Discovery Neuroscience, Pharmaceuticals Division, F. Hoffmann-La Roche, CH-4070 Basel, Switzerland.
Neuron. 2012 Apr 12;74(1):49-56. doi: 10.1016/j.neuron.2012.03.009.
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. Previous studies have implicated mGlu5 in the pathogenesis of the disease, but a crucial unanswered question is whether pharmacological mGlu5 inhibition is able to reverse an already established FXS phenotype in mammals. Here we have used the novel, potent, and selective mGlu5 inhibitor CTEP to address this issue in the Fmr1 knockout mouse. Acute CTEP treatment corrects elevated hippocampal long-term depression, protein synthesis, and audiogenic seizures. Chronic treatment that inhibits mGlu5 within a receptor occupancy range of 81% ± 4% rescues cognitive deficits, auditory hypersensitivity, aberrant dendritic spine density, overactive ERK and mTOR signaling, and partially corrects macroorchidism. This study shows that a comprehensive phenotype correction in FXS is possible with pharmacological intervention starting in young adulthood, after development of the phenotype. It is of great interest how these findings may translate into ongoing clinical research testing mGlu5 inhibitors in FXS patients.
脆性 X 综合征 (FXS) 是最常见的遗传性智力障碍形式。先前的研究表明 mGlu5 在疾病的发病机制中起作用，但一个关键的未解决的问题是，药理 mGlu5 抑制是否能够在哺乳动物中逆转已经建立的 FXS 表型。在这里，我们使用新型、强效和选择性的 mGlu5 抑制剂 CTEP 来解决 Fmr1 敲除小鼠中的这个问题。急性 CTEP 治疗可纠正升高的海马体长时程抑制、蛋白质合成和听觉性癫痫发作。在受体占有率为 81%±4%的范围内抑制 mGlu5 的慢性治疗可挽救认知缺陷、听觉过敏、异常树突棘密度、过度活跃的 ERK 和 mTOR 信号，并部分纠正巨睾症。这项研究表明，通过在表型出现后开始的年轻成年期进行药理干预，可以实现 FXS 的全面表型纠正。这些发现如何转化为正在进行的 FXS 患者的 mGlu5 抑制剂临床试验非常有趣。
