Duchenne muscular dystrophy (DMD) is a recessive, X-linked genetic disease occurring at a frequency of about 1 in 5000 new-born males. DMD leads to premature death of patients in the 2nd-4th decade of life. The disease is caused by mutation in the DMD gene that encodes the dystrophin protein. 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 braindystrophin 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.
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, FDA approved an exon 53 skipping compound (golodirsen).
Current research focuses on optimization of the exon skipping technique in pre-clinical studies, improving delivery of exon skipping compounds and the identification of molecular biomarkers to be used as outcome measures in clinical trials. Furthermore, basic research focuses on the levels of dystrophin needed for improved muscle function, the processing of the dystrophin transcript and the mechanisms involved in muscle regeneration and dystrophic pathology. In collaboration with (inter)national colleagues we are assessing whether the exon skipping approach has therapeutic potential also for other diseases. In another international collaboration, we are studying the function of dystrophin in (developing) brain in mouse models and dystrophinopathy patients.
Example of exon skipping: Exon 51 skipping restores the reading frame for deletion of exon 48-50
The Leiden Center for RNA Theapeutics (LCRT) is coordinated by Prof. Aartsma-Rus and Dr. Willeke van Roon-Mom. The LCRT aims to develop antisense-mediated exon skipping therapies and other RNA therapies for very rare diseases.
The international rare disease research consortium (IRDIRC) is a global consortium aiming to improve access to diagnosis and treatments for rare disease patients.
Darter is an Action of the Cooperation of Science and Technology (COST) that aims to improve delivery of antisense therapies through networking (CA17103).
Brain involvement in dystrophinpathies (BIND) is a Horizon 2020 funded collaborative network that aims to elucidate how lack of dystrophin or expression of an altered dystrophin impacts the brain.