Duchenne muscular dystrophy is a fatal neuromuscular disorder affecting around one in 3,500–5,000 male births that is characterized by progressive muscular deterioration. It is inherited in an X-linked recessive fashion and is caused by loss-of-function mutations in the DMD gene coding for dystrophin, a cytoskeletal protein that stabilizes the plasma membrane of muscle fibers. In September 2016, the US Food and Drug Administration granted accelerated approval for eteplirsen (or Exondys 51), a drug that acts to promote dystrophin production by restoring the translational reading frame of DMD through specific skipping of exon 51 in defective gene variants. Eteplirsen is applicable for approximately 14% of patients with DMD mutations. This article extensively reviews and discusses the available information on eteplirsen to date, focusing on pharmacological, efficacy, safety, and tolerability data from preclinical and clinical trials. Issues faced by eteplirsen, particularly those relating to its efficacy, will be identified. Finally, the place of eteplirsen and exon skipping as a general therapeutic strategy in Duchenne muscular dystrophy treatment will be discussed.

Duchenne muscular dystrophy (DMD), the commonest form of muscular dystrophy, is caused by lack of dystrophin. One of the most promising therapeutic approaches is antisense-mediated elimination of frame-disrupting mutations by exon skipping. However, this approach faces two major hurdles: limited applicability of each individual target exon and uncertain function and stability of each resulting truncated dystrophin. Skipping of exons 45-55 at the mutation hotspot of the DMD gene would address both issues. Theoretically it could rescue more than 60% of patients with deletion mutations. Moreover, spontaneous deletions of this specific region are associated with asymptomatic or exceptionally mild phenotypes. However, such multiple exon skipping of exons 45-55 has proved technically challenging. We have therefore designed antisense oligo (AO) morpholino mixtures to minimize self-or heteroduplex formation. These were tested as conjugates with cell-penetrating moieties (vivo-morpholinos). We have tested the feasibility of skipping exons 45-55 in H2K-mdx52 myotubes and in mdx52 mice, which lack exon 52. Encouragingly, with mixtures of 10 AOs, we demonstrated skipping of all 10 exons in vitro, in H2K-mdx52 myotubes and on intramuscular injection into mdx52 mice. Moreover, in mdx52 mice in vivo, systemic injections of 10 AOs induced extensive dystrophin expression at the subsarcolemma in skeletal muscles throughout the body, producing up to 15% of wild-type dystrophin protein levels, accompanied by improved muscle strength and histopathology without any detectable toxicity. This is a unique successful demonstration of effective rescue by exon 45-55 skipping in a dystrophin-deficient animal model. personalized medicine | nucleic acid therapy | molecular therapy | oligonucleotides | gene therapy D uchenne muscular dystrophy (DMD), the commonest form of muscular dystrophy, is characterized by progressive deterioration of muscle function (1). DMD is caused mainly by frame-shifting deletion or nonsense mutations in the DMD gene, which encodes the protein dystrophin (2). At the milder end of the disease spectrum, Becker muscular dystrophy (BMD) is a form of dystrophin deficiency that presents with a large spectrum of severities, from borderline DMD to almost asymptomatic cases. BMD typically results from in-frame deletions in the DMD gene that allow the expression of limited amounts of an internally truncated but partly functional protein (3).Skipping of exons in DMD muscle so as to restore an in-frame and asymptomatic or very mild Becker-like transcript is among the more promising therapeutic approaches to treatment of DMD (4). To this end, systemic administration of antisense oligonucleotides (AOs) targeting specific exon(s) in the DMD gene has been shown to restore the reading frame and induce body-wide production of partially functional BMD-like dystrophin in mouse and dog models of DMD (5-7). Recently, phase I/II human clinical trials with AOs targeting exon 51 have been completed (8, 9).Although promising, future developm...