Abstract
Duchenne Muscular Dystrophy (DMD) is a lethal progressive muscle-wasting disease. New treatment strategies relying on DMD gene exon-skipping therapy have recently been approved and about 30% of patients could be amenable to exon 51, 53 or 45 skipping. We evaluated the spectrum of deletions reported in DMD registries, and designed a method to screen newborns and identify DMD deletions amenable to exon 51, 53 and 45 skipping. We developed a multiplex qPCR assay identifying hemi(homo)-zygotic deletions of the flanking exons of these therapeutic targets in DMD exons (i.e. exons 44, 46, 50, 52 and 54). We conducted an evaluation of our new method in 51 male patients with a DMD phenotype, 50 female carriers of a DMD deletion and 19 controls. Studies were performed on dried blood spots with patient’s consent. We analyzed qPCR amplification curves of controls, carriers, and DMD patients to discern the presence or the absence of the target exons. Analysis of the exons flanking the exon-skipping targets permitted the identification of patients that could benefit from exon-skipping. All samples were correctly genotyped, with either presence or absence of amplification of the target exon. This proof-of-concept study demonstrates that this new assay is a highly sensitive method to identify DMD patients carrying deletions that are rescuable by exon-skipping treatment. The method is easily scalable to population-based screening. This targeted screening approach could address the new management paradigm in DMD, and could help to optimize the beneficial therapeutic effect of DMD therapies by permitting pre-symptomatic care.
Highlights
Duchenne Muscular Dystrophy (DMD) is a lethal progressive muscle-wasting disease
To determine the efficiency of our approach, we assessed the percentage of DMD patients reported in the LOVD-DMD registry that would be identified by our assay and would be rescuable by either exon-51, exon-53 or exon-45 skipping therapy (Fig. 1B)
This analysis shows that assaying the flanking exons is an effective approach to identify many patients that could benefit from these therapies (Table 1)
Summary
Duchenne Muscular Dystrophy (DMD) is a lethal progressive muscle-wasting disease. New treatment strategies relying on DMD gene exon-skipping therapy have recently been approved and about 30% of patients could be amenable to exon [51, 53] or 45 skipping. All samples were correctly genotyped, with either presence or absence of amplification of the target exon This proof-of-concept study demonstrates that this new assay is a highly sensitive method to identify DMD patients carrying deletions that are rescuable by exon-skipping treatment. The method is scalable to population-based screening This targeted screening approach could address the new management paradigm in DMD, and could help to optimize the beneficial therapeutic effect of DMD therapies by permitting pre-symptomatic care. Novel therapeutic approaches to DMD involving exon skipping have been developed These RNA-level therapies aim to skip the flanking exon of an out-of-frame mutation to transform it to an in-frame mutation, in order to induce the synthesis of a truncated and partially functional dystrophin protein[4,5]. Several other similar approaches, such as, suvodirsen, viltolarsen, casimersen, or rAAV-U7snRNA-E538, targeting exons [51, 53] or 45, are or have been under evaluation to expand the spectrum of treatable DMD patients
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