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

Abstract

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.

DNA methylation and regulation of gene expression: Guardian of our health

“…A promising development on this aspect, comes from the work of Wei et al, who have shown that although DNA methylation patterns between brain and peripheral tissues is differential, DNA methylation levels of the Amyloid Precursor Protein (APP) gene is consistent in both tissues and is a prospective candidate for a viable AD pathogenesis biomarker [ 82 ]. The phenotypic manifestation of Fragile X syndrome (FXS) has been correlated with eIF4E phosphorylation in both human and mice patients [ 31 , 37 , 75 ] and currently, the available treatments to modulate eIF4E activity are by the usage of the anti-diabetic drug Metformin [ 28 ], the anti-cancer drug eFT508 or tomivosertib [ 74 ] among others which have unwanted side effects. Presently for treatment of FXS, efforts are being taken to induce expression of the FMR1 gene, whose repression results in the disease manifestation.…”

Towards Kinase Inhibitor Therapies for Fragile X Syndrome: Tweaking Twists in the Autism Spectrum Kinase Signaling Network

“…Treatment with eFT508 restored hyperactive and anxiety-related behaviors, synaptic signaling, memory, and learning abnormalities, as well as aberrant social interactions. Together, these findings bring eFT508 to the forefront as a potential treatment for the FXS [161].…”

From Translation to Treatment

“…Use of one of them, eFT508 (tomivosertib, Table 1 ), has revealed roles for the MNK/eIF4E pathway in the immune checkpoint 35 and some cancer models (e.g., 36 ). Interestingly, this MNK inhibitor also showed efficacy in countering neuropathic pain 37 and relieved deficits, including behavioural ones, associated with Fragile X syndrome 38 .…”