools to induce exon skipping in Duchenne patients. This approach was pioneered by Judith van Deutekom at the Department of Human Genetics (Leiden University Medical Center, the Netherlands), Steve Wilton (University of Western Australia, Australia) and Masafumi Matsuo (Kobe University Graduate School of Medicine, Japan). The strategy aims to restore the disrupted dystrophin open reading frame in Duchenne patients to allow generation of partly functional, Becker-like proteins by hiding an exon from the splicing machinery with an AON (for more information see www.dmd.nl/gt). Proof of concept has been obtained in patient-derived cultured muscle cells and the mdx mouse model. In collaboration with Prosensa Holding we recently obtained clinical proof of concept through an exploratory study in which four DMD patients received a local dose of a 2’O-methyl phosphorothioate (2OMePS) AON targeting exon 51. In close collaboration with Prosensa B.V, current research focuses on safe and efficient systemic delivery.

Websites

http://www.lumc.nl
http://www.dmd.nl/gt 
 

Dr. Annemieke Aartsma-Rus is a senior postdoc at the Department of Human Genetics and leader of the DMD genetic therapy group. She is the scientific representative of the LUMC in the TREAT-NMD governing board. During her PhD research she was involved in the development of therapeutic antisense-mediated exon skipping for DMD. She successfully defended her thesis titled “Development of an antisense-mediated exon skipping therapy for Duchenne muscular Dystrophy – Making sense out of nonsense” in February 2005 and now continues to work on the further optimization of the exon skipping therapy.
 

Christa de Winter ( BASc) has been working as a research technician on antisense-mediated exon skipping since November 2003. Her work mainly involves comparing different systemic delivery methods and AON dosing regimes in dystrophic mouse models.

Hans Heemskerk (MSc) started working as a PhD student in May 2005. His project focuses on the development of safe and efficient antisense formulations for systemic treatment of muscle tissue in DMD patients.

Maaike van Putten (MSc) started as a PhD student in September 2007. Her project will focus on the assessment of the levels of exon skipping and dystrophin that are required for functional improvement in dystrophic mouse models.

Prof. Dr. Gert-Jan van Ommen is head of the Department of Human Genetics at the LUMC. Amongst others, he has supervised research on neuromuscular and neurodegenerative diseases (with a focus on Duchenne Muscular Dystrophy and Huntington Disease). In addition he was involved in the development and application of genome research and diagnostic technology for disease study, diagnosis, therapy and prevention, including the societal aspects of genetic advances. The antisense-mediated exon skipping therapy approach for DMD was pioneered in the department under his supervision, and brought into a first clinical trial in the LUMC on his initiative and guidance.

Dr. Peter-Bram’t Hoen works as a senior postdoc at the Department of Human Genetics. He has set up high-throughput RNA and protein profiling studies for muscle diseases, established a muscle gene expression databases containing data from all studies published and supervises research on the identification of biomarkers that correlate with disease severity in several mouse models for muscular dystrophies. These biomarker profiles can be used to assess therapeutic effects after (AON) treatment.

The Laboratory for Diagnostic Genome Analysis (LDGA) (Clinical Genetics; www.lumc.nl/klingen/dna) in Leiden performs mutation analysis for many disorders nationally and internationally. Dr. Ieke Ginjaar is a staff member at the Department of Clinical genetics. She is responsible for DNA/RNA and protein diagnostics of DMD/BMD and LGMD in the Netherlands. She set up dystrophin analysis in muscle tissue and still performs immunological analysis for D/BMD/LGMD patients. Her mutation database, which includes all mutations found in Dutch B/DMD patients will be instrumental in setting up a Dutch DMD patient registry that includes clinical data as well.

Dr. Johan Den Dunnen is a staff member at the Departments of Human and Clinical Genetics. He has a long standing interest in research and diagnosis of DMD and is the original autor intellectualis of the exon skipping approach. He initiated the Leiden Muscular Dystrophy pages (www.DMD.nl), curates the DMD mutation database, storing all DMD mutations published and submitted worldwide, and he has established and maintains the LOVD system, which will be employed to set up the Dutch DMD patient registry. Finally, he has supervised the generation of the hDMD mouse model, containing a full copy of the human DMD gene in the mouse genome. This human dystrophin functionally compensates the lack of mouse dystrophin in the mdx mouse, so hDMD/mdx mice are healthy. This mouse models allows testing human specific AONs in vivo.

Laura van Vliet (BASc) started as a research technician in June 2007 and is involved in the generation of hDMD deletion mouse models. The deletion models would allow testing the therapeutic effect of human AONs in a mouse model

Dr Jan Verschuuren is a neurologist at the Department of Neurology of the LUMC, where he heads the neuromuscular section. He was the PI on the recent trial on intramuscular treatment of Duchenne patients with antisense oligonucleotide in Leiden. He was one of the initiators of the Dutch ALADIN (All against Duchenne in the Netherlands) consortium, which aims to standardize Duchenne patient care in the Netherlands. He is involved in setting up a patient registry for Dutch DMD patients.

Dr Chiara Straathof and Dr. Truus Overweg-Plandsoen are neurologist/neuromyologist and child neurologist, respectively, at the Department of Neurology of the LUMC. Under the umbrella of the ALADIN consortium they aim to standardize patient care in the Netherlands. They are responsible for the organization of the limb girdle outpatient clinic with emphasis on Duchenne and SMA. During their (half) day visits patients are seen by a multidisciplinary team consisting of a neurologist, pediatrician, pediatric cardiologist, orthopedic surgeon, rehabilitation physician, and neuromuscular nurse.

Dr Janneke van den Bergen started working at the Department of Neurology in October 2007 as an AGIKO (Dutch term for physician who combines a PhD study with a neurological training). She will be involved in the clinical assessment of Dutch DMD patients and implementing this information in the Dutch DMD patient registry.

Prof. Dr Bert Bakker, professor of Molecular genetics at the LUMC, leads the Laboratory for Diagnostic Genome Analysis (LDGA) at the department of Clinical Genetics; www.lumc.nl/klingen/dna). Since 1985 when he performed the first prenatal diagnosis for DMD worldwide, genetic tests for neuromuscular dystrophies have been among his major interests. The LDGA is an international reference centre for the molecular diagnosis of DMD/BMD, FSHD, LGMDs.

Prof. Dr. Silvère van der Maarel is Professor of Medical Epigenetics at the Department of Human Genetics of the Leiden University Medical Center. His research focus is on the (epigenetic) disease mechanisms underlying facioscapulohumeral muscular dystrophy (FSHD). Other research themes include oculopharyngeal muscular dystrophy (OPMD) and the limb girdle muscular dystrophies (LGMD). By means of intracellularly expressed antibody domains he aims to uncover disease mechanisms in muscular dystrophy.

Dr. Judith van Deutekom pioneered the antisense-mediated exon skipping strategy at the Department of Human Genetics starting in 1998. As Head of Research of Prosensa Holding she is now further exploring the field of RNA modification technology for application to DMD and other hereditary neuromuscular diseases.