Phase II and III drugs for the treatment of fragile X syndrome

Abstract

Introduction: Fragile X syndrome (FXS), the most common inherited form of intellectual disability and autism, is caused by expansion of CGG trinucleotide repeats in FMR1 and marked reduction or absence of the gene product, FMRP. FMRP suppresses synaptic protein synthesis resulting from group 1 metabotropic glutamate receptor (mGluR) activation, a process critical to normal synaptic plasticity. FXS can be characterized as a disorder of synaptic plasticity with physical, cognitive and behavioral manifestations attributable to, at least in part, excessive mGluR activity and downstream effects.

Areas covered: This paper reviews the ‘mGluR theory' of FXS and the targeted drugs investigated in Phase II and III trials based on this theory of pathogenesis. A literature review was conducted using the PubMed database with search terms ‘fragile X syndrome', ‘mGluRs', ‘pharmacotherapy' and specific drug-related terms. Other resources were identified by review of relevant reference lists and consultation with experts in the field.

Expert opinion: While preclinical trials of targeted drugs in animal models of FXS have been encouraging, more studies are needed to determine clinical efficacy in humans. Challenges to clinical trial design and direction for future drug studies, including consideration of NMDA receptor partial agonists and mGluR2/3 agonists, are discussed.

Keywords::

• autism
• FMRP
• fragile X syndrome
• GABA
• GABA receptor agonists
• glutamate
• group 1 metabotropic glutamate receptors
• intellectual disability
• mGluR2/3 agonists
• mGluR5 antagonists
• NMDAR partial agonists
• oxytocin
• synaptic plasticity

Acknowledgments

The authors would like to thank Ben Kelmendi, MD, of Yale University Department of Psychiatry, for graciously designing the illustration in this manuscript.

Notes

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