Exon skipping gene editing in Duchenne Muscular Dystrophy using Antisense Oligonucleotides (AONs) restore an open reading frame, thereby establishing expression of a truncated but functional dystrophin. Currently one of the most attractive approaches for the treatment of DMD. Early human clinical trials testing either 2′-O methyl–- modified oligoribonucleotides with a uniform phosphorothioate backbone (2’OMe) or phosphorodiamidate morpholino oligomers (PMO), both targeting the DMD exon 51, reported encouraging results.

Our goal here was to investigate the potential of our novel 2’OMe AONs conjugated with a cell-penetrating transporter in vitro. These modified AONs are inflexible and have an extremely high affinity for RNA and DNA. In addition, they are nontoxic and nuclease resistant with extremely efficient modulators of pre-mRNA splicing. We have evaluated the exon skipping potential of our AONs for exon 51/52 in DMD patient derived primary skin fibroblasts converted into forced myoblasts using adenoviral vector Ad5.f50.ADApt.MyoD .

Our in vitro and in vivo results demonstrate that this novel chemistry particularly has a potential future therapy for patients with DMD and other neuromuscular disorders or with other diseases that are eligible for exon-skipping approaches requiring whole-body treatment.