Theoretic applicability of antisense-mediated exon skipping for Duchenne muscular dystrophy mutations.
Antisense-mediated exon skipping aiming for reading frame restoration is currently a promising therapeutic application for Duchenne muscular dystrophy (DMD). This approach is mutation specific, but as the majority of DMD patients have deletions that cluster in hotspot regions, the skipping of a small number of exons is applicable to relatively large numbers of patients. To assess the actual applicability of the exon skipping approach, we here determined for deletions, duplications and point mutations reported in the Leiden DMD mutation database, which exon(s) should be skipped to restore the open reading frame. In theory, single and double exon skipping would be applicable to 79% of deletions, 91% of small mutations, and 73% of duplications, amounting to 83% of all DMD mutations. Exon 51 skipping, which is being tested in clinical trials, would be applicable to the largest group (13%) of all DMD patients. Further research is needed to determine the functionality of different in-frame dystrophins and a number of hurdles has to be overcome before this approach can be applied clinically.
Aartsma-Rus
Annemieke
A
Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. a.m.nus@lumc.nl
Fokkema
Ivo
I
Verschuuren
Jan
J
Ginjaar
Ieke
I
van Deutekom
Judith
J
van Ommen
Gert-Jan
GJ
den Dunnen
Johan T
JT
D017398:Alternative Splicing; D016189:Dystrophin / Q000235:genetics*; D005091:Exons / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000628:therapy; D009154:Mutation; D016376:Oligonucleotides, Antisense / Q000235:genetics*; D016366:Open Reading Frames / Q000235:genetics
D016189:Dystrophin; D016376:Oligonucleotides, Antisense