Gaboxadol Normalizes Behavioral Abnormalities in a Mouse Model of Fragile X Syndrome (P1.323)

Objective: Fragile X syndrome (FXS), is the most common form of inherited intellectual disability, is characterized by autism-like features that include anxiety, irritability, aggression, hyperactivity, and abnormal restricted and repetitive behaviors.

Background: FXS is caused by mutations that disrupt expression of the FMR1 gene that codes for FMRP, a multifunctional RNA binding protein. Published studies in FXS mouse models point to deficits in extrasynaptic GABA_A mediated tonic inhibition.

Design/Methods: Described here are the results of efforts aimed at characterizing the effects of Gaboxadol (aka THIP and OV101), a brain penetrant small molecule specific for delta subunit containing extrasynaptic GABA_A receptors (dSEGAs), on behavioral endpoints that are abnormal in Fmr1^−/y mice and readily translatable to clinical evaluation in patients.

Results: Acute administration of 0.5 mg/kg Gaboxadol (GBX) to Fmr1 KO2 mice fully normalized behavioral abnormalities relevant to hyperactivity (distance in open field; p<0.0001 for WT-Veh vs. Mut-Veh and p>0.05 for WT-Veh vs. Mut-GBX), anxiety (center distance in open field, number light dark transitions, entries in successive alley test; p<0.0001 for WT-Veh vs. Mut-Veh and p>0.05 for WT-Veh vs. Mut-GBX for all tests), irritability/aggression (number of tail rattles, number of bites, latency to attack; p<0.0001 for WT-Veh vs. Mut-Veh and p>0.05 for WT-Veh vs. Mut-GBX for all tests), and restricted and repetitive behaviors (counterclockwise revolutions, time grooming, stereotypy count; p<0.0001 for WT-Veh vs. Mut-Veh and p>0.05 for WT-Veh vs. Mut-GBX for all tests).

Conclusions: Results support clinical evaluation of OV101, the only clinically characterized dSEGA described, in FXS.

Disclosure: Dr. Cogram has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ovid Pharmaceutical, FRAXA Research Foundation, AMO Pharmaceutical and Neuren Pharmaceutical. Dr. Cogram has received personal compensation in an editorial capacity for Frontiers Ageing Neuroscience. Dr. Deacon has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ovid Therapeutics and AMO Pharmaceuticals. Dr. von Schimmelmann has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ovid Therapeutics. Dr. During has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ovid Therapeutics. Dr. During has received compensation for serving on the Board of Directors of Ovid Therapeutics. Dr. During holds stock and/or stock options in Ovid Therapeutics, which sponsored research in which Dr. During was involved as an investigator. Dr. During holds stock and/or stock options in Ovid Therapeutics. Dr. Abrahams has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ovid Therapeutics. Dr. Abrahams has received royalty, license fees, or contractual rights payments from UCLA.