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Metabotropic glutamate receptor 5 as drug target for Fragile X syndrome

Sebastian H Scharf1, Georg Jaeschke2, Joseph G Wettstein1

  • 1Roche Pharmaceutical Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.

Current Opinion in Pharmacology
|December 10, 2014
PubMed

Insights

Fragile X syndrome (FXS) treatments targeting mGluR5 showed promise in mouse models but failed in human clinical trials. Further research is needed to understand why these mGlu5 inhibitors were ineffective in FXS patients.

Area of Science:

  • Neurogenetics
  • Molecular Medicine
  • Pharmacology

Background:

  • Fragile X syndrome (FXS) is a genetic disorder causing intellectual disability, linked to FMR1 gene silencing.
  • FXS patients exhibit significant neuropsychiatric symptoms but lack neurodegeneration.
  • The 'mGluR theory of FXS' suggested mGlu5 inhibitors as a potential therapy.

Purpose of the Study:

  • To evaluate the therapeutic efficacy of mGlu5 inhibitors in treating Fragile X syndrome.
  • To investigate the 'mGluR theory of FXS' in a clinical setting.

Main Methods:

  • Preclinical studies utilized Fmr1 knock-out mice to test mGlu5 inhibitors.
  • Clinical trials were conducted using basimglurant and mavoglurant in FXS patients.

Main Results:

  • mGlu5 inhibitors successfully corrected various disease phenotypes in Fmr1 knock-out mice.
  • Clinical trials with basimglurant and mavoglurant demonstrated no significant therapeutic benefit in FXS patients.

Conclusions:

  • Despite promising preclinical data, mGlu5 inhibitors were not effective for treating Fragile X syndrome in humans.
  • The reasons for the discrepancy between mouse model and human trial outcomes remain unclear and warrant further investigation.

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