Leiden University Medical Center

At the Leiden University Medical Centre (LUMC), we are continually seeking to improve the quality of healthcare. The LUMC aims for excellence in patient care, research, teaching, training and continuing education and has a long history in the field of neuromuscular disorders.

The research in the Center for Human and Clinical Genetics (http://www.humgen.nl) is aimed at the elucidation of molecular mechanisms of genetic diseases with a strong focus on DMD, BMD, LGMD and FSHD. The DNA diagnosis for these diseases in the Netherlands is performed at the Leiden Diagnostic Genome Analysis laboratory (http://www.lgtc.nl), which is part of the Center for Human and Clinical Genetics. The Department of Neurology has multidisciplinary polyclinics for neuromuscular disorder patients and is setting up the Dutch B/DMD patient registry (which feeds into the global TREAT-NMD database, see www.lumc.nl/duchenne for more information).

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 Therapeutics (Leiden, the Netherlands) a first clinical trial was performed at the Department of Neurology in 2006, which! showed local dystrophin restoration. Current trials performed by Prosensa and GSK focus on systemic administration and assessment of safety and efficacy in patients.