Wang Mingxing, Wu Bo, Shah Sapana N, Lu Peijuan, Lu Qilong
McColl-Lockwood Laboratory for Muscular Dystrophy Research, Department of Neurology, Cannon Research Center, Carolinas Medical Center, 1000 Blythe Blvd., Charlotte, NC 28203, USA.
McColl-Lockwood Laboratory for Muscular Dystrophy Research, Department of Neurology, Cannon Research Center, Carolinas Medical Center, 1000 Blythe Blvd., Charlotte, NC 28203, USA.
Mol Ther Nucleic Acids. 2019 Jun 7;16:663-674. doi: 10.1016/j.omtn.2019.04.023. Epub 2019 May 2.
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.
反义寡核苷酸（AO）疗法一直是杜氏肌营养不良症的特异性治疗方法，目前正在进行临床试验。然而，AO的治疗应用仍然有限，特别是因为缺乏实现疗效所必需的高效细胞递送方法。在本研究中，我们研究了几种氨基糖苷类药物（AGs）在体外和体内改善反义磷酰胺吗啉代寡聚物（PMO）递送的潜力。与Endoporter相比，AGs的细胞毒性更低，Endoporter是目前体外PMO最有效的递送试剂，并且AGs将PMO递送效率提高了9至15倍。在mdx小鼠中观察到全身PMO靶向的肌营养不良蛋白外显子23跳跃显著增强，与仅使用PMO相比，AG3（卡那霉素）和AG7（西索米星）可使跳跃增加6倍。在测试剂量下未发现明显的肌肉损伤。这些结果确立了AGs作为治疗肌肉营养不良症或其他疾病的PMO递送增强剂。
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