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Fragile X syndrome: a preclinical review on metabotropic glutamate receptor 5 (mGluR5) antagonists and drug development

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Abstract

Rationale

Fragile X syndrome (FXS) is considered the leading inherited cause of intellectual disability and autism. In FXS, the fragile X mental retardation 1 (FMR1) gene is silenced and the fragile X mental retardation protein (FMRP) is not expressed, resulting in the characteristic features of the syndrome. Despite recent advances in understanding the pathophysiology of FXS, there is still no cure for this condition; current treatment is symptomatic. Preclinical research is essential in the development of potential therapeutic agents.

Objectives

This review provides an overview of the preclinical evidence supporting metabotropic glutamate receptor 5 (mGluR5) antagonists as therapeutic agents for FXS.

Results

According to the mGluR theory of FXS, the absence of FMRP leads to enhanced glutamatergic signaling via mGluR5, which leads to increased protein synthesis and defects in synaptic plasticity including enhanced long-term depression. As such, efforts to develop agents that target the underlying pathophysiology of FXS have focused on mGluR5 modulation. Animal models, particularly the Fmr1 knockout mouse model, have become invaluable in exploring therapeutic approaches on an electrophysiological, behavioral, biochemical, and neuroanatomical level. Two direct approaches are currently being investigated for FXS treatment: reactivating the FMR1 gene and compensating for the lack of FMRP. The latter approach has yielded promising results, with mGluR5 antagonists showing efficacy in clinical trials.

Conclusions

Targeting mGluR5 is a valid approach for the development of therapeutic agents that target the underlying pathophysiology of FXS. Several compounds are currently in development, with encouraging results.

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Financial disclosures and acknowledgments

FG and BGM are employees of Novartis Pharma AG and hold shares with Novartis Pharma AG. FG and BGM have also received reimbursement from Novartis Pharma AG for travel expenses. GN received honoraria and compensation from Novartis for providing biological samples as part of a collaborative project. This work was supported by The Netherlands Organisation for Health Research and Development (ZonMw) 912-07-022 (AP and RW), E-Rare program entitled “Cure FXS” (no. EU/FIS PS09102673) (RW), FRAXA Research Foundation (RW and GN), Telethon (GGP10150) (GN) and Associazione Italiana Sindrome X Fragile (GN). Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. We thank Emma Burke, of iMed Comms, who provided medical writing assistance with this review. The authors have full control of all primary data and agree to allow Psychopharmacology to review the data if requested.

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Authors and Affiliations

  1. Department of Clinical Genetics, Erasmus Medical Center, Room Ee 971a, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands

    Andreea S. Pop & Rob Willemsen

  2. Novartis Pharma AG, Novartis Institutes for BioMedical Research Basel, Postfach, 4002, Basel, Switzerland

    Baltazar Gomez-Mancilla & Fabrizio Gasparini

  3. Institute of Medical Genetics, Catholic University School of Medicine, Largo F. Vito 1, Rome, 00168, Italy

    Giovanni Neri

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  1. Andreea S. Pop
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  2. Baltazar Gomez-Mancilla
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  3. Giovanni Neri
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  4. Rob Willemsen
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  5. Fabrizio Gasparini
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Correspondence to Rob Willemsen or Fabrizio Gasparini.

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Pop, A.S., Gomez-Mancilla, B., Neri, G. et al. Fragile X syndrome: a preclinical review on metabotropic glutamate receptor 5 (mGluR5) antagonists and drug development. Psychopharmacology 231, 1217–1226 (2014). https://doi.org/10.1007/s00213-013-3330-3

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  • DOI: https://doi.org/10.1007/s00213-013-3330-3

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