Duchenne muscular dystrophy (DMD) arises from mutations in the dystrophin gene. The dystrophin gene is composed of 79 exons, and the majority of mutations in DMD are deletions, often spanning multiple exons.¹ In 2016, the US Food and Drug Administration (FDA) granted accelerated approval for eteplirsen (Exondys51), an antisense oligonucleotide compound designed to block exon 51 of dystrophin to restore the reading frame in patients with DMD with specific mutations (Figure, A).² This treatment is directed at ≈10% to 15% of patients with DMD (≈1500 treatment-eligible individuals). The approval of eteplirsen is game changing for the field of molecular gene correction. However, its approval was viewed as controversial because of the unconventional clinical trial data and limited efficacy.

Eteplirsen (Exondys51)-mediated reading-frame correction of Duchenne muscular dystrophy (DMD) mutations. A, Top, Schematic of the dystrophin protein and its domains. ABD1 indicates actin binding domain; CR, cysteine rich domain; CT, C-terminal domain; and H, hinge regions. The spectrin-like repeats are numbered. The red bar indicates the approximate exon 51 targeting region. Middle, Schematic showing eteplirsen-mediated reading-frame correction of a DMD frameshift mutation. The normal dystrophin locus from exons 41 to 52 is shown, indicating the reading frame of each exon. Many patients with DMD have variable-sized deletions spanning exons 47 to 50, disrupting the reading frame (dashed blue line). Eteplirsen (red box) is an antisense oligonucleotide that binds to exon-splicing enhancer sequences in exon 51, causing its exclusion from mRNA. Because exon 51 is excluded, exons 46 (or 47, 48, and 49) joins to exon 52 (solid blue line) to restore an open reading frame. B, Antisense oligonucleotides have complementary sequences to those within an exon, in this case exon 51. Chemical modifications to the antisense oligonucleotides permit the double-stranded hybrid …

杜氏肌营养不良症（DMD）由肌营养不良蛋白基因的突变引起。肌营养不良蛋白基因由79个外显子组成，DMD中的大多数突变是缺失，通常跨越多个外显子。¹ 2016年，美国食品药品监督管理局（FDA）加快了对eteplirsen（Exondys51）的批准，这是一种反义寡核苷酸化合物，旨在阻断肌营养不良蛋白的外显子51，以恢复具有特定突变的DMD患者的阅读框架（图A）。 。²该治疗针对约10％至15％的DMD患者（约1500名有治疗资格的患者）。eteplirsen的批准正在改变分子基因校正领域。然而，由于非常规的临床试验数据和有限的疗效，其批准被认为是有争议的。

Eteplirsen（Exondys51）介导的杜兴氏肌营养不良症（DMD）突变的阅读框校正。A，顶，抗肌萎缩蛋白及其域的示意图。ABD1指示肌动蛋白结合结构域；CR，富含半胱氨酸的结构域；CT，C-末端结构域；H，铰链区。像血影蛋白一样的重复被编号。红条表示外显子51的大致靶向区域。中间，示意图显示了eteplirsen介导的DMD移码突变的阅读框校正。显示了来自外显子41至52的正常肌营养不良蛋白基因座，指示每个外显子的阅读框。许多DMD患者的缺失大小介于外显子47至50之间，大小可变，破坏了阅读框（蓝色虚线）。Eteplirsen（红色框）是一种反义寡核苷酸，可与外显子51中的外显子剪接增强子序列结合，从而将其从mRNA中排除。因为排除了外显子51，所以外显子46（或47、48和49）连接到外显子52（蓝色实线）以恢复开放阅读框。B，反义寡核苷酸与外显子（在本例中为第51外显子）中的序列互补。反义寡核苷酸的化学修饰允许双链杂交……