Gertjan van Ommen

Session nine: What is the future for translational research in rare diseases?

Fundamental, translational and clinical research for NMDs

Gertjan van Ommen, Willem Hoogaars, Maaike van Putten, Dwi Kemaladewi, Peter 't Hoen, Johan den Dunnen, Annemieke Aartsma-Rus - Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

It has been known for decades that Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene that disrupt dystrophin function, a protein that is essential to maintain muscle fiber stability during contraction. The most promising therapeutic approach is antisense-mediated exon skipping, aiming at reframing the disrupted transcript to allow production of an internally deleted dystrophin protein with partial functionality. This approach is currently tested in phase 3 clinical trials by Prosensa/GSK for the skipping of exon 51 (applicable to 13% of patients). For the ultimate, broadly applicable therapy still many unknowns and hurdles require extensive study and, hence, close collaboration between fundamental, translational and clinical researchers and patients. An example is the issue on how much dystrophin is needed for functional improvement or to prevent muscle damage. We generated a mouse model to study the effect of small amounts of dystrophin on normalizing muscle function and survival. Furthermore, therapeutic monitoring of patients in clinical trials would be greatly facilitated by serum biomarkers that correlate with disease severity and dystrophin levels. In a collaborative effort in the BIO-NMD consortium we have identified several candidate markers. Finally, we are developing supporting exon skipping to improve myogenesis and reduce fibrosis, as dystrophin exon skipping is reliant on existing muscle tissue. We aim is to induce partial knockdown and TFG-beta receptors ALK4 and ALK5, simultaneously increasing muscle growth and reducing fibrosis. The examples underline how a close collaboration between fundamental, translational and clinical researchers remains necessary to accelerate preclinical research towards the translational stage.

Gertjan van Ommen

22 Feb 2012