Metabotropic glutamate receptor 5 as drug target for Fragile X syndrome

• FXS is a single gene CGG-repeat disorder with a complex neuropsychiatric phenotype. Currently, there are no drugs approved for the treatment of FXS.
• The mGluR theory of FXS proposes therapeutic benefits of mGlu5 inhibitors.
• In Fmr1 KO mice, mGlu5 inhibitors can correct a broad range of disease phenotypes.
• FXS clinical trials with basimglurant and mavoglurant did not report efficacy.

Fragile X syndrome (FXS) is the most common monogenic form of inherited mental retardation caused by a trinucleotid repeat expansion and transcriptional shutdown of the FMR1 gene. FXS patients present a complex and often severe neuropsychiatric phenotype yet have mild somatic symptoms, normal life expectancies, and no indications of neurodegeneration. The therapeutic potential of mGlu5 inhibitors was proposed in the ‘mGluR theory of FXS’ based on early insights into the molecular pathophysiology of FXS. Studies in Fragile X mental retardation 1 (Fmr1) knock-out mice, a widely used disease model, demonstrated that mGlu5 inhibitors can correct a broad range of disease-related phenotypes. Recent clinical trials, however, with two different mGlu5 inhibitors (basimglurant and mavoglurant) showed no therapeutic benefit in FXS patients for reasons as yet unclear.

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