Duchenne Muscular Dystrophy (DMD)

Dystrophin is part of the dystrophin-glycoprotein complex (DGC), which bridges the inner cytoskeleton (F-actin) and the extra-cellular matrix. In this manner it provides stability to muscle fibers during contraction. Becker muscular dystrophy (BMD) is a milder, less progressive form of the disease is also caused by changes in the same DMD gene. In general, DMD patients carry mutations which yield an incomplete dystrophin protein (nonsense or frame shift mutations) that is not functional, while in BMD internally deleted proteins of reduced molecular weight (derived from in-frame deletions) are expressed, which are partially functional. The DMD gene is highly complex, containing at least seven independent, tissue-specific promoters and two polyA-addition sites. Furthermore, dystrophin transcripts are alternatively spliced, producing a range of different transcripts, encoding a large set of protein isoforms. Dystrophin is also expressed in brain, where it has as yet unknown functions. However, lack of brain dystrophin probably underlies cognitive problems that many DMD patients experience. Our research focuses on improving DMD diagnosis, studying dystrophin function in muscle and brain and developing potential therapies.

The antisense-mediated exon skipping strategy aims to restore the disrupted open reading frame of dystrophin transcripts for Duchenne patients, to allow the production of internally deleted, partially functional dystrophins as found in Becker patients. The applicability of this strategy has been confirmed in patient-derived cell cultures, mouse models and in patients in clinical trials. An application for accelerated marketing authorization approval has been filed for exon 51 skipping with the Food and Drug Administration (FDA, USA) in April 2015. In January 2016 FDA announced that the exon 51 skipping compound (drisapersen) is not ready for approval in its current form. Later that year the FDA approved another exon 51 skipping compound (eteplirsen), which is based on drisapersen but contains another chemical modification. In 2019 and 2020, FDA approved exon 53 skipping compounds golodirsen and viltolarsen, respectively.

Prof.dr. Annemieke M. Aartsma-Rus
Principal Investigator / Professor Translational Genetics

Pietro Spitali
Assistant professor

Maaike van Putten
Assistant professor

Marlen C. Lauffer
Senior Researcher

Remko Goossens
Researcher

Tiberiu L. Stan
Researcher / Coordinator Validation lab

Pauline de Graaf
Project manager

Sarah Engelbeen
PhD student

Ivo F.A.C. Fokkema
PhD student / ICT developer