Long-term efficacy of systemic multiexon skipping targeting dystrophin exons 45-55 with a cocktail of vivo-morpholinos in mdx52 mice.
Long-term efficacy of systemic multiexon skipping targeting dystrophin exons 45-55 with a cocktail of vivo-morpholinos in mdx52 mice.
复制标题
DOI：
10.1038/mtna.2014.76
复制
发表时间：
2015-02-03
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
反义介导的外显子跳读可以恢复阅读框架，是治疗Duchenne型肌营养不良症最有前途的方法。剩余的挑战包括对患者的有限适用性和截短的肌营养不良蛋白的功能不清楚。靶向肌营养不良蛋白基因突变热点处的外显子45-55的多外显子跳跃可以克服这两个挑战。之前，我们描述了外显子45-55在体内与Vivo-Morpholinos混合物跳跃的可行性;然而，Vivo-Morpholinos的长期疗效和安全性仍有待确定。在这项研究中，我们通过每2周静脉注射6 mg/kg 10-Vivo-吗啉代混合物（每种vPMO 0.6 mg/kg）持续18周，对营养不良外显子-52敲除（mdx 52）小鼠检查外显子45-55跳跃的功效和毒性。诱导了整个外显子45-55区域的系统性跳跃，并且蛋白质印迹分析显示骨骼肌中抗肌萎缩蛋白蛋白质恢复到正常水平的5-27%，伴随着组织病理学和肌肉强度的改善。治疗结束时未发现明显的免疫应答及肝肾毒性反应。我们证明了我们的新方案与10-Vivo-Morpholino鸡尾酒是有效的和安全的长期重复全身给药在营养不良的小鼠模型。
Antisense-mediated exon skipping, which can restore the reading frame, is a most promising therapeutic approach for Duchenne muscular dystrophy. Remaining challenges include the limited applicability to patients and unclear function of truncated dystrophin proteins. Multiexon skipping targeting exons 45–55 at the mutation hotspot of the dystrophin gene could overcome both of these challenges. Previously, we described the feasibility of exons 45–55 skipping with a cocktail of Vivo-Morpholinos in vivo; however, the long-term efficacy and safety of Vivo-Morpholinos remains to be determined. In this study, we examined the efficacy and toxicity of exons 45–55 skipping by intravenous injections of 6 mg/kg 10-Vivo-Morpholino cocktail (0.6 mg/kg each vPMO) every 2 weeks for 18 weeks to dystrophic exon-52 knockout (mdx52) mice. Systemic skipping of the entire exons 45–55 region was induced, and the Western blot analysis exhibited the restoration of 5–27% of normal levels of dystrophin protein in skeletal muscles, accompanied by improvements in histopathology and muscle strength. No obvious immune response and renal and hepatic toxicity were detected at the end-point of the treatment. We demonstrate our new regimen with the 10-Vivo-Morpholino cocktail is effective and safe for long-term repeated systemic administration in the dystrophic mouse model.
登录
查看更多内容
影响因子：
3.7
作者：
Nakamura H;Kimura E;Mori-Yoshimura M;Komaki H;Matsuda Y;Goto K;Hayashi YK;Nishino I;Takeda S;Kawai M
通讯作者：
Kawai M
影响因子：
10.8
作者：
Jearawiriyapaisarn, Natee;Moulton, Hong M.;Willis, Monte S.
通讯作者：
Willis, Monte S.
影响因子：
2.7
作者：
Morcos, Paul A.;Li, Yongfu;Jiang, Shan
通讯作者：
Jiang, Shan
影响因子：
6
作者：
Magri, Francesca;Govoni, Alessandra;Comi, Giacomo Pietro
通讯作者：
Comi, Giacomo Pietro
影响因子：
2.7
作者：
Ferguson DP;Dangott LJ;Lightfoot JT
通讯作者：
Lightfoot JT