Research ArticleFragile X Syndrome

Effects of STX209 (Arbaclofen) on Neurobehavioral Function in Children and Adults with Fragile X Syndrome: A Randomized, Controlled, Phase 2 Trial

Science Translational Medicine  19 Sep 2012:
Vol. 4, Issue 152, pp. 152ra127
DOI: 10.1126/scitranslmed.3004214

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A Fragile Balancing Act

A wide array of symptoms—including intellectual disability, anxiety, seizures, and autistic behavior—are associated with fragile X syndrome (FXS). Although some symptoms can be managed (or masked) with drugs or other therapies, treatments that target the fundamental impairments are not available. Henderson et al. and Berry-Kravis et al. now provide evidence that activation of a particular neuronal receptor can improve symptoms in both mice and humans.

FXS is caused by silencing of the FMR1 gene, which encodes FMRP, an RNA binding protein that inhibits protein synthesis. In a mouse model of FXS, dendritic protein synthesis is abnormally high; FMRP is believed to regulate mRNAs important for neuronal development. Furthermore, these mice—and some humans with FXS—have an increased density of dendritic spines, which are dynamic structures that make neuronal connections. Dendritic spine plasticity is linked to learning and memory. Normally, FMRP may balance mRNA translation that is stimulated by activation of synaptic receptors that respond to glutamate, an excitatory neurotransmitter. Indeed, inhibitors of these receptors rescue many irregular phenotypes in the animal models but are not yet approved for human use. These mice also exhibit deficient signaling through a different set of receptors, which respond to the inhibitory neurotransmitter GABA—and for which clinically approved agonists already exist. Henderson et al. tested one such GABAB receptor agonist, STX209, in the mouse model and found that it decreased mRNA translation in the cortex and corrected the increased dendritic spine density. Berry-Kravis et al. studied the effects of STX209 in a double-blind, placebo-controlled crossover trial, in which 63 FXS patients received placebo or drug for 4 weeks and then switched to the other treatment. Although a measure of irritability and aggression was unchanged, social avoidance improved; the drug was well tolerated. Thus, this targeted approach, which may help restore the balance between excitatory and inhibitory neurotransmission, has promise for improving social function in FXS.