ReviewPost-screenFragile X syndrome neurobiology translates into rational therapy
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
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Cited by (31)
GABAergic abnormalities in the fragile X syndrome
2020, European Journal of Paediatric NeurologyModelling fragile X syndrome in the laboratory setting: A behavioral perspective
2018, Behavioural Brain ResearchCitation 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 TreatmentImpaired GABAergic inhibition in the hippocampus of Fmr1 knockout mice
2017, NeuropharmacologyCitation 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).