Aminoglycoside Enhances the Delivery of Antisense Morpholino Oligonucleotides in vitro and in mdx Mice

Antisense oligonucleotide (AO) therapy has been the specific treatment for Duchenne muscular dystrophy with ongoing clinical trials. However, therapeutic applications of AO remain limited due to particularly the lack of efficient cellular delivery methods imperative for achieving efficacy. In this study, we investigated a few of Aminoglycosides (AGs) for their potential to improve delivery of antisense phosphorodiamidate morpholino oligomer (PMO) both in vitro and in vivo. The AGs showed lower cytotoxicity compared with Endoporter-the currently most effective delivery reagent for PMO in vitro, and improved efficiency in PMO delivery 9-15 fold over PMO alone. Significant enhancement in PMO targeted dystrophin exon 23 skipping systemically was observed in mdx mice, up to 6-fold increase with AG3 (kanamycin) and AG7 (sisomicin) as compared to PMO only. No muscle damage was clearly detected under the test dosages. These results endow AGs as PMO delivery enhancing agents for treating muscular dystrophy or other diseases.