The 10th Oligonucleotide Therapy Approved: Golodirsen for Duchenne Muscular Dystrophy
The 10th Oligonucleotide Therapy Approved: Golodirsen for Duchenne Muscular Dystrophy
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DOI：
10.1089/nat.2020.0845
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发表时间：
2020-02-11
影响因子：
4
通讯作者：
Corey, David R.
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文献类型：
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作者：
Aartsma-Rus, Annemieke;Corey, David R.
golodirsen 用于治疗具有合格突变的杜氏肌营养不良症 (DMD) 患者的疗法 (www.drugs.com/newdrugs/fda-approves-vyondys-53-golodirsenduchenne-muscular-dystropy-dmd-患者-amenable-skip ping-exon-5119.html)。这使得 FDA 和/或欧洲药品管理局 (EMA) 批准的寡核苷酸药物数量达到 10 种，用于治疗 DMD 的寡核苷酸药物数量达到 2 种（表 1）。与之前批准的 eteplirsen 相比，此次批准争议较少，但仍不是一帆风顺。使用剪接调节作为 DMD 疗法的想法源于这样一个事实，即功能性肌营养不良蛋白的缺乏会导致严重的进行性肌肉萎缩，而允许产生部分功能性肌营养不良蛋白的突变与一种进展较慢的疾病——贝克尔肌营养不良症 (BMD) 相关。 DMD 反义寡核苷酸介导的剪接调节旨在调节剪接，使 DMD 患者能够产生 BMD 样肌营养不良蛋白。由于并非所有 DMD 患者都携带相同的突变，因此该方法是针对突变的。然而，大多数突变聚集在热点区域，因此某些外显子的跳跃适用于更大的患者群体，例如，外显子 51 跳跃将适用于 14% 的患者，而外显子 45 和外显子 53 跳跃将适用于另外 9% 和 8% 的 DMD 患者 [1, 2]。 Golodirsen（外显子 53 跳跃）和 eteplirsen（外显子 51 跳跃）均由 Sarepta Therapeutics 开发，均为磷酸二酰胺吗啉寡聚物。基于治疗患者肌营养不良蛋白表达增加，Eteplirsen 于 2016 年获得 FDA 加速批准。正如已经提到的，这一批准是有争议的，所涉及的问题之前已经详细讨论过[3]。简而言之，根据 FDA 的说法，当时 Sarepta Therapeutics 尚未令人信服地显示出治疗的功能益处，而骨骼肌活检中肌营养不良蛋白的增加很小：* 48 周后增加 0.4%，* 治疗 188 周后增加 0.9% [3]。值得注意的是，肌营养不良蛋白定量非常具有挑战性，Sarepta Therapeutics 投入了大量精力使其蛋白质印迹系统获得 FDA 的认可 [4]。尽管如此，量化非常微小的增加的准确度仍然值得怀疑[5]。 Sarepta Therapeutics 必须在 2021 年之前向 FDA 提供证据
Therapeutics for golodirsen to treat Duchenne muscular dystrophy (DMD) patients with eligible mutations (www. drugs. com/newdrugs/fda-approves-vyondys-53-golodirsenduchenne-muscular-dystrophy-dmd-patients-amenable-skip ping-exon-5119. html). This brings the number of FDA and/or European Medicines Agency (EMA) approved oligonucleotide drugs to 10 and the number of oligonucleotide drugs for treatment of DMD to 2 (Table 1). The approval is less controversial than that of previously approved eteplirsen, but it was still not a smooth ride.The idea to use splice modulating as a therapy for DMD stems from the fact that lack of functional dystrophin causes severe progressive muscle wasting, while mutations that allow the production of partially functional dystrophins are associated with a less progressive disease, Becker muscular dystrophy (BMD). Antisense oligonucleotide-mediated splicing modulation for DMD aims to modulate splicing such that DMD patients can produce BMD-like dystrophin. As not all DMD patients carry the same mutation, this approach is mutation specific. However, most mutations cluster in a hotspot region and as such the skipping of certain exons applies to larger groups of patients, for example, exon 51 skipping would apply to 14% of patients, whereas exon 45 and exon 53 skipping would apply to an additional 9% and 8% of DMD patients [1, 2]. Golodirsen (exon 53 skipping) and eteplirsen (exon 51 skipping) are both developed by Sarepta Therapeutics and are both phosphorodiamidate morpholino oligomers. Eteplirsen received accelerated approval in 2016 from the FDA based on increased expression in dystrophin in treated patients. As already mentioned, this approval was controversial, and the issues involved have been discussed in detail previously [3]. In brief, according to FDA, functional benefits from treatment had at that time not been convincingly shown by Sarepta Therapeutics, whereas the increases in dystrophin in a skeletal muscle biopsy were minimal:* 0.4% after 48 weeks and* 0.9% after 188 weeks of treatment [3]. Notably, dystrophin quantification is very challenging and Sarepta Therapeutics invested a lot of effort in making its Western blotting system acceptable to FDA [4]. Still, it is questionable how accurate one can quantify very minute increases [5]. Sarepta Therapeutics has until 2021 to show evidence to FDA