Emerging genetic therapies to treat Duchenne muscular dystrophy.
Emerging genetic therapies to treat Duchenne muscular dystrophy.
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DOI：
10.1097/wco.0b013e32832fd487
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发表时间：
2009-10
影响因子：
4.8
通讯作者：
Spencer MJ
中科院分区：
文献类型：
--
作者：
Nelson SF;Crosbie RH;Miceli MC;Spencer MJ
杜氏肌营养不良症是一种进行性肌肉退行性疾病引起的肌营养不良蛋白突变。这篇综述的目的是强调两种新兴的治疗方法，旨在修复主要的遗传缺陷，称为“外显子跳跃”和“无义密码子抑制”。PTC 124是一种抑制无义密码子翻译终止的药物。PTC 124可以导致人杜氏肌营养不良症肌肉中某些肌营养不良蛋白表达的恢复，突变导致过早停止。针对外显子跳跃开发的两种药物PRO 051和AVI-4658导致外显子51从成熟mRNA中排除。他们可以恢复翻译阅读框架的肌营养不良蛋白基因缺失的患者的肌营养不良蛋白转录本的一个特定的子集，并导致一些恢复受影响的男孩的肌肉在体内肌营养不良蛋白的表达。这两种方法都完成了I期试验，没有严重的不良事件。这些用于纠正抗肌萎缩蛋白缺乏症的原发性遗传缺陷的新疗法是第一代针对纠正人类特定突变的疗法之一。因此，它们代表了个性化医学的范式形成方法，有可能为杜氏肌营养不良症患者带来改变生活的治疗。
Duchenne muscular dystrophy is a progressive muscle degenerative disease caused by dystrophin mutations. The purpose of this review is to highlight two emerging therapies designed to repair the primary genetic defect, called `exon skipping' and `nonsense codon suppression'. A drug, PTC124, was identified that suppresses nonsense codon translation termination. PTC124 can lead to restoration of some dystrophin expression in human Duchenne muscular dystrophy muscles with mutations resulting in premature stops. Two drugs developed for exon skipping, PRO051 and AVI-4658, result in the exclusion of exon 51 from mature mRNA. They can restore the translational reading frame to dystrophin transcripts from patients with a particular subset of dystrophin gene deletions and lead to some restoration of dystrophin expression in affected boys' muscle in vivo. Both approaches have concluded phase I trials with no serious adverse events. These novel therapies that act to correct the primary genetic defect of dystrophin deficiency are among the first generation of therapies tailored to correct specific mutations in humans. Thus, they represent paradigm forming approaches to personalized medicine with the potential to lead to life changing treatment for those affected by Duchenne muscular dystrophy.