Exon skipping for nonsense mutations in Duchenne muscular dystrophy: too many mutations, too few patients?
BACKGROUND
Duchenne muscular dystrophy (DMD), one of the most common and lethal genetic disorders, is caused by mutations of the dystrophin gene. Removal of an exon or of multiple exons using antisense molecules has been demonstrated to allow synthesis of truncated 'Becker muscular dystrophy-like' dystrophin.


METHODS
Approximately 15% of DMD cases are caused by a nonsense mutation. Although patient databases have previously been surveyed for applicability to each deletion mutation pattern, this is not so for nonsense mutations. Here, we examine the world-wide database containing notations for more than 1200 patients with nonsense mutations. Approximately 47% of nonsense mutations can be potentially treated with single exon skipping, rising to 90% with double exon skipping, but to reach this proportion requires the development of exon skipping molecules targeting some 68 of dystrophin's 79 exons, with patient numbers spread thinly across those exons. In this review, we discuss progress and remaining hurdles in exon skipping and an alternative strategy, stop-codon readthrough.


CONCLUSIONS
Antisense-mediated exon skipping therapy is targeted highly at the individual patient and is a clear example of personalized medicine. An efficient regulatory path for drug approval will be a key to success.
University of Alberta, Department of Medical Genetics, School of Human Development, Faculty of Medicine and Dentistry, 829 Medical Sciences Building, Edmonton, AB T6G 2H7, Canada. toshifum@ualberta.ca
Toshifumi
T
Yokota
William
W
Duddy
Yusuke
Y
Echigoya
Hanna
H
Kolski
D000818:Animals; D018389:Codon, Nonsense; D016189:Dystrophin / Q000235:genetics*; D005091:Exons; D020022:Genetic Predisposition to Disease; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D020388:Muscular Dystrophy, Duchenne / Q000453:epidemiology / Q000235:genetics / Q000628:therapy*; D020320:Oligoribonucleotides, Antisense / Q000627:therapeutic use*; D010641:Phenotype; D057285:Precision Medicine; D057170:Translational Research, Biomedical
D018389:Codon, Nonsense; D016189:Dystrophin; D020320:Oligoribonucleotides, Antisense