The Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK.
Mol Ther. 2012 Feb;20(2):462-7. doi: 10.1038/mt.2011.248. Epub 2011 Nov 15.
We previously conducted a proof of principle; dose escalation study in Duchenne muscular dystrophy (DMD) patients using the morpholino splice-switching oligonucleotide AVI-4658 (eteplirsen) that induces skipping of dystrophin exon 51 in patients with relevant deletions, restores the open reading frame and induces dystrophin protein expression after intramuscular (i.m.) injection. We now show that this dystrophin expression was accompanied by an elevated expression of α-sarcoglycan, β-dystroglycan (BDG) and--in relevant cases--neuronal nitric oxide synthase (nNOS) at the sarcolemma, each of which is a component of a different subcomplex of the dystrophin-associated glycoprotein complex (DAPC). As expected, nNOS expression was relocalized to the sarcolemma in Duchenne patients in whom the dystrophin deletion left the nNOS-binding domain (exons 42-45) intact, whereas this did not occur in patients with deletions that involved this domain. Our results indicate that the novel internally deleted and shorter dystrophin induced by skipping exon 51 in patients with amenable deletions, can also restore the dystrophin-associated complex, further suggesting preserved functionality of the newly translated dystrophin.
我们之前在杜氏肌营养不良症（DMD）患者中进行了一项原理验证；剂量递增研究，使用的是能够诱导相关缺失患者外显子 51 跳跃的 morpholino 剪接转换寡核苷酸 AVI-4658（eteplirsen），恢复开放阅读框并在肌内（i.m.）注射后诱导肌营养不良蛋白表达。我们现在表明，这种肌营养不良蛋白表达伴随着肌膜上α- sarcoglycan、β-肌营养不良蛋白（BDG）和--在相关情况下--神经元型一氧化氮合酶（nNOS）的表达升高，每个都是不同的肌营养不良相关糖蛋白复合物（DAPC）亚复合物的组成部分。正如预期的那样，在肌营养不良蛋白缺失保留了 nNOS 结合域（外显子 42-45）完整的患者中，nNOS 表达被重新定位于肌膜，而在涉及该域缺失的患者中则没有发生这种情况。我们的结果表明，在可治疗缺失的患者中，通过跳跃外显子 51 诱导的新型内部缺失和较短的肌营养不良蛋白，也可以恢复肌营养不良相关复合物，进一步表明新翻译的肌营养不良蛋白具有保留的功能。
