Abstract
Fragile X syndrome (FXS) is characterized by sensory hypersensitivity and neural hyperexcitability linked to GABAergic dysfunction. BAER-101, formerly known as AZD7325, is a positive allosteric modulator of GABAA receptors with functional selectivity for α2/α3 subunits, designed to enhance inhibitory tone while minimizing sedation associated with α1 activation. This study evaluated the acute and chronic effects of BAER-101 on behavioral and electrophysiological outcomes in individuals with FXS. The study employed a within-subject 3 × 2 factorial design, with three dosing conditions (Low Dose: 5 mg; High Dose: 15 mg; Placebo, all twice a day) and two time factors (Acute: same-day pre-/post-dose comparison; Chronic: after two weeks of consecutive dosing). Behavioral endpoints included clinician- and parent-rated symptom severity and laboratory measures of attention and memory, while electrophysiological endpoints comprised resting-state and auditory-evoked scalp-recorded 128-channel EEG metrics including bandpower, inter-trial coherence, and event-related potentials. Behavioral results showed limited evidence for improvements: across tasks, most effects were nonsignificant, with only marginal dose-related trends. The isolated findings lacked consistency or dose-dependence and are likely attributable to random variation. Test–retest reliability of behavioral measures was generally lower than published estimates (ICC ≈ 0.4–0.75), suggesting that measurement noise and small sample size may have obscured true drug effects. EEG spectral power analysis showed significant drug × time interactions, but follow-up comparisons did not support consistent pre-/post-drug changes, suggesting these effects reflected noise rather than drug response. ERP analyses indicated small, nonsystematic reductions in amplitude of onset-evoked potentials during chirp and habituation paradigms following BAER-101 treatment, without clear dose dependency. Test–retest reliability for EEG measures was lower than previously reported, with intraclass correlation coefficients ≈ 0.6 relative to prior work. Overall, no robust behavioral or electrophysiological improvements were observed with BAER-101 at the tested doses and durations.
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Data availability
The data that support the findings of this study are available on request from the corresponding author, [CAE]. The data are not publicly available due to restrictions due to their containing information that could compromise the privacy of research participants.
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The work was supported by the FRAXA Research Foundation, the Cincinnati Children’s Research Foundation, and the State of Ohio Third Frontier Fund.
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CAE and EVP conceptualized the experiments. LKW, CAE, EVP, RS, LMS, and KCD all participated in data collection. LAD, HK, and MM conducted the primary data analyses and data modeling and wrote the major portions of the manuscripts. All authors reviewed and edited the manuscript and agree with the contents as written.
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This study was funded by the Cincinnati Children’s Hospital Research Foundation, the State of Ohio’s Ohio Development Services Agency, and the FRAXA Research Foundation. Drug and matching placebo were provided by Baergic Bio, Inc. CAE is a co-inventor on a patent describing the method of use of BAER-101 in fragile X syndrome with the patent held by the Cincinnati Children’s Hospital Research Foundation. The authors otherwise have no conflicts or financial agreements in direct conflict with any information reported in this manuscript.
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De Stefano, L.A., Kim, H., Erickson, C.A. et al. Acute and chronic dosing of the GABA A alpha 2,3 selective agonist BAER-101 do not alter behavior but may impact auditory-evoked EEG responses in adults with fragile X syndrome. Sci Rep (2026). https://doi.org/10.1038/s41598-026-44380-0
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DOI: https://doi.org/10.1038/s41598-026-44380-0
