RG1662, a Selective GABAA α5 Receptor Negative Allosteric Modulator, Increases Gamma Power in Young Adults with Down Syndrome. (P6.273)

Abstract

OBJECTIVE: We investigated the effect of RG1662, a GABAAα5 (GABRA5) negative allosteric modulator (NAM), on quantitative EEG (qEEG) in young adults with Down syndrome (DS). BACKGROUND: Intellectual disability associated with DS is believed to relate partly to excessive GABAergic tone. Gamma oscillations are generated by synchronization of pyramidal neurons by fast-spiking GABAergic interneurons. RG1662 is a highly selective NAM of GABA-A receptors containing the GABRA5 subunit, a target for enhancement of cognition. DESIGN/METHODS: In a randomized, double blind, placebo-controlled, multiple ascending dose study in young adults with DS aged 18-30 years, subjects received placebo, 80, 160, or 370 mg BID of RG1662 for 5 weeks (n = 8 per group). EEG recordings were obtained at baseline, day 1, and day 10. We performed a power band analysis and fit an MMRM model to the data. A classifier was also built to separate EEG features in people with DS from matched typically developing (TD) controls using PCA and an SVM algorithm. In addition, extracellular recordings in brain slices from WT and GABRA5 KO mice were used to explore GABRA5-dependency of the effects. RESULTS: There were no EEG signs of epileptiform abnormality. We observed statistically significant (p < 0.001) dose-dependent increases in gamma power after 10 days of dosing with RG1662. We were able to construct a multivariate DS index with good sensitivity and specificity (ROC AUC = 0.87). We observed a dose-dependent lowering of the DS index. Also, RG1662 modulated carbachol-induced gamma oscillations in hippocampal brain slices of WT mice, but not GABRA5 KO mice. CONCLUSIONS: GABRA5 inhibition results in clear qEEG effects in young adults with DS and may be a useful pharmacodynamic biomarker for this class of compounds. Rodent experiments suggest these effects are GABRA5-dependent. We are investigating EEG data from TD controls given multiple ascending doses of RG1662.

Disclosure: Dr. Bolognani has received personal compensation for activities with Roche as an employee. Dr. Squassante has received personal compensation for activities with Roche Diagnostics Corporation as an employee. Dr. Liogier d'Ardhuy has received personal compensation for activities with Roche Diagnostics Corporation as an employee. Dr. Hernandez has received personal compensation for activities with Roche Diagnostics Corporation as an employee. Dr. Knoflach has received personal compensation for activities with Roche Diagnostics Corporation as an employee. Dr. Baldinotti has received personal compensation for activities with Roche as an employee. Dr. Noeldeke has received personal compensation for activities with Roche Diagnostics Corporation as an employee. Dr. Wandel has received personal compensation for activities with Roche Diagnostics Corporation as an employee. Dr. Nave has received personal compensation for activities with Roche Diagnostics Corporation as an employee. Dr. Khwaja has received personal compensation for activities with Roche Diagnostics Corporation as an employee.