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Efficient skipping of single exon duplications in DMD Patient-Derived cell lines using an antisense oligonucleotide approach
Journal article   Peer reviewed

Efficient skipping of single exon duplications in DMD Patient-Derived cell lines using an antisense oligonucleotide approach

N. Wein, A. Vulin, A.R. Findlay, F. Gumienny, N. Huang, S.D. Wilton and K.M. Flanigan
Journal of Neuromuscular Diseases, Vol.4(3), pp.199-207
2017
DOI: https://doi.org/10.3233/JND-170233
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Abstract

Background:Exon skipping strategies in Duchenne muscular dystrophy (DMD) have largely been directed toward altering splicing of exons flanking out-of-frame deletions, with the goal of restoring an open mRNA reading frame that leads to production of an internally deleted but partially functional dystrophin protein. Objective:We sought to apply exon skipping to duplication mutations, assuming that the inherently limited efficiency of antisense oligonucleotide-induced exon skipping would more frequently skip a single copy of a duplicated exon, rather than both and result in significant amounts of wild-type DMD mRNA. Methods:We tested this hypothesis in fibroblast cell lines derived from patients with a variety of single or multiple exon duplications that have been modified to allow transdifferentiation into a myogenic lineage. Results:Using a variety of 2’O-methyl antisense oligonucleotides, significant skipping was induced for each duplication leading to a wild-type transcript as a major mRNA product. Conclusions:This study provides another proof of concept for the feasibility of therapeutic skipping in patients carrying exon duplications in order to express wild-type, full-length mRNA, although careful evaluation of the skipping efficiency should be performed as some exons are easier to skip than others. Such a personalized strategy is expected to be highly beneficial for this subset of DMD patients, compared to inducing expression of an internally-deleted dystrophin.

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