PDF(Pubmed)
Abstract：
Fragile X syndrome (FXS) is a rare neurodevelopmental disorder caused by a CGG repeat expansion ≥ 200 repeats in 5\' untranslated region of the FMR1 gene, leading to intellectual disability and cognitive difficulties, including in the domain of communication. A recent phase 2a clinical trial testing BPN14770, a phosphodiesterase 4D inhibitor, showed improved cognition in 30 adult males with FXS on drug relative to placebo. The initial study found significant improvements in clinical measures assessing cognition, language, and daily functioning in addition to marginal improvements in electroencephalography (EEG) results for the amplitude of the N1 event-related potential (ERP) component. EEG results suggest BPN14770 improved neural hyperexcitability in FXS. The current study investigated the relationship between BPN14770 pharmacokinetics (PK) and the amplitude of the N1 ERP component from the initial data. Consistent with the original group-level finding in period 1 of the study, participants who received BPN14770 in the period 1 showed a significant correlation between N1 amplitude and serum concentration of BPN14770. These findings strengthen the validity of the original result, indicating that BPN14770 improves cognitive performance by modulating neural hyperexcitability. This study represents the first report of significant correlation between a reliably abnormal EEG marker and serum concentration of a novel pharmaceutical in FXS.
摘要：
脆性X综合征（FXS）是一种罕见的神经发育障碍，由FMR1基因5个非翻译区的CGG重复序列扩增≥200个重复序列引起，导致智力残疾和认知困难，包括在通信领域。最近的2a期临床试验测试BPN14770，一种磷酸二酯酶4D抑制剂，与安慰剂相比，30名使用FXS的成年男性的认知能力得到了改善。最初的研究发现，评估认知的临床措施有了显著的改善，语言,和日常功能，除了脑电图（EEG）的边际改善外，还导致N1事件相关电位（ERP）分量的幅度。EEG结果表明BPN14770改善了FXS的神经过度兴奋。本研究从初始数据调查了BPN14770药代动力学（PK）与N1ERP成分幅度之间的关系。与研究第一阶段的原始小组水平发现一致，在第1期接受BPN14770治疗的参与者显示N1振幅与BPN14770血清浓度之间存在显著相关性.这些发现加强了原始结果的有效性，表明BPN14770通过调节神经过度兴奋来改善认知表现。这项研究代表了可靠的异常EEG标志物与FXS中新型药物的血清浓度之间存在显着相关性的第一份报告。
