Moving towards successful exon-skipping therapy for Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X chromosome-linked lethal muscular disorder with progressing muscle wasting and weakness caused by mutations in the gene encoding a subsarcolemmal protein dystrophin. For a long time, there was no effective cure; however, advances in molecular biology have allowed the development of radical treatment approaches. Among them, exon-skipping therapy using antisense oligonucleotides is very promising, because it corrects the reading frame of the dystrophin-encoding gene and restores protein expression, resulting in the conversion of DMD to a clinically milder form, Becker muscular dystrophy (BMD). However, clinical trials in exon-skipping therapy did not provide satisfactory results, which may be attributed to inefficient exon skipping, low expression level of restored dystrophin and inadequate methods of muscle function evaluation. To date, exon-skipping approaches have particularly focused on the correction of the gene-reading frame. However, the problem is that the relationship between the resultant and expected phenotypes in terms of definite symptomatic improvement has not yet been elucidated. In other words, previously conducted clinical trials have not been planned based on the comprehensive assessment of genotype-phenotype relationship in BMD, which demonstrates a broad range of symptom severity depending on the functional activity of the truncated dystrophin. The analysis I present in this review strongly suggests that the development of exon-skipping therapy and its clinical trials should be based on large-cohort studies of BMD.