Metabotropic glutamate receptor 5 as drug target for Fragile X syndrome
2015
Fragile X syndrome(FXS) is the most common
monogenicform of inherited mental retardation caused by a
trinucleotid repeat expansionand transcriptional
shutdownof the
FMR1gene. 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
FragileX 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.
Keywords:
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