Local dystrophin restoration with antisense oligonucleotide PRO051
Local dystrophin restoration with antisense oligonucleotide PRO051
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DOI：
10.1056/nejmoa073108
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发表时间：
2007-12-27
影响因子：
158.5
通讯作者：
van Ommen, Gert-Jan B.
中科院分区：
文献类型：
--
作者：
van Deutekom, Judith C.;Janson, Anneke A.;van Ommen, Gert-Jan B.
背景：杜兴氏肌营养不良症与严重的进行性肌肉无力有关，通常导致 20 至 35 岁之间的死亡。通过在信使 RNA (mRNA) 剪接过程中诱导特定的外显子跳跃，反义化合物最近被证明可以纠正 DMD 基因的开放阅读框，从而恢复体外和动物模型体内肌营养不良蛋白的表达。我们探讨了单次肌肉注射反义寡核苷酸 PRO051 在患有这种疾病的患者中的安全性、不良事件概况和局部肌营养不良蛋白恢复作用。方法：根据突变状态、肌肉状况和体外对 PRO051 的阳性外显子跳跃反应而选择的 4 名患者接受了胫骨前肌注射 0.8 mg 剂量的 PRO051。 28天后进行活检。评估了安全性措施、mRNA 组成和肌营养不良蛋白表达。结果：PRO051 注射与临床明显的不良事件无关。每个患者的 64% 至 97% 的肌纤维中都表现出外显子 51 和肌膜肌营养不良蛋白的特异性跳跃。总蛋白提取物中肌营养不良蛋白的含量为对照样本的 3% 至 12%，肌营养不良蛋白与层粘连蛋白 α2 的数量比为对照样本的 17% 至 35%。结论：肌肉注射反义寡核苷酸 PRO051 诱导 4 名具有适当突变的杜兴氏肌营养不良症患者肌营养不良蛋白合成，表明进一步的研究是可行的。
Background: Duchenne's muscular dystrophy is associated with severe, progressive muscle weakness and typically leads to death between the ages of 20 and 35 years. By inducing specific exon skipping during messenger RNA (mRNA) splicing, antisense compounds were recently shown to correct the open reading frame of the DMD gene and thus to restore dystrophin expression in vitro and in animal models in vivo. We explored the safety, adverse-event profile, and local dystrophin-restoring effect of a single, intramuscular dose of an antisense oligonucleotide, PRO051, in patients with this disease.Methods: Four patients, who were selected on the basis of their mutational status, muscle condition, and positive exon-skipping response to PRO051 in vitro, received a dose of 0.8 mg of PRO051 injected into the tibialis anterior muscle. A biopsy was performed 28 days later. Safety measures, composition of mRNA, and dystrophin expression were assessed.Results: PRO051 injection was not associated with clinically apparent adverse events. Each patient showed specific skipping of exon 51 and sarcolemmal dystrophin in 64 to 97% of myofibers. The amount of dystrophin in total protein extracts ranged from 3 to 12% of that found in the control specimen and from 17 to 35% of that of the control specimen in the quantitative ratio of dystrophin to laminin alpha 2.Conclusions: Intramuscular injection of antisense oligonucleotide PRO051 induced dystrophin synthesis in four patients with Duchenne's muscular dystrophy who had suitable mutations, suggesting that further studies might be feasible.