title: 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.
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, NY USA; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY USA.
authors.forename: Reymundo
authors.initials: R
authors.lastname: Lozano
authors.affiliation: Medical Investigation of Neurodevelopmental Disorders MIND Institute, UC Davis, CA, USA; Institute for Pediatric Regenerative Medicine and Shriners Hospital for Children of Northern California, Sacramento, CA, USA; Department of Pathology and Laboratory Medicine, UC Davis, Sacramento, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Martinez-Cerdeno
authors.affiliation: Medical Investigation of Neurodevelopmental Disorders MIND Institute, UC Davis, CA, USA; Department of Pediatrics, UC Davis, Sacramento, CA, USA.
authors.forename: Randi J
authors.initials: RJ
authors.lastname: Hagerman
mesh_terms: D000483:Alleles; D000818:Animals; D002986:Clinical Trials as Topic / Q000379:methods; D015195:Drug Design; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D018755:GABA Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D058990:Molecular Targeted Therapy; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D018755:GABA Agonists; D005680:gamma-Aminobutyric Acid; C497683:FMR1 protein, human