Graduate School of Arts and Sciences, the University of Tokyo, Tokyo, Japan.
Sci Rep. 2013;3:2242. doi: 10.1038/srep02242.
Phosphorodiamidate morpholino oligonucleotide (PMO)-mediated control of the alternative splicing of the chloride channel 1 (CLCN1) gene is a promising treatment for myotonic dystrophy type 1 (DM1) because the abnormal splicing of this gene causes myotonia in patients with DM1. In this study, we optimised a PMO sequence to correct Clcn1 alternative splicing and successfully remedied the myotonic phenotype of a DM1 mouse model, the HSALR mouse. To enhance the efficiency of delivery of PMO into HSALR mouse muscles, Bubble liposomes, which have been used as a gene delivery tool, were applied with ultrasound exposure. Effective delivery of PMO led to increased expression of Clcn1 protein in skeletal muscle and the amelioration of myotonia. Thus, PMO-mediated control of the alternative splicing of the Clcn1 gene must be important target of antisense therapy of DM1.
磷酰二胺吗啉代寡核苷酸（PMO）介导的氯离子通道 1（CLCN1）基因的选择性剪接的控制是肌强直性营养不良 1 型（DM1）的一种有前途的治疗方法，因为该基因的异常剪接导致 DM1 患者出现肌肉僵硬。在这项研究中，我们优化了 PMO 序列以纠正 Clcn1 选择性剪接，并成功地纠正了 DM1 小鼠模型，即 HSALR 小鼠的肌强直表型。为了提高 PMO 进入 HSALR 鼠肌肉的递送效率，应用了已用作基因递送工具的泡囊脂质体并进行了超声暴露。PMO 的有效递送导致骨骼肌中 Clcn1 蛋白的表达增加，并改善了肌强直。因此，PMO 介导的 Clcn1 基因选择性剪接的控制可能是 DM1 反义治疗的重要靶点。
