Editors' ChoiceDRUG DEVELOPMENT

A therapy for FXS?

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Sci. Signal.  04 Jul 2017:
Vol. 10, Issue 486, eaao2238
DOI: 10.1126/scisignal.aao2238

The antidiabetic drug metformin might be repurposed to treat patients with fragile X syndrome.

Fragile X syndrome (FXS) is the most common monogenic cause of learning disability and autism spectrum disorder. FXS is caused by loss of FMR1 expression on the X chromosome that leads to increased mRNA translation, which impairs neurological development. There presently is no cure for FXS. Gantois et al. discovered that metformin, a widely prescribed drug for type II diabetes in children and adults and which crosses the blood-brain barrier, corrected various neurological and behavioral phenotypes of FXS in a mouse model. Fmr1−/y mice have increased abundance of the kinase RAF and enhanced activity of its downstream kinases and gene targets. A chronic (10-day) treatment with metformin reduced the abundance of RAF and suppressed the activation of downstream signaling components (the kinases MEK, ERK, and mTOR) and translation initiation factor eIF4E in the prefrontal cortex and hippocampus of Fmr1−/y mice. Decreased mTOR activity correlated with decreased expression of the gene encoding MMP9, a protease that regulates synaptic function. Metformin suppressed repetitive behavior, the incidence of macroorchidism, and defects in dendritic spine development and synaptic activity in Fmr1−/y mice, phenotypes that are common in FXS patients. Although further tests are needed to assess whether metformin can specifically improve cognitive function in mammals (it does in fly models of FXS) and assess the extent of its benefits versus its side effects (there are many), the findings suggest that metformin might be repurposed for use in FXS patients.

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