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Assessment of the feasibility of exon 45–55 multiexon skipping for duchenne muscular dystrophy

DOI: 10.1186/1471-2350-9-105

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We here tested the feasibility of inducing multiexon 45–55 in control and patient muscle cell cultures using various AON cocktails.In all experiments, the exon 45–55 skip frequencies were minimal and comparable to those observed in untreated cells.We conclude that current state of the art does not sufficiently support clinical development of multiexon skipping for DMD.Antisense-mediated exon skipping is emerging as a very promising therapeutic approach for Duchenne muscular dystrophy (DMD) [1]. The aim of this approach is to restore the disrupted reading frame of DMD transcripts, and allow synthesis of partly functional, internally deleted Becker-like dystrophins, rather than prematurely truncated non-functional Duchenne dystrophins. This can be achieved by antisense oligonucleotides (AONs) that target specific exons and hide them from the splicing machinery during pre-mRNA splicing, resulting in the skipping of said exons [2]. Proof of concept of this strategy has been obtained in numerous patient-derived cell cultures with different types of mutations, the mdx mouse model and recently in a first clinical trial where AONs were injected locally in the tibialis anterior muscle of 4 Duchenne patients [1,3-9]. One of the disadvantages of this therapy is its mutation specificity: different exons have to be skipped to restore the reading frame for different mutations [10]. Fortunately, most mutations involve deletions of one or more exons between exon 45 and 53 or between exon 2–20 (50% and 15% of all mutations, respectively) [11]. Therefore, restoration of the reading frame for over 50% of all patients (75% of deletion patients) is theoretically feasible using a strategically selected set of only 10 exons [12]. Skipping of exon 51 is beneficial for the largest group of patients (19% of all deletions, or 13% of all Duchenne patients, (Aartsma-Rus et al. accepted manuscript).Nevertheless, it would be more straightforward if a single formulation of AONs would be applicable


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