Approximately 70% of mutations responsible for DMD lead to a disrupted reading frame, resulting in a truncated nonfunctional dystrophin protein [3, 10]. The observation that there is a milder allelic variant caused by in-frame mutations, namely Becker's muscular dystrophy (BMD), which allows the translation of a smaller but partially functional dystrophin , provided a strong rationale for the application of the exon skipping strategy to DMD (with the aim of converting DMD into its milder BMD form). Although many different antisense oligonucleotide (AON) chemistries exist, such as locked nucleic acid and peptide nucleic acids, and others have been optimized recently, so far, two classes are under clinical experimentation: 2′O-methylphosphorothioate oligoribonucleotides (2′OMe) and phosphorodiamidate morpholino oligomers (PMOs). Both chemistries target specific exons, hiding them from the splicing machinery and causing their skipping during the splicing process. AONs have been indeed extensively and successfully tested in vitro  and, most importantly, in vivo [13-20]. Consequently, AON-based skipping of exon 51 underwent clinical experimentation and other trials are currently being developed, including skipping of exons other than exon 51 . The first two clinical trials tested the intramuscular administration of 2′OMe (PRO051/GSK 2402968) and PMO (AVI-4658/Eteplirsen), respectively [22, 23]. Furthermore, systemic phase I/II studies have been completed [24, 25] demonstrating that exon skipping for DMD is so far safe, with dystrophin levels of up to 19% of normal controls detected in the PMO study. Although the outcome of randomized placebo-controlled studies for both AONs is expected in the near future, the use of either 2′OMe and PMO is still limited by the fact that they cannot be utilized for a significant number of DMD patients, in particular those with large deletions or with mutations in regulatory or N-/C-terminal regions of dystrophin . Moreover, another hurdle to overcome is the relatively rapid clearance from the circulation, which means that repeated administrations (and probably a lifelong treatment) will be crucial to enable long-term therapeutic efficacy. To solve this problem, different groups have explored the possibility of the in situ production of AONs. Accordingly, chimeric small nuclear RNAs (snRNAs) have been designed to shuttle AONs that omit exon 51. Among these snRNAs, viral vector-mediated U7 and U1snRNA expression showed a long-lasting restoration of dystrophin in vitro [26, 27] and in vivo [28-31]. Moreover, recent work has focused on the optimization of U1snRNA constructs and on testing the feasibility of multiple exon skipping [32, 33]. This strategy requires a vector-mediated gene therapy approach, although it could offer the possibility of a long-lasting repair (because it will not require the repeated administration of AONs).
AONs are also becoming candidate therapeutics for other forms of muscular dystrophy, such as myotonic dystrophy type 1 [34-38], limb-girdle muscular dystrophy 2B  and Fukuyama congenital muscular dystrophy . Further clinical translation from this work is expected in the near future.