Duchenne muscular dystrophy is a severe, progressive muscle-wasting disease that is caused by mutations that abolish the production of functional dystrophin protein. The exon skipping approach aims to restore the disrupted dystrophin reading frame, to allow the production of partially functional dystrophins, such as found in the less severe Becker muscular dystrophy. Exon skipping is achieved by antisense oligonucleotides (AONs). Several chemical modifications have been tested in nonclinical and clinical trials. The morpholino phosphorodiamidate oligomer eteplirsen has been approved by the Food and Drug Administration, whereas clinical development with the 2'-O-methyl phosphorothioate (2OMePS) AON drisapersen was recently stopped. In this study, we aimed to study various aspects of 2OMePS AONs in nonclinical animal studies. We show that while efficiency of exon skipping restoration is comparable in young and older C57BL/10ScSn-Dmdmdx/J (mdx/BL10) mice, functional improvement was only observed for younger treated mice. Muscle quality did not affect exon skipping efficiency as exon skip and dystrophin levels were similar between mdx/BL10 and more severely affected, age-matched D2-mdx mice. We further report that treadmill running increases AON uptake and dystrophin levels in mdx/BL10 mice. Finally, we show that even low levels of exon skipping and dystrophin restoration are sufficient to significantly increase the survival of mdx-utrn-/- mice from 70 to 97 days.

中文翻译：

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受临床试验结果启发的在mdx和mdx-utrn-/-小鼠中进行2'-O-甲基硫代磷酸硫代反义寡核苷酸的非临床外显子跳过研究。

杜兴氏肌营养不良症是一种严重的进行性肌肉萎缩性疾病，由消除功能性肌营养不良蛋白产生的突变引起。外显子跳过方法旨在恢复破坏性的肌营养不良蛋白阅读框架，从而产生部分功能性营养不良蛋白，例如在较不严重的贝克尔肌营养不良症中发现的。外显子跳跃是通过反义寡核苷酸（AON）实现的。在非临床和临床试验中已经测试了几种化学修饰。吗啉代磷酸二氨基酯低聚物eteplirsen已获得食品和药物管理局的批准，而2'-O-硫代磷酸硫代磷酸酯（2OMePS）AON地塞哌森的临床开发最近已停止。在这项研究中，我们旨在在非临床动物研究中研究2OMePS AON的各个方面。我们显示，虽然在年轻和年长的C57BL / 10ScSn-Dmdmdx / J（mdx / BL10）小鼠中外显子跳过恢复的效率相当，但仅在较年轻的小鼠中观察到功能改善。肌肉质量不会影响外显子跳跃效率，因为mdx / BL10与年龄更严重，年龄匹配的D2-mdx小鼠之间的外显子跳跃和肌营养不良蛋白水平相似。我们进一步报告说，跑步机运行会增加mdx / BL10小鼠的AON摄取和肌营养不良蛋白水平。最后，我们表明，即使是低水平的外显子跳跃和肌营养不良蛋白恢复，也足以显着增加mdx-utrn-/-小鼠的生存时间，从70天提高至97天。肌肉质量不会影响外显子跳跃效率，因为mdx / BL10与年龄更严重，年龄匹配的D2-mdx小鼠之间的外显子跳跃和肌营养不良蛋白水平相似。我们进一步报告说，跑步机运行会增加mdx / BL10小鼠的AON摄取和肌营养不良蛋白水平。最后，我们表明，即使是低水平的外显子跳跃和肌营养不良蛋白恢复，也足以显着增加mdx-utrn-/-小鼠的生存时间，从70天提高至97天。肌肉质量不会影响外显子跳跃效率，因为mdx / BL10与年龄更严重，年龄匹配的D2-mdx小鼠之间的外显子跳跃和肌营养不良蛋白水平相似。我们进一步报告说，跑步机运行会增加mdx / BL10小鼠的AON摄取和肌营养不良蛋白水平。最后，我们表明，即使是低水平的外显子跳跃和肌营养不良蛋白恢复，也足以显着增加mdx-utrn-/-小鼠的生存时间，从70天提高至97天。