University of Alberta, Department of Medical Genetics, School of Human Development, Faculty of Medicine and Dentistry, 829 Medical Sciences Building, Edmonton, AB T6G 2H7, Canada.
Expert Opin Biol Ther. 2012 Sep;12(9):1141-52. doi: 10.1517/14712598.2012.693469. Epub 2012 Jun 1.
Duchenne muscular dystrophy (DMD), one of the most common and lethal genetic disorders, is caused by mutations of the dystrophin gene. Removal of an exon or of multiple exons using antisense molecules has been demonstrated to allow synthesis of truncated 'Becker muscular dystrophy-like' dystrophin.
Approximately 15% of DMD cases are caused by a nonsense mutation. Although patient databases have previously been surveyed for applicability to each deletion mutation pattern, this is not so for nonsense mutations. Here, we examine the world-wide database containing notations for more than 1200 patients with nonsense mutations. Approximately 47% of nonsense mutations can be potentially treated with single exon skipping, rising to 90% with double exon skipping, but to reach this proportion requires the development of exon skipping molecules targeting some 68 of dystrophin's 79 exons, with patient numbers spread thinly across those exons. In this review, we discuss progress and remaining hurdles in exon skipping and an alternative strategy, stop-codon readthrough.
Antisense-mediated exon skipping therapy is targeted highly at the individual patient and is a clear example of personalized medicine. An efficient regulatory path for drug approval will be a key to success.
杜氏肌营养不良症（DMD）是最常见和最致命的遗传疾病之一，由肌营养不良蛋白基因突变引起。使用反义分子去除外显子或多个外显子已被证明可允许截短的“贝克型肌营养不良症样”肌营养不良蛋白的合成。
大约 15%的 DMD 病例是由无义突变引起的。尽管以前已经对患者数据库进行了调查，以确定其是否适用于每种缺失突变模式，但对无义突变却并非如此。在这里，我们检查了包含 1200 多名无义突变患者记录的全球数据库。大约 47%的无义突变可以通过单外显子跳跃治疗，通过双外显子跳跃治疗上升到 90%，但要达到这一比例，需要开发针对肌营养不良蛋白的 79 个外显子中的约 68 个外显子的外显子跳跃分子，而患者数量在这些外显子中分布稀疏。在这篇综述中，我们讨论了外显子跳跃和替代策略——终止密码子通读的进展和剩余障碍。
反义介导的外显子跳跃治疗针对个体患者，是个性化医疗的一个明显例子。高效的药物审批监管途径将是成功的关键。
