Duchenne muscular dystrophy: from gene diagnosis to molecular therapy

摘要

Duchenne muscular dystrophy (DMD) is the most common inherited muscular disease with a worldwide incidence of 1 in 3500 male births. DMD is a lethal disorder of childhood caused by deficiency of muscle dystrophin. Interestingly, a milder form of the disease called Becker muscular dystrophy (BMD) is distinguished form DMD by delayed onset, later dependence on wheelchair support and longer life span. Both DMD and BMD are caused by mutations in the dystrophin gene and their clinical difference can be explained by the reading frame rule. Many attempts have been made to express dystrophin in DMD patients, but an effective treatment has not yet been established. Identification of dystrophin Kobe promoted the understanding of the regulatory mechanism of dystrophin pre-mRNA splicing. As a result, the molecular therapy whereby the correction of the translational reading frame of dystrophin mRNA is provided by inducing exon skipping with antisense oligonucleotides has been proposed to transform severe DMD into the milder form. Consequently, a 31-mer phosphorothioate oligonucleotides against the splicing enhancer sequence of exon 19 of the dystrophin gene (antisense oligonucleotides : AO) was shown to be able to induce exon 19 skipping. Furthermore, the transfection of AO into cultured myocytes from a DMD case with an out-of-frame deletion of exon 20 promoted expression of dystrophin successfully. Subsequently, we have treated DMD patients with intravenous infusion of the AO. In addition current protocols of molecular therapy for DMD are discussed.