The mGluR theory of fragile X syndrome

A key advance for understanding fragile X was the isolation of the FMR1 gene and subsequent generation of the Fmr1 knockout mouse -- a mouse that mimics the human condition as it does not express the FMR protein. Studying the Fragile X mouse provides insights into the mechanism of fragile X in humans. By studying the brain of these mice, Seaside scientific founder Mark Bear, discovered a connection between metabotropic glutamate receptor subtype 5 (mGluR5) signaling and fragile X syndrome. Specifically, the evidence suggests that most if not all of the neurological and psychiatric consequences of fragile X can be accounted for by exaggerated signaling through mGluR5 receptors.

Therefore, modulating the excessive signaling through this pathway with selective mGluR5 receptor antagonists provides a potential treatment for symptoms associated with FXS. Experiments using prototypic mGluR5 antagonists in the Fragile X knock-out mouse and fly models have demonstrated profound efficacy in both species. The profound efficacy in fragile X animals suggests that mGluR antagonists could provide significant benefits to people with fragile X syndrome, autism and other developmental disorders.

The mGluR5 hypothesis represents a unique opportunity linking genetics and the resulting molecular disruption to a specific and novel treatment. The profound ability of mGluR5 antagonists to reverse the behavioral disorders in animal models of fragile X provides compelling support for clinical testing of our candidate drug, STX107.

There is still a great deal to be learned about the molecular pathways underlying disorders of brain development and cognitive function. However, one thing is certain: FMR protein is only one of many proteins and signaling pathways regulating brain development. If we are correct that key aspects of fragile X syndrome are due to disruption of this pathway, it seems reasonable to anticipate that other disorders with similar symptoms might be traced to defects elsewhere in the same molecular pathways. It is interesting to note that other types of human developmental disorder, including autism, have many of the same core characteristics as FXS including developmental delay and cognitive impairment, increased incidence of childhood epilepsy, reduced motor coordination, anxiety, and altered gastrointestinal function. Thus, we expect the mGluR theory could have broad applicability beyond fragile X syndrome and plan to test this hypothesis in human clinical trials.

Next: Lead Drug Candidate »