Advances in the Understanding of the Gabaergic Neurobiology of FMR1 Expanded Alleles Leading to Targeted Treatments for Fragile X Spectrum Disorder

Abstract

Fragile X spectrum disorder (FXSD) includes: fragile X syndrome (FXS), fragile X-associated tremor ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI), as well as other medical, psychiatric and neurobehavioral problems associated with the premutation and gray zone alleles. FXS is the most common monogenetic cause of autism (ASD) and intellectual disability (ID). The understanding of the neurobiology of FXS has led to many targeted-treatment trials in FXS. The first wave of phase II clinical trials in FXS were designed to target the mGluR5 pathway; however the results did not show significant efficacy and the trials were terminated. The advances in the understanding of the GABA system in FXS have shifted the focus of treatment trials to GABA agonists, and a new wave of promising clinical trials is under way. Ganaxolone and allopregnanolone (GABA agonists) have been studied in individuals with FXSD and are currently in phase II trials. Both allopregnanolone and ganaxolone may be efficacious in treatment of FXS and FXTAS, respectively. Allopregnanolone, ganaxolone, riluzole, gaboxadol, tiagabine, and vigabatrin are potential GABAergic treatments. The lessons learned from the initial trials have not only shifted the targeted system, but also have refined the design of clinical trials. The results of these new trials will likely impact further clinical trials for FXS and other genetic disorders associated with ASD.

Fragile X-Associated Tremor/Ataxia Syndrome: From Molecular Pathogenesis to Development of Therapeutics

“…Allopregnanolone exhibits effective rescue in Alzheimer’s disease mouse models and human cells, such as restoring learning and memory, in addition to improving neuronal proliferation and survival (Wang et al, 2010; Chen et al, 2011; Singh et al, 2012). Allopregnanolone is already in use in Alzheimer’s disease and traumatic brain injury clinical trials, making it a very likely treatment choice for FXTAS (Lozano et al, 2015). …”

Body fluid levels of neuroactive amino acids in autism spectrum disorders: a review of the literature

“…Therefore, many researchers have been trying to establish quantitative diagnostic criteria that could contribute to an early and more accurate ASD diagnosis. Many interacting factors are probably contributing to the etiology of ASD, and these potential factors are described in several excellent review articles (Lam et al 2006; Pardo and Eberhart 2007; Aoki et al 2012; Parellada et al 2014; Lozano et al 2015; Rozas et al 2015; Subramanian et al 2015; Zhang et al 2015; Martin et al 2016; Muller et al 2016; Park et al 2016); this review focuses on amino acids.…”

“…Several preclinical and clinical studies have implicated neuroactive amino acids in the etiology of ASD, fragile X syndrome, and tuberous sclerosis complex (TSC), but most of these studies have focused on glutamate, GABA, and/or glutamine (El-Ansary and Al-Ayadhi 2014; Rojas 2014; Santini et al 2014; Rozas et al 2015; Cochran et al 2015; Lozano et al 2015; Robertson et al 2016). Other amino acids could also be involved and it may be important to conduct comprehensive studies in which a number of these amino acids are investigated simultaneously.…”

Development of Genetic Testing for Fragile X Syndrome and Associated Disorders, and Estimates of the Prevalence of FMR1 Expansion Mutations

“…Trials of drugs that target mGluR5 showed initial promise in model systems but clinical trials were abandoned due to lack of efficacy. Knockout mouse models exhibit downregulation of the gamma-aminobutyric acid (GABA) system and thus GABA agonists are the focus of current clinical trials [57]. Reactivation of the methylated FMR1 gene with the demethylating agent 5-azadeoxycytidine is being tested in in vitro models and may provide a potential therapeutic approach [58].…”