Division of Biomedical Sciences, School of Medicine, University of California, 900 University Avenue, Riverside, CA, 92521, USA.
Takeda International - UK, Rare Diseases Therapeutic Area Unit, 1 Kingdom Street, London, W2 6BD, UK.
Neurotherapeutics. 2021 Apr;18(2):1175-1187. doi: 10.1007/s13311-021-01005-w. Epub 2021 Feb 16.
Fragile X syndrome (FXS) is a genetic neurodevelopmental syndrome characterized by increased anxiety, repetitive behaviors, social communication deficits, delayed language development, and abnormal sensory processing. Recently, we have identified electroencephalographic (EEG) biomarkers that are conserved between the mouse model of FXS (Fmr1 KO mice) and humans with FXS. In this study, we test a specific candidate mechanism for engagement of multielectrode array (MEA) EEG biomarkers in the FXS mouse model. We administered TAK-063, a potent, selective, and orally active phosphodiesterase 10A (PDE10A) inhibitor, to Fmr1 KO mice, and examined its effects on MEA EEG biomarkers. We demonstrate significant dose-related amelioration of inter-trial phase coherence (ITPC) to temporally modulated auditory stimuli by TAK-063 in Fmr1 KO mice. Our data suggest that TAK-063 improves cortical auditory stimulus processing in Fmr1 KO mice, without significantly depressing baseline EEG power or causing any noticeable sedation or behavioral side effects. Thus, the PDE10A inhibitor TAK-063 has salutary effects on normalizing EEG biomarkers in a mouse model of FXS and should be pursued in further translational treatment development.
脆性 X 综合征（FXS）是一种遗传性神经发育综合征，其特征为焦虑增加、重复行为、社交沟通障碍、语言发育迟缓以及感觉处理异常。最近，我们已经确定了 FXS 小鼠模型（Fmr1 KO 小鼠）和 FXS 患者之间保守的脑电图（EEG）生物标志物。在这项研究中，我们测试了 FXS 小鼠模型中多电极阵列（MEA）EEG 生物标志物的一个特定候选机制。我们给 Fmr1 KO 小鼠施用 TAK-063，一种强效、选择性和口服活性的磷酸二酯酶 10A（PDE10A）抑制剂，并检测其对 MEA EEG 生物标志物的影响。我们证明了 TAK-063 对 Fmr1 KO 小鼠的时间调制听觉刺激的试验间相位相干性（ITPC）有显著的剂量相关改善。我们的数据表明，TAK-063 改善了 Fmr1 KO 小鼠的皮质听觉刺激处理，而不会显著抑制基线 EEG 功率或引起任何明显的镇静或行为副作用。因此，PDE10A 抑制剂 TAK-063 对 FXS 小鼠模型中 EEG 生物标志物的正常化具有有益作用，应该在进一步的转化治疗开发中进行探索。
