Phase 2a study of ataluren-mediated dystrophin production in patients with nonsense mutation Duchenne muscular dystrophy.
Phase 2a study of ataluren-mediated dystrophin production in patients with nonsense mutation Duchenne muscular dystrophy.
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DOI：
10.1371/journal.pone.0081302
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Peltz SW
中科院分区：
文献类型：
--
作者：
Finkel RS;Flanigan KM;Wong B;Bönnemann C;Sampson J;Sweeney HL;Reha A;Northcutt VJ;Elfring G;Barth J;Peltz SW
大约13%的Duchenne肌营养不良症（DMD）男孩在肌营养不良蛋白基因中存在无义突变，导致相应mRNA中的过早终止密码子和无法产生功能蛋白。Ataluren（PTC 124）能够使核糖体通读过早终止密码子，从而产生全长功能蛋白。这项2a期开放标签、序贯剂量范围试验招募了38名患有无义突变DMD的男孩。第一组（n = 6）每天三次接受阿他卢仑，剂量为4、4和8 mg/kg的早晨、中午和晚上;第二组（n = 20）以10、10、20 mg/kg给药;第三组（n = 12）以20、20、40 mg/kg给药。 治疗持续时间为28天。治疗前和治疗后肌肉活检标本中通过免疫染色评估的全长肌营养不良蛋白表达的变化是主要终点。在评估肌营养不良蛋白/血影蛋白比率的定量分析中，38名受试者中的23名（61%）表现出治疗后肌营养不良蛋白表达的增加。定性分析也显示肌营养不良蛋白表达的阳性变化。表达与无义突变类型或外显子位置无关。在mdx小鼠模型中，参与者在中剂量和高剂量水平下一致地达到了活性的阿他卢仑谷血浆浓度。Ataluren通常耐受良好。Ataluren在这项短期研究中显示出活性和安全性，支持在无义突变DMD的2b期、双盲、长期研究中评估10、10、20 mg/kg和20、20、40 mg/kg的Ataluren。 ClinicalTrials.gov NCT00264888
Approximately 13% of boys with Duchenne muscular dystrophy (DMD) have a nonsense mutation in the dystrophin gene, resulting in a premature stop codon in the corresponding mRNA and failure to generate a functional protein. Ataluren (PTC124) enables ribosomal readthrough of premature stop codons, leading to production of full-length, functional proteins. This Phase 2a open-label, sequential dose-ranging trial recruited 38 boys with nonsense mutation DMD. The first cohort (n = 6) received ataluren three times per day at morning, midday, and evening doses of 4, 4, and 8 mg/kg; the second cohort (n = 20) was dosed at 10, 10, 20 mg/kg; and the third cohort (n = 12) was dosed at 20, 20, 40 mg/kg. Treatment duration was 28 days. Change in full-length dystrophin expression, as assessed by immunostaining in pre- and post-treatment muscle biopsy specimens, was the primary endpoint. Twenty three of 38 (61%) subjects demonstrated increases in post-treatment dystrophin expression in a quantitative analysis assessing the ratio of dystrophin/spectrin. A qualitative analysis also showed positive changes in dystrophin expression. Expression was not associated with nonsense mutation type or exon location. Ataluren trough plasma concentrations active in the mdx mouse model were consistently achieved at the mid- and high- dose levels in participants. Ataluren was generally well tolerated. Ataluren showed activity and safety in this short-term study, supporting evaluation of ataluren 10, 10, 20 mg/kg and 20, 20, 40 mg/kg in a Phase 2b, double-blind, long-term study in nonsense mutation DMD. ClinicalTrials.gov NCT00264888
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