Systemic Administration of PRO051 in Duchenne's Muscular Dystrophy
Systemic Administration of PRO051 in Duchenne's Muscular Dystrophy
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DOI：
10.1056/nejmoa1011367
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发表时间：
2011-04-21
影响因子：
158.5
通讯作者：
van Deutekom, Judith C.
中科院分区：
文献类型：
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作者：
Goemans, Nathalie M.;Tulinius, Mar;van Deutekom, Judith C.
背景：在Duchenne‘s肌营养不良症患者中局部肌肉注射反义寡核苷酸PRO051可导致Duchenne’s肌营养不良症患者在信使前信使RNA剪接时跳过外显子51，并促进肌纤维膜上新的dystrophin表达。目前的1-2a期研究旨在评估全身注射PRO051的安全性、药代动力学、分子和临床效应。方法我们对12名患者进行了为期5周的每周腹部皮下注射PRO051，其中3名患者分别给予4种可能的剂量(每公斤体重0.5、2.0、4.0和6.0 mg)。在两个时间点评估胫前肌RNA剪接和蛋白质水平的变化。所有患者随后都进入了为期12周的开放标签延长阶段，在此期间，他们都接受了PRO051，剂量为每公斤每公斤6.0毫克。安全性、药代动力学、血清肌酸激酶水平、肌肉力量和功能。结果最常见的不良事件是给药部位的刺激性反应，在延长期，轻度和可变的蛋白尿以及尿α1-微球蛋白水平升高；没有严重的不良事件。PRO051在循环中的平均终端半衰期为29天。当剂量为每公斤2.0 mg或以上时，PRO051可诱导可检测到的、特异的外显子-51跳过。根据治疗后活检的测量，在12名患者中有10名患者在大约60%到100%的肌肉纤维中观察到新的肌营养不良蛋白的表达，这一表达以剂量依赖的方式增加到健康肌肉中的15.6%。在12周延长期后，6分钟步行试验的平均(+/-SD)改善35.2+/-28.7m(基线为384+/-121m)。结论系统应用PRO051对Duchenne肌营养不良症患者显示出剂量依赖性的分子效应，在延长治疗12周后，6分钟步行试验略有改善。
BACKGROUNDLocal intramuscular administration of the antisense oligonucleotide PRO051 in patients with Duchenne's muscular dystrophy with relevant mutations was previously reported to induce the skipping of exon 51 during pre-messenger RNA splicing of the dystrophin gene and to facilitate new dystrophin expression in muscle-fiber membranes. The present phase 1-2a study aimed to assess the safety, pharmacokinetics, and molecular and clinical effects of systemically administered PRO051.METHODSWe administered weekly abdominal subcutaneous injections of PRO051 for 5 weeks in 12 patients, with each of four possible doses (0.5, 2.0, 4.0, and 6.0 mg per kilogram of body weight) given to 3 patients. Changes in RNA splicing and protein levels in the tibialis anterior muscle were assessed at two time points. All patients subsequently entered a 12-week open-label extension phase, during which they all received PRO051 at a dose of 6.0 mg per kilogram per week. Safety, pharmacokinetics, serum creatine kinase levels, and muscle strength and function were assessed.RESULTSThe most common adverse events were irritation at the administration site and, during the extension phase, mild and variable proteinuria and increased urinary a 1 -microglobulin levels; there were no serious adverse events. The mean terminal half-life of PRO051 in the circulation was 29 days. PRO051 induced detectable, specific exon-51 skipping at doses of 2.0 mg or more per kilogram. New dystrophin expression was observed between approximately 60% and 100% of muscle fibers in 10 of the 12 patients, as measured on post-treatment biopsy, which increased in a dose-dependent manner to up to 15.6% of the expression in healthy muscle. After the 12-week extension phase, there was a mean (+/- SD) improvement of 35.2 +/- 28.7 m (from the baseline of 384 +/- 121 m) on the 6-minute walk test.CONCLUSIONSSystemically administered PRO051 showed dose-dependent molecular efficacy in patients with Duchenne's muscular dystrophy, with a modest improvement in the 6-minute walk test after 12 weeks of extended treatment.