Elsevier

Drug Discovery Today

Volume 19, Issue 4, April 2014, Pages 510-519
Drug Discovery Today

Review
Post-screen
Fragile X syndrome neurobiology translates into rational therapy

https://doi.org/10.1016/j.drudis.2014.01.013Get rights and content

Highlights

  • Fragile X pathophysiological mechanisms were identified in animal models.

  • Targeted treatments are being developed based on molecular defects.

  • The first clinical trials in fragile X patients have been initiated.

Causal genetic defects have been identified for various neurodevelopmental disorders. A key example in this respect is fragile X syndrome, one of the most frequent genetic causes of intellectual disability and autism. Since the discovery of the causal gene, insights into the underlying pathophysiological mechanisms have increased exponentially. Over the past years, defects were discovered in pathways that are potentially amendable by pharmacological treatment. These findings have inspired the initiation of clinical trials in patients. The targeted pathways converge in part with those of related neurodevelopmental disorders raising hopes that the treatments developed for this specific disorder might be more broadly applicable.

Introduction

The identification of FMR1 as the gene causing fragile X syndrome raised hope for the treatment of patients [1]. The most frequent mutation is a dynamic mutation of a polymorphic CGG repeat in the 5′ untranslated region of the FMR1 gene. Expansion beyond a threshold of 200 repeats results in hypermethylation of the repeat and surrounding promoter region. The associated transcriptional silencing leads to absence of the encoded fragile X mental retardation protein (FMRP). Since the discovery of the causal gene, numerous research groups have tried to unravel the function of FMRP. It is an RNA-binding protein that fulfils a multitude of functions within the cell, including regulation of transport and translation of RNA targets, reviewed in [2].

Animal models have been developed to increase our understanding of the molecular pathophysiology of the syndrome, reviewed in 3, 4, 5. The Fmr1 knockout mouse has been extensively characterised and displays phenotypes that are compatible with the symptoms of fragile X patients (Table 1) [6]. Studies in the >Fmr1 knockout mouse have revealed the involvement of various neurotransmitter receptors and several intracellular signalling pathways in fragile X pathophysiology. These findings were crucial for the identification of therapeutic targets and have led to the first clinical trials in patients. Fragile X syndrome is thus a prime example of how fundamental insights into pathophysiological mechanisms can be translated into clinical practice. In this review, we summarise the different targets for treatment that have been identified in animal models as well as the clinical trials in fragile X patients.

Section snippets

FMRP loss of function disturbs a wide spectrum of neuronal functions

FMRP is ubiquitously expressed, most abundantly in brain and testes, which is reflected in the fragile X phenotype (Table 1) 7, 8. In neurons, the majority of FMRP is located in the cytoplasm, including in the cell body, dendrites and axons 8, 9. FMRP has three RNA-binding domains, including two K homology domains (KH1 and KH2) and an arginine-glycine-glycine (RGG) box, and binds a subset of neuronal mRNAs. High-throughput sequencing of RNAs isolated by crosslinking immunoprecipitation

Clinical trials

Some of the therapeutic strategies identified in animal models have already led to clinical trials in fragile X patients. Open-label and double-blind, placebo-controlled trials were reported. Because a strong placebo effect can be anticipated in clinical trials, we will only mention the latter category. The efficacy of the mGluR5 NAM AFQ056/Mavoglurant (Novartis) was evaluated in a Phase II clinical trial in adult males with fragile X syndrome (n = 30, age 18–35 years) [87]. The observation that

Challenges for translation of therapy

It is encouraging that a subset of the pathways that are disturbed by absence of FMRP in fragile X syndrome are potentially amendable to treatment. Neurotransmitter receptors and several intracellular signalling pathways are among the most promising targets (reflected in Fig. 1 and Table 2). Preclinical studies in animal models showed encouraging results as summarised in Table 2. Multiple aspects of the Fmr1 knockout mouse phenotype were corrected after treatment with selected drugs. Although

Concluding remarks

Interference with molecular pathways disturbed in fragile X syndrome has led to the initiation of clinical trials. Whereas the results of Phase III clinical trials are eagerly awaited, the results of the Phase II studies showed encouraging results in a way that some behavioural aspects of the phenotype were significantly improved in at least a subset of patients. Thus fragile X syndrome has become the prototype of a neurodevelopmental disorder for which targeted treatment could become a reality.

Acknowledgements

Our research on fragile X syndrome is funded by grants from FRAXA, FWO (Fonds Wetenschappelijk Onderzoek) and Fondation Jérôme Lejeune to R.F.K. and a PhD grant from the Agency for Innovation by Science and Technology (IWT) to S.B.

Glossary

2-AG
2-arachidonoyl-sn-glycerol
5-HT
serotonin
ABC-C
Aberrant Behaviour Checklist–community edition
ABC-I
Aberrant Behaviour Checklist–irritability
ABC-SA
Aberrant Behaviour Checklist–social avoidance
AMPA-R
α-amino-3-hydroxyl-4-isoxazole propionic acid receptors
APP
amyloid precursor protein
CGI-I
Clinician's Global Impression-Improvement
CNS
Central nervous system
DGL-α
diacylglycerol lipase-α
dnPAK
dominant negative p21-activated kinase
eCB
endocannabinoid
ERK
extracellular signal related kinase
FMRP
fragile X mental

References (101)

  • C.T. Chiu et al.

    Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders

    Pharmacol. Ther.

    (2010)
  • W.W. Min

    Elevated glycogen synthase kinase-3 activity in Fragile X mice: key metabolic regulator with evidence for treatment potential

    Neuropharmacology

    (2009)
  • C.J. Yuskaitis

    Lithium ameliorates altered glycogen synthase kinase-3 and behavior in a mouse model of fragile X syndrome

    Biochem. Pharmacol.

    (2010)
  • A.V. Franklin

    Glycogen synthase kinase-3 inhibitors reverse deficits in long-term potentiation and cognition in fragile X mice

    Biol. Psychiatry

    (2014)
  • L. Hou

    Dynamic translational and proteasomal regulation of fragile X mental retardation protein controls mGluR-dependent long-term depression

    Neuron

    (2006)
  • E.K. Osterweil

    Lovastatin corrects excess protein synthesis and prevents epileptogenesis in a mouse model of fragile X syndrome

    Neuron

    (2013)
  • A. Bhattacharya

    Genetic removal of p70 S6 kinase 1 corrects molecular, synaptic, and behavioral phenotypes in fragile X syndrome mice

    Neuron

    (2012)
  • L. Costa

    Activation of 5-HT7 serotonin receptors reverses metabotropic glutamate receptor-mediated synaptic plasticity in wild-type and Fmr1 knockout mice, a model of Fragile X syndrome

    Biol. Psychiatry

    (2012)
  • C. D’Hulst

    The complexity of the GABA(A) receptor shapes unique pharmacological profiles

    Drug Discov. Today

    (2009)
  • C. D’Hulst et al.

    The GABA(A) receptor: a novel target for treatment of fragile X?

    Trends Neurosci.

    (2007)
  • I. Heulens

    Pharmacological treatment of fragile X syndrome with GABAergic drugs in a knockout mouse model

    Behav. Brain Res.

    (2012)
  • L.K. Pacey

    Genetic deletion of regulator of G-protein signaling 4 (RGS4) rescues a subset of fragile X related phenotypes in the FMR1 knockout mouse

    Mol. Cell Neurosci.

    (2011)
  • D.C. Adusei

    Early developmental alterations in GABAergic protein expression in Fragile X knockout mice

    Neuropharmacology

    (2010)
  • H.J. Carlisle et al.

    Spine architecture and synaptic plasticity

    Trends Neurosci.

    (2005)
  • M.L. Hayashi

    Altered cortical synaptic morphology and impaired memory consolidation in forebrain-specific dominant-negative PAK transgenic mice

    Neuron

    (2004)
  • S. Veeraragavan

    Genetic reduction of muscarinic M4 receptor modulates analgesic response and acoustic startle response in a mouse model of fragile X syndrome (FXS)

    Behav. Brain Res.

    (2012)
  • S.E. Rotschafer

    Minocycline treatment reverses ultrasonic vocalization production deficit in a mouse model of Fragile X syndrome

    Brain Res.

    (2012)
  • L.E. Dansie

    Long-lasting effects of minocycline on behavior in young but not adult Fragile X mice

    Neuroscience

    (2013)
  • Z.H. Liu et al.

    Dissociation of social and nonsocial anxiety in a mouse model of fragile X syndrome

    Neurosci Lett

    (2009)
  • L. Chen et al.

    Fragile X mice develop sensory hyperreactivity to auditory stimuli

    Neuroscience

    (2001)
  • D.M. Nielsen

    Alterations in the auditory startle response in Fmr1 targeted mutant mouse models of fragile X syndrome

    Brain Res

    (2002)
  • M.R. Santoro

    Molecular mechanisms of fragile X syndrome: a twenty-year perspective

    Annu. Rev. Pathol.

    (2012)
  • S.M. McBride

    Using Drosophila as a tool to identify pharmacological therapies for fragile X syndrome

    Drug Discov. Today: Technol.

    (2012)
  • M.C. Ng

    Behavioral and synaptic circuit features in a zebrafish model of fragile X syndrome

    PLoS One

    (2013)
  • I. Heulens et al.

    Fragile X syndrome: from gene discovery to therapy

    Front. Biosci.

    (2011)
  • C.E. Bakker

    Fmr1 knockout mice: a model to study fragile X mental retardation

    Cell

    (1994)
  • H.L. Hinds

    Tissue specific expression of FMR-1 provides evidence for a functional role in fragile X syndrome

    Nat. Genet.

    (1993)
  • D. Devys

    The FMR-1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers of a fragile X premutation

    Nat. Genet.

    (1993)
  • S.B. Christie

    The FXG: a presynaptic fragile X granule expressed in a subset of developing brain circuits

    J. Neurosci.

    (2009)
  • D.E. Eberhart

    The fragile X mental retardation protein is a ribonucleoprotein containing both nuclear localization and nuclear export signals

    Hum. Mol. Genet.

    (1996)
  • K.M. Huber

    Altered synaptic plasticity in a mouse model of fragile X mental retardation

    Proc. Natl. Acad. Sci. U. S. A.

    (2002)
  • M. Qin

    Postadolescent changes in regional cerebral protein synthesis: an in vivo study in the FMR1 null mouse

    J. Neurosci.

    (2005)
  • S.A. Hays

    Altered neocortical rhythmic activity states in Fmr1 KO mice are due to enhanced mGluR5 signaling and involve changes in excitatory circuitry

    J. Neurosci.

    (2011)
  • D.D. Krueger et al.

    Toward fulfilling the promise of molecular medicine in fragile X syndrome

    Annu. Rev. Med.

    (2011)
  • D.M. O’Leary

    Selective mGluR5 antagonists MPEP and SIB-1893 decrease NMDA or glutamate-mediated neuronal toxicity through actions that reflect NMDA receptor antagonism

    Br. J. Pharmacol.

    (2000)
  • M.F. Vinueza Veloz

    The effect of an mGluR5 inhibitor on procedural memory and avoidance discrimination impairments in Fmr1 KO mice

    Genes Brain Behav.

    (2012)
  • A.S. Pop

    Rescue of dendritic spine phenotype in Fmr1 KO mice with the mGluR5 antagonist AFQ056/Mavoglurant

    Psychopharmacology (Berl.)

    (2012)
  • A.M. Thomas

    Group I metabotropic glutamate receptor antagonists alter select behaviors in a mouse model for fragile X syndrome

    Psychopharmacology (Berl.)

    (2012)
  • C. Gross

    Excess phosphoinositide 3-kinase subunit synthesis and activity as a novel therapeutic target in fragile X syndrome

    J. Neurosci.

    (2010)
  • M.A. Mines et al.

    Glycogen synthase kinase-3: a promising therapeutic target for fragile x syndrome

    Front. Mol. Neurosci.

    (2011)
  • Cited by (31)

    • GABAergic abnormalities in the fragile X syndrome

      2020, European Journal of Paediatric Neurology
    • Modelling fragile X syndrome in the laboratory setting: A behavioral perspective

      2018, Behavioural Brain Research
      Citation Excerpt :

      A number of mGluR5 antagonists have been tested [221,222]. However, clinical trials were discontinued because the mGluR5 antagonists tested were either not effective or they were showing side effects [221–223]. Another pharmacological approach that has been investigated is based on the correction of the GABA/glutamate imbalance observed in FXS by modifying ionotropic glutamate receptor activity.

    • The GABAergic system contributions to the fragile X syndrome phenotype

      2017, Fragile X Syndrome: From Genetics to Targeted Treatment
    • Impaired GABAergic inhibition in the hippocampus of Fmr1 knockout mice

      2017, Neuropharmacology
      Citation Excerpt :

      FMRP is an RNA binding protein that interacts with many neuronal mRNAs and is thought to be involved in the regulation of mRNA transport, translation and stability (Bassell and Warren, 2008; De Rubeis and Bagni, 2010). Studies in animal models of fragile X syndrome have proven to be essential for unraveling the molecular mechanisms underlying the disease and led to the identification of potential therapeutic targets (Bagni et al., 2012; Braat and Kooy, 2014; Darnell and Klann, 2013; Heulens and Kooy, 2011; Wijetunge et al., 2012). Exaggerated group 1 metabotropic glutamate receptor (mGluR) signaling (Bear et al., 2004) in parallel with impaired GABAergic signaling (Braat and Kooy, 2015a,b) are among the targets identified, suggesting the clinical consequences of the absence of FMRP are at least in part due to a disturbance of the inhibition/excitation balance (Contractor et al., 2015).

    View all citing articles on Scopus
    View full text