A Highly Selective MNK Inhibitor Rescues Deficits Associated with Fragile X Syndrome in Mice

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 theFmr1gene. Loss ofFmr1results 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 ofFmr1in 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.

Automated summary

Fragile X syndrome is the most common inherited source of intellectual disability in humans, caused by epigenetic silencing of the Fmr1 gene. The MNK inhibitor eFT508 shows potential in alleviating deficits associated with FXS by targeting downstream pathways. This study highlights the ability of eFT508 to improve various phenotypic abnormalities linked to FXS.