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

Details

• Alternative Title:
  Curr Pharm Des
• Personal Author:
  Lozano, Reymundo ; Martinez-Cerdeno, Veronica ; Hagerman, Randi J.
• Description:
  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.
• Subjects:
  Alleles Animals Article ASD Treatments Autism Clinical Trials Clinical Trials As Topic Drug Design Fragile X-associated Tremor Ataxia Syndrome Fragile X Mental Retardation Protein Fragile X Spectrum Disorder Fragile X Syndrome FXS FXSD FXTAS GABA GABAA GABA Agonists GABA System Gamma-Aminobutyric Acid Humans Molecular Targeted Therapy Targeted Treatments

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• Source:
  Curr Pharm Des. 21(34):4972-4979
• Pubmed ID:
  26365141
• Pubmed Central ID:
  PMC4830341
• Document Type:
  Journal Article
• Funding:
  90DD0596/DD/NCBDD CDC HHSUnited States/ ; R01 MH094681/MH/NIMH NIH HHSUnited States/ ; GM082773/GM/NIGMS NIH HHSUnited States/ ; U50 DD000596/DD/NCBDD CDC HHSUnited States/ ; HD036071/HD/NICHD NIH HHSUnited States/ ; R01 HD036071/HD/NICHD NIH HHSUnited States/ ; T32 GM082773/GM/NIGMS NIH HHSUnited States/
• Volume:
  21
• Issue:
  34
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:f631ae7377cac6b81a3649344ed62c84cc5d843050c404ba132347e27e4379b9
• Download URL:
  https://stacks.cdc.gov/view/cdc/38936/cdc_38936_DS1.pdf
• File Type:
  [PDF - 88.54 KB ]