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

Mingxing Wang; Bo Wu; Sapana N Shah; Peijuan Lu; Qilong Lu

doi:10.1016/j.omtn.2019.04.023

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

Mol Ther Nucleic Acids. 2019 Jun 7:16:663-674. doi: 10.1016/j.omtn.2019.04.023. Epub 2019 May 2.

Authors

Mingxing Wang¹, Bo Wu², Sapana N Shah², Peijuan Lu², Qilong Lu²

Affiliations

¹ McColl-Lockwood Laboratory for Muscular Dystrophy Research, Department of Neurology, Cannon Research Center, Carolinas Medical Center, 1000 Blythe Blvd., Charlotte, NC 28203, USA. Electronic address: mingxing.wang@atriumhealth.org.
² McColl-Lockwood Laboratory for Muscular Dystrophy Research, Department of Neurology, Cannon Research Center, Carolinas Medical Center, 1000 Blythe Blvd., Charlotte, NC 28203, USA.

Abstract

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

Keywords: PMO; aminoglycoside; antisense delivery; exon skipping; muscular dystrophy.