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Curr Opin Pharmacol. 2015 Feb;20:124-34. doi: 10.1016/j.coph.2014.11.004. Epub 2014 Dec 2.

Metabotropic glutamate receptor 5 as drug target for Fragile X syndrome.

Author information

1
Roche Pharmaceutical Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.
2
Roche Pharmaceutical Research and Early Development, Small Molecules Research, Discovery Chemistry, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.
3
Roche Pharmaceutical Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland. Electronic address: lothar.lindemann@roche.com.

Abstract

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.

PMID:
25488569
DOI:
10.1016/j.coph.2014.11.004
[Indexed for MEDLINE]

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