Our understanding of fragile X syndrome (FXS) pathophysiology continues to improve and numerous potential drug targets have been identified. Yet, current prescribing practices are only symptom-based in order to manage difficult behaviors, as no drug to date is approved for the treatment of FXS. Drugs impacting a diversity of targets in the brain have been studied in recent FXS-specific clinical trials. While many drugs have focused on regulation of enhanced glutamatergic or deficient GABAergic neurotransmission, compounds studied have not been limited to these mechanisms. As a single-gene disorder, it was thought that FXS would have consistent drug targets that could be modulated with pharmacotherapy and lead to significant improvement. Unfortunately, despite promising results in FXS animal models, translational drug treatment development in FXS has largely failed. Future success in this field will depend on learning from past challenges to improve clinical trial design, choose appropriate outcome measures and age range choices, and find readily modulated drug targets. Even with many negative placebo-controlled study results, the field continues to move forward exploring both the new mechanistic drug approaches combined with ways to improve trial execution. This review summarizes the known phenotype and pathophysiology of FXS and past clinical trial rationale and results, and discusses current challenges facing the field and lessons from which to learn for future treatment development efforts.

To date, no drug is approved for the treatment of Fragile X Syndrome (FXS) although many drugs are used to manage challenging behaviors from a symptomatic perspective in this population. While our understanding of FXS pathophysiology is expanding, efforts to devise targeted FXS-specific treatments have had limited success in placebo-controlled trials. Compounds aimed at rectifying excessive glutamate and deficient gamma-aminobutyric acid (GABA) neurotransmission, as well as other signaling pathways known to be affected by Fragile X Mental Retardation Protein (FMRP) are under various phases of development in FXS. With the failure of several metabotropic glutamate receptor subtype 5 (mGlur5) selective antagonists under clinical investigation, no clear single treatment appears to be greatly effective. These recent challenges call into question various aspects of clinical study design in FXS. More objective outcome measures are under development and validation. Future trials will likely be aimed at correcting multiple pathways known to be disrupted by the loss of FMRP. This review offers a brief summary of the prevalence, phenotypic characteristics, genetic causes and molecular functions of FMRP in the brain (as these have been extensively reviewed elsewhere), discusses the most recent finding in FXS drug development, and summarizes FXS trials utilizing symptomatic treatment.

BackgroundFragile X Syndrome (FXS) occurs as a result of a silenced fragile X mental retardation 1 gene (FMR1) and subsequent loss of fragile X mental retardation protein (FMRP) expression. Loss of FMRP alters excitatory/inhibitory signaling balance, leading to increased neuronal hyperexcitability and altered behavior. Acamprosate (the calcium salt of N-acetylhomotaurinate), a drug FDA-approved for relapse prevention in the treatment of alcohol dependence in adults, is a novel agent with multiple mechanisms that may be beneficial for people with FXS. There are questions regarding the neuroactive effects of acamprosate and the significance of the molecule’s calcium moiety. Therefore, the electrophysiological, cellular, molecular, and behavioral effects of acamprosate were assessed in the Fmr1 -/y (knock out; KO) mouse model of FXS controlling for the calcium salt in several experiments.Methods Fmr1 KO mice and their wild-type (WT) littermates were utilized to assess acamprosate treatment on cortical UP state parameters, dendritic spine density, and seizure susceptibility. Brain extracellular-signal regulated kinase 1/2 (ERK1/2) activation was used to investigate this signaling molecule as a potential biomarker for treatment response. Additional adult mice were used to assess chronic acamprosate treatment and any potential effects of the calcium moiety using CaCl2 treatment on behavior and nuclear ERK1/2 activation.ResultsAcamprosate attenuated prolonged cortical UP state duration, decreased elevated ERK1/2 activation in brain tissue, and reduced nuclear ERK1/2 activation in the dentate gyrus in KO mice. Acamprosate treatment modified behavior in anxiety and locomotor tests in Fmr1 KO mice in which control-treated KO mice were shown to deviate from control-treated WT mice. Mice treated with CaCl2 were not different from saline-treated mice in the adult behavior battery or nuclear ERK1/2 activation.ConclusionsThese data indicate that acamprosate, and not calcium, improves function reminiscent of reduced anxiety-like behavior and hyperactivity in Fmr1 KO mice and that acamprosate attenuates select electrophysiological and molecular dysregulation that may play a role in the pathophysiology of FXS. Differences between control-treated KO and WT mice were not evident in a recognition memory test or in examination of acoustic startle response/prepulse inhibition which impeded conclusions from being made about the treatment effects of acamprosate in these instances.Electronic supplementary materialThe online version of this article (doi:10.1186/s11689-017-9184-y) contains supplementary material, which is available to authorized users.