Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome
Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome
复制标题
DOI：
10.1073/pnas.1311141111
复制
发表时间：
2014-03-25
影响因子：
11.1
通讯作者：
Kaufmann, Walter E.
中科院分区：
文献类型：
--
作者：
Khwaja, Omar S.;Ho, Eugenia;Kaufmann, Walter E.
Rett综合征(RTT)是一种严重的X连锁神经发育障碍，主要影响女性，与编码甲基CpG结合蛋白2的基因MECP2的突变有关。小鼠模型表明，重组人胰岛素样生长因子1(RhIGF1)(Mecasermin)可能会改善许多临床特征。我们评估了12名患有MECP2突变的女孩(9名患有RTT)的IGF-1的安全性、耐受性和药代动力学特征。此外，我们使用自动心肺测量、EEG、一套以RTT为导向的临床评估和两份标准化的行为问卷对疗效进行了初步评估。第1阶段试验包括4周多次递增剂量(MAD)(每天两次，每次40-120微克/公斤)和20周最大剂量开放标签延长(OLE)。12名受试者完成了MAD，10名受试者完成了整个研究，没有发现低血糖或严重不良事件的证据。在MAD结束时，脑脊液中IGF-1水平的升高证明了Mecasermin到达了中枢神经系统的隔室。药物遵循非线性动力学，在外周隔室有较大的分布。心肺功能检测显示，在OLE期间呼吸暂停有所改善。在OLE期间，一些神经行为参数，特别是焦虑和情绪指标也有所改善。情绪和焦虑分数的这些改善得到了脑电中右侧额叶α波段不对称的逆转支持，脑电是焦虑和抑郁的指标。我们的数据表明，对于患有RTT的女孩来说，IGF-1是安全和耐受性良好的，临床前研究表明，IGF-1可以改善某些呼吸和行为异常。
Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models suggest that recombinant human insulin-like growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40-120 mu g/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities.