Fragile X syndrome (FXS) is the most common inherited source of intellectual disability in humans. FXS is caused by mutations that trigger epigenetic silencing of the Fmr1 gene. Loss of Fmr1 results in increased activity of the mitogen-activated protein kinase (MAPK) pathway. An important downstream consequence is activation of the mitogen-activated protein kinase interacting protein kinase (MNK). MNK phosphorylates the mRNA cap-binding protein, eukaryotic initiation factor 4E (eIF4E). Excessive phosphorylation of eIF4E has been directly implicated in the cognitive and behavioral deficits associated with FXS. Pharmacological reduction of eIF4E phosphorylation is one potential strategy for FXS treatment. We demonstrate that systemic dosing of a highly specific, orally available MNK inhibitor, eFT508, attenuates numerous deficits associated with loss of Fmr1 in mice. eFT508 resolves a range of phenotypic abnormalities associated with FXS including macroorchidism, aberrant spinogenesis, and alterations in synaptic plasticity. Key behavioral deficits related to anxiety, social interaction, obsessive and repetitive activities, and object recognition are ameliorated by eFT508. Collectively, this work establishes eFT508 as a potential means to reverse deficits associated with FXS.

脆性 X 综合征 (FXS) 是人类智力障碍最常见的遗传原因。FXS 是由触发Fmr1基因表观遗传沉默的突变引起的。Fmr1缺失会导致丝裂原激活蛋白激酶 (MAPK) 通路活性增加。一个重要的下游结果是丝裂原激活蛋白激酶相互作用蛋白激酶（MNK）的激活。MNK 磷酸化 mRNA 帽结合蛋白、真核起始因子 4E (eIF4E)。eIF4E 的过度磷酸化直接涉及与 FXS 相关的认知和行为缺陷。药理学降低 eIF4E 磷酸化是 FXS 治疗的一种潜在策略。我们证明，高度特异性、口服的 MNK 抑制剂 eFT508 的全身给药可以减轻小鼠中与Fmr1缺失相关的众多缺陷。eFT508 解决了一系列与 FXS 相关的表型异常，包括大睾丸发育、棘发生异常和突触可塑性改变。eFT508 改善了与焦虑、社交互动、强迫性和重复性活动以及物体识别相关的关键行为缺陷。总的来说，这项工作将 eFT508 确立为扭转 FXS 相关赤字的潜在手段。