Over the last 10 to 15 years much effort has been put into the development of a safe and efficient gene therapy for DMD. However, the DMD gene and its product initially seemed too large and too complex to allow a straightforward approach. Over the last few years an innovative tool has emerged with which an escape route can be utilized that nature had already hinted at. Some DMD patients have rare, dystrophin-positive fibres (“revertant fibers”), originating from reading frame-restoring exon skipping. Several laboratories have recently shown that we can actually enhance or induce this therapeutic exon skipping using small synthetic antisense oligoribonucleotides, the so called AONs. Through inducing the skipping of exons during the splicing, AONs can restore the reading-frame of the dystrophin transcript (mRNA), and thus convert DMD into BMD-like fibers.
Due to the mutation-specific nature of the exon skipping approach, only subsets of patients are eligible for the skipping of a certain exon, leading to clinical trials generally being conducted in small cohorts of patients. This harbours the risk of significant treatment-induced changes being masked by inter patient variability. The lack of objective functional outcome measures increases this risk even further. At the moment the most commonly used functional measure used as a primary endpoint in clinical trials for DMD is the 6 minute walk test (6MWD), where the outcome may be influenced by patient’s motivation especially in non-placebo controlled trials. The identification of functional and molecular biomarkers makes it able to monitor disease progression and treatment response is a priority for the field, also to avoid invasive muscle biopsies that are often required upon trial participation and which constitute a burden for patients and their families.