Eteplirsen, a phosphorodiamidate morpholino anti-sense oligonucleotide (PMO) that modulates splicing to treat Duchenne muscular dystrophy (DMD) patients, received accelerated approval by Food and Drug Administration (FDA) on September 19, 2016 [1]. This heralded a number of firsts: it is the first drug that is approved for DMD in the United States, the first approved oligonucleotide that modulates splicing, the first approved PMO, and also the first oligonucleotide to be approved based on very limited data. Although its approval was shrouded in controversy, eteplirsen could also become the first oligonucleotide to be a commercial success. This brief commentary reviews the disease, the therapy, the clinical data, and what eteplirsen’s approval means for the oligonucleotide therapeutics field. DMD is an X-linked progressive disease by which patients lose muscle function from an early age, resulting in wheelchair dependency generally around the age of 12, the need for assisted ventilation around the age of 20, and premature death in the third–fourth decade of life. Apart from symptomatic care, there is no treatment; while their peers gain skills and become independent, DMD patients will lose one function after another until they rely on around-the-clock care before they die prematurely. Given the severe and progressive nature and the unmet medical need, the disease clearly qualifies for the FDA-accelerated approval pathway. DMD is caused by mutations in the dystrophin gene. Normally, dystrophin stabilizes muscle fibers during contraction by connecting the actin cytoskeleton within muscle fibers to the extracellular matrix surrounding muscle fibers. DMD patients have mutations that disrupt the reading frame and/or cause premature truncation of protein translation. Interestingly, mutations that maintain the reading frame allow the production of an internally deleted protein that is partially functional, owing to the fact that the crucial domains of dystrophin are located at the very beginning and end of the protein, whereas the middle is largely redundant. These internally deleted dystrophins are found in the later onset and less progressive Becker muscular dystrophy. The exon skipping approach stems from the fact that most DMD patients have in theory the genetic capacity to produce Becker-like dystrophins. Using antisense oligonucleotides (AONs) to interfere with the splicing process, the reading frame can be restored to allow the production of a partially functional Becker-type dystrophin rather than a nonfunctional DMD-type dystrophin. Depending on the mutation present in any individual patient, one or more different exons may need to be skipped to restore the reading frame. However, because mutations cluster, skipping certain exons is expected to be therapeutic in larger groups of patients, with most notably exon 51 skipping applying to 13%–14% of patients. Ultimately, exon skipping of various exons may be an effective therapy in more DMD patients. After obtaining proof of concept in patient-derived cell models and animal models, two AON chemistries were clinically developed for exon skipping in DMD. The 2′-O-methyl phosphorothioate exon 51 skipper drisapersen was developed by Prosensa/GSK/BioMarin. After a first dose-finding study, 12 DMD patients were treated on and off with 6mg/kg for more than 6 years in an open-label study. Eight of the 10 ambulant patients were stable in the distance walked in 6 min for the duration of the study, whereas 2 patients lost ambulation [2]. Drisapersen was then tested in two phase 2 and one phase 3 placebo-controlled trials in more than 300 DMD patients. The primary endpoint in these trials was the 6 …