Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Abstract

Fragile X syndrome (FXS) is an inherited neurodevelopmental disease caused by loss of function of the fragile X mental retardation protein (FMRP). In the absence of FMRP, signaling through group 1 metabotropic glutamate receptors is elevated and insensitive to stimulation, which may underlie many of the neurological and neuropsychiatric features of FXS. Treatment of FXS animal models with negative allosteric modulators of these receptors and preliminary clinical trials in human patients support the hypothesis that metabotropic glutamate receptor signaling is a valuable therapeutic target in FXS. However, recent research has also shown that FMRP may regulate diverse aspects of neuronal signaling downstream of several cell surface receptors, suggesting a possible new route to more direct disease-targeted therapies. Here, we summarize promising recent advances in basic research identifying and testing novel therapeutic strategies in FXS models, and evaluate their potential therapeutic benefits. We provide an overview of recent and ongoing clinical trials motivated by some of these findings, and discuss the challenges for both basic science and clinical applications in the continued development of effective disease mechanism-targeted therapies for FXS.

Excess Protein Synthesis in FXS Patient Lymphoblastoid Cells Can Be Rescued with a p110β-Selective Inhibitor

“…However, evidence is emerging that FMRP has a major function in regulating neurotransmitter-induced signal transduction upstream of protein synthesis, which might cause the aberrant protein synthesis observed in the absence of FMRP (1,3,4,(7)(8)(9). Pharmacological inhibition or genetic reduction of a few signal transduction pathways regulating protein synthesis, such as group 1 metabotropic glutamate receptors (mGlu 1/5 ), glycogen synthase kinase 3 (GSK3), extracellular signal regulated kinase 1/2 (ERK1/2) and phosphoinositide-3 kinase (PI3K), were shown to rescue aberrant protein synthesis and several protein synthesis-dependent phenotypes in FXS mice [reviewed in (10,11)]. Of note, treatment with two different protein synthesis inhibitors rescued cognitive impairments in a Drosophila model for FXS (12).…”

Intervention in the Context of Development: Pathways Toward New Treatments

“…A number of studies have now reported rescue of multiple phenotypes in Fmr1 knockout animals with mGlu5 receptor-negative allosteric modulator drugs with different selectivity at various points in development and with a range of treatment duration (Michalon et al, 2012). Although the mGlu5 theory of FXS has the most support from genetic and pharmacological rescue studies in mice, a number of other potential treatments have also been proposed, including GABA receptor agonists, minocycline, and lithium (Bagni and Oostra, 2013;Gross et al, 2012;Henderson et al, 2012;King and Jope, 2013). With multiple pharmacological approaches rescuing some brain or behavioral phenotypes in Fmr1 knockout animals, the overall data suggest either multiple pathways toward treatment or a lack of specificity to some of these rescued phenotypes.…”

The molecular basis of cognitive deficits in pervasive developmental disorders: Table 1.

“…In spite of our current insights into the pathophysiology of FXS, no treatment strategy has as yet attempted to rescue disease phenotypes by regulating translational control elements directly. Current therapeutic efforts are focused on manipulating cell surface receptors and signaling kinases far upstream of translation (Gross et al 2012). FMRP is a member of the RNA-binding protein family, of which mutations in another member, Fmr2 or AFF-2, causes FRAXE condition, which is one of the most common forms of nonsyndromic X-linked mental retardation (Stettner et al 2011).…”

“…FMRP mediates different aspects of RNA metabolism, including trafficking of RNP particles, translation of specific mRNA transcripts via regulation of translation initiation and elongation, and targeted degradation via the RISC complex (Jin et al 2004;Park et al 2008;Kao et al 2010;Melko and Bardoni 2010). FXS model mice, where the Fmr1 gene has been deleted, have been exhaustively studied and shown to display the "triad of deficits" features associated with PDD (Gross et al 2012). Intriguingly, most pharmacological and genetic rescue strategies have opted to evaluate hyperactivity, motor skill learning, and the seizure susceptibility of FXS model mice, with only recent reports highlighting the effect of such molecular manipulations on social interactions (Mines et al 2010;Goebel-Goody et al 2012;Rotschafer et al 2012).…”