Neurobehavioral features and targeted treatments in fragile X syndrome: Current insights and future directions

Abstract

SummaryFragile X syndrome (FXS) is the leading known monogenetic cause of autism spectrum disorder (ASD) and inherited form of intellectual disability (ID). As the major and growing public health problem worldwide, ASD is purely behaviorally defined whereas FXS is a medical/genetic disorder characterized by ID and ASD in males and learning and behavioral/emotional problems (social anxiety, attention network) in both genders. FXS is caused by a mutation in the Fragile X Mental Retardation 1 gene (FMR1) that leads to the epigenetic silencing of the gene and absence of its encoded protein, the fragile X mental retardation protein (FMRP). FMRP selectively targets approximately 4% of the transcribed mRNAs in the brain. Namely, to date, 842 such target mRNAs in mammalian brains have been identified and many of them converge on the same pathway as nonsyndromic ASD. Thus, FXS is the most studied 'disorder of synapse' model for syndromic ASD in the field of neuroscience. There are currently no effective treatments for either FXS or ASD.In this review article, we discuss recent progress and future directions in translating breakthrough preclinical findings that reveal potential therapeutic targets into clinical trials for humans with FXS of potential relevance for ASD. To date, a total of 20 double-blinded, randomized, placebo-controlled clinical trials in FXS have been identified through the FDA ClinicalTrial.gov website. The majority of these trials were completed between 2008−2015. These mostly phase II trials in adults and adolescents tested 13 compounds and have primarily targeted excitatory/inhibitory imbalance theory of FXS and ASD, namely a reversal of social/behavioral symptoms that are part of the core FXS phenotype but not the core synaptic dysfunction in FXS. Despite much progress in the field propelled by the preclinical advances, these clinical studies illustrate the gaps and challenges of translating therapies from animal models to humans with FXS and ASD ('building a bridge and walking on it'). Specifically, recent challenges in the clinical trials demonstrate the need to study for longer period of time (6−12 months), prepubertal age group(s), develop more objective clinical outcome measures (i.e., clinician-based, relevant learning paradigms, and desired biomarkers), and longer placebo run-ins to minimize the placebo impact for both FXS and ASD. Ultimately, a truly satisfactory FXS, and ASD, therapy may likely involve a combination of drugs (and learning paradigms), each targeting a different aspect of the core synaptic, cognitive and behavioral impairments in FXS.

Drugs development and fragile X syndrome translational success story

“…In fact, pre-clinical study breakthroughs have enabled clinical trials in humans with FXS more than with any other neurodevelopmental disorder, including the wide range of ASD. This is demonstrated in a multitude of advanced clinical trials whose aim is to introduce the drugs that can modify the core neurocognitive problems in FXS and possibly in ASD [15,16,57,58]. FXS has well characterized genetics, there is advanced neurobiological knowledge about it, and an animal model is available.…”

“…These advances, in conjunction with increasing work on psychopharmacology of preclinical breakthroughs such as arbaclofen, an GABA-B agonist, and mavoglurant (AFQ056), mGluR5 antagonist [52][53][54], has propelled this global neurodehvelopmental disorder into the most translated among all neurodevelopmental disorders. Indeed, more than two dozen randomized, double-blind, placebo-controlled trials to target the core excitatory/inhibitory imbalance and other manifestations of FXS have been conducted in the past decade [57,58]. Specifically, to date, a total of 22 conetrolled studies have been identified through a search of the literature and other sources; 19/22 (86%) have been registered on the National Institute of Health (NIH) www.ClinicalTrials.gov website as required by the Food and Drug Administration (FDA) Act of 2007 [57,58].…”

“…Indeed, more than two dozen randomized, double-blind, placebo-controlled trials to target the core excitatory/inhibitory imbalance and other manifestations of FXS have been conducted in the past decade [57,58]. Specifically, to date, a total of 22 conetrolled studies have been identified through a search of the literature and other sources; 19/22 (86%) have been registered on the National Institute of Health (NIH) www.ClinicalTrials.gov website as required by the Food and Drug Administration (FDA) Act of 2007 [57,58]. As expected from FXS neurobiology, the vast majority of these studies have targeted the core excitatory/inhibitory imbalance in the disorder, primarily through either mGluR 5 antagonists [(six studies on mavoglurant (AFQ056), basimglurant (RO4917523)] or gamma-aminobutyrics acid (GABA) agOonists (three studies on arbaclofen, an agonist of GABA-B, and one study on ganaxolone, a GABA-A modulator), respectively.…”

“…Indeed, there is a need to sort out response variability with biomarkers both to identify potential responders and to establish target engagement. Failed trials should also serve as 'lesasons learned' when planning clinical trials in this area [57,58]. Considering the progress of the studies in this field of medicine and their results, it is necessary to validate the available tools that measure outcomes in cognitive, language, and behavioral biomarkers in FXS patients as well as in individuals with ASD [59,67].…”

Fragile X syndrome: Lessons learned from the most translated neurodevelopmental disorder in clinical trials

“…These preclinical breakthroughs have generated much interest by the field to translate into humans with FXS, and possibly ASD. Indeed, a January 2016 search of the US Food and Drug Administration (FDA) and National Institute of Health (NIH) www.clinicaltrials.gov website and the scientific literature revealed 22 doubleblind, placebo-controlled clinical trials in humans with FXS, mostly from 2008 to 2015 [9]. Reflecting the key preclinical findings, the vast majority of the clinical trial studies targeted the aforementioned excitatory/inhibitory imbalances (14/22, 64%) [9].…”