gaboxadol (OV101) / Lundbeck, Ovid Therapeutics, Angelini Group, Healx - LARVOL DELTA

Distinct neuronal activity profiles and EEG signatures observed across neuroactive steroid GABAAR PAMs are driven by differential activation of GABAAR subtypes (Neuroscience 2025) - "Furthermore, c-Fos mapping revealed that compounds with higher Delta-subunit activity induced more widespread brain activation patterns, resembling those produced by the Delta-subunit-selective GABAAR agonist gaboxadol. In summary, NAS GABAAR PAMs produce a range of physiological effects depending on their relative activity at Delta- versus Gamma-subunit-containing receptors. We propose that increased EEG theta power by NAS GABAAR PAMs serves as an in vivo biomarker of potentiation at Delta-subunit-containing GABAARs and is associated with widespread increases in neuronal activation as measured by c-Fos expression."

CNS Disorders • FOS • KEAP1

Recurrent neonatal seizures increase tonic inhibition and respond to enhancers of δ-containing GABAA receptors. (PubMed, JCI Insight) - "About one-third of neonatal seizures do not respond to the first-line anticonvulsant phenobarbital, which activates phasic inhibition and whose effectiveness decreases over time...We investigated the impact of THIP (gaboxadol) on neonatal behavioral seizures, neuronal apoptosis, and neurodegeneration in vivo...We conclude that recurrent neonatal seizures increase tonic inhibition. Therefore, enhancing tonic inhibition may be a treatment strategy for prolonged neonatal status epilepticus."

Journal • CNS Disorders • Epilepsy • Inflammatory Arthritis

Adverse events of pharmacological interventions for insomnia disorder in adults: a systematic review and network meta-analysis. (PubMed, Front Psychiatry) - "Compared with placebo, zolpidem (somnolence: relative risk [RR] 1.85; dizziness: RR 2.33; headache: RR 1.26), zopiclone (somnolence: RR 2.02; dizziness: RR 2.33; dysgeusia: RR 7.84), indiplon (somnolence: RR 3.46; dizziness: RR 2.30; headache: RR 1.63), gaboxadol (dizziness: RR 3.44), eszopiclone (somnolence: RR 2.00; dizziness: RR 3.18; dysgeusia: RR 10.54), estazolam (somnolence: RR 2.08), flunitrazepam (somnolence: RR 3.04), flurazepam (somnolence: RR 2.52), lemborexant (somnolence: RR 6.57), nitrazepam (somnolence: RR 3.80), Ramelteon (somnolence: RR 2.19), suvorexant (somnolence: RR 3.32), Temazepam (somnolence: RR 3.77), trazodone (somnolence: RR 2.86), triazolam (somnolence: RR 2.35), and esmirtazapine (somnolence: RR 4.63; dizziness: RR 2.87) had the most harmful profile in nervous system disorders...Data on some drugs like flurazepam, nitrazepam, triazolam, and zaleplon in some outcomes were mainly based on limited study with rare event and thus was highly..."

Adverse events • Journal • Retrospective data • Review • CNS Disorders • Gastroenterology • Gastrointestinal Disorder • Infectious Disease • Insomnia • Otorhinolaryngology • Pain • Psychiatry • Respiratory Diseases • Sinusitis • Sleep Disorder • Xerostomia

Ethanol-induced rapid eye movement sleep suppression in rats: Comparison with subtype-selective GABAA receptor compounds. (PubMed, J Psychopharmacol) - "Analysis of sleep-wake states after administration of ethanol or GABAAR compounds with varying subtype selectivity suggests that positive modulation of α1, 2, 3, and/or 5 subunit-containing GABAARs is sufficient to suppress REM sleep, and any or all may be involved in ethanol-induced REM sleep suppression. Also, our study suggests that α4/6 subunit-containing GABAARs may be involved in ethanol-induced increases in SWS. The lack of similarity between ethanol and the GABAAR compounds in the pharmaco-EEG analysis suggests that neurotransmitter systems besides the GABAergic system are likely involved in the effects of ethanol on EEG spectral power."

Journal • Preclinical • Addiction (Opioid and Alcohol) • CNS Disorders • Sleep Disorder

Current and Emerging Precision Therapies for Developmental and Epileptic Encephalopathies. (PubMed, Pediatr Neurol) - "Targeted approaches for channelopathies include antisense oligonucleotides and gene therapies, such as zorevunersen and ETX101 for SCN1A-related Dravet syndrome, alongside novel small molecules for other ion channel disorders. Advances in targeting neurotransmitter receptor dysfunctions, including γ-aminobutyric acid and glutamate receptor variants, highlight the use of modulators such as gaboxadol, radiprodil, and l-serine, alongside emerging gene therapies...Future directions focus on addressing the challenges in developing and implementing gene-based therapies, integrating systems biology, leveraging artificial intelligence for data analysis, and fostering collaboration among stakeholders. The rapidly advancing field of precision therapeutics for DEEs holds promise to improve outcomes through tailored, equitable, and patient-centered care."

Journal • Review • CNS Disorders • Developmental Disorders • Epilepsy • Gene Therapies • Metabolic Disorders • Movement Disorders • XBP1

A subtype-selective photoswitchable agonist for precise manipulation of GABAA receptors. (PubMed, Br J Pharmacol) - "GABAARs are potential therapeutic targets for many disorders. However, their physiological and pathophysiological roles remain largely unexplored. Az-IGU may enable photopharmacological studies of α4/6β3δ GABAARs, providing new opportunities for biomedical and neurobiological applications."

Journal

FlyVISTA, an integrated machine learning platform for deep phenotyping of sleep in Drosophila. (PubMed, Sci Adv) - "FlyVISTA reveals the distinct spatiotemporal dynamics of sleep and wake-associated microbehaviors at baseline, following administration of the sleep-inducing drug gaboxadol, and with dorsal fan-shaped body drivers. We identify a microbehavior ("haltere switch") exclusively seen during quiescence that indicates a deeper sleep stage. These results enable the rigorous analysis of sleep in Drosophila and set the stage for computational analyses of microbehaviors in quiescent animals."

Journal

Action potential-dependent α4-containing GABAA receptors contribute to epileptogenicity in focal cortical dysplasia. (PubMed, Epilepsy Res) - "In the presence of tetrodotoxin (voltage-gated Na+ channel inhibitor), frequency and amplitude of miniature inhibitory postsynaptic currents were also increased upon treatment with gaboxadol. However, higher magnitude of change was observed in spontaneous inhibitory postsynaptic currents compared to miniature inhibitory postsynaptic currents on gaboxadol treatment, suggesting action potential-dependent α4-containing GABAA receptor activity may influence epileptogenicity in FCD."

Journal • CNS Disorders • Developmental Disorders • Epilepsy • Psychiatry

Non-Steroidal Anti-Inflammatory Drugs Are Inhibitors of the Intestinal Proton-Coupled Amino Acid Transporter (PAT1): Ibuprofen and Diclofenac Are Non-Translocated Inhibitors. (PubMed, Pharmaceutics) - "Background/Objectives: The proton-coupled amino acid transporter (PAT1) is an intestinal absorptive solute carrier responsible for the oral bioavailability of some GABA-mimetic drug substances such as vigabatrin and gaboxadol... NSAIDs such as ibuprofen, diclofenac, and flurbiprofen inhibited proline uptake via hPAT1, with IC50 values of 954 (logIC50 2.98 ± 0.1) µM, 272 (logIC50 2.43 ± 0.1) µM, and 280 (logIC50 2.45 ± 0.1) µM, respectively... NSAIDs interact with hPAT1 as non-translocated non-competitive inhibitors, and molecular modeling points to a binding mode involving an allosteric site distinct from the substrate binding site. The present findings could be used as a starting point for developing specific hPAT1 inhibitors."

Journal

Molecular and cellular targets of GABAergic anesthetics in the mesopontine tegmentum that enable pain-free surgery. (PubMed, Pain) - "Likewise, low-concentration gaboxadol/THIP, also selective for GABAAδ-Rs, was effective, whereas benzodiazepines and zolpidem, which selectively target GABAAγ2-Rs, were not...Immunolabeling revealed that this GABAA-R isoform is expressed exclusively by a distinct subpopulation of MPTA "δ-cells" that reside in close apposition to effector neurons. This suggests that during wakefulness, δ-cells serve as inhibitory interneurons which, when silenced by GABAergic agents, disinhibit (excite) the effector-neurons, triggering transition to unconsciousness."

Journal • Anesthesia • Pain

Advancing Therapeutic Frontiers for Angelman Syndrome: Insights From a Systematic Review (ISPOR-EU 2024) - "A dose-finding study of GTX-102, an antisense oligonucleotide therapy, highlighted improvements in symptoms and skill acquisition on the CGI-I-AS in five patients but was paused due to serious adverse events...Gaboxadol, minocycline, and levodopa were all observed to be well-tolerated... This review illustrates the challenges and potential of current pharmacological and non-pharmacological interventions in managing AS. While some pharmacological treatments show promise, the efficacy varies, highlighting the importance of integrating diverse therapeutic approaches. Continued innovation, particularly in genetic therapies and integrative treatment models, along with rigorous testing, are essential to develop more effective strategies for AS."

Review • CNS Disorders • Developmental Disorders • Gene Therapies • Pediatrics • Psychiatry • UBE3A

Clinically-probed mechanisms of action in Fragile-X Syndrome fail to normalize translational EEG phenotypes in Fmr1 knockout mice. (PubMed, Neuropharmacology) - "Gaboxadol did not normalize any EEG phenotypes. We conclude that these compounds have limited ability to normalize these EEG phenotypes."

Journal • Preclinical • CNS Disorders • Developmental Disorders • Fragile X Syndrome • Genetic Disorders • Psychiatry • FMR1

Regulation of proteostasis by sleep in Drosophila models of Tauopathy (Neuroscience 2024) - "In contrast, sleep induction using gaboxadol led to reduced hyperphosphorylated Tau accumulation in neurons as a result of modulated autophagic flux and enhanced clearance of ubiquitinated Tau, suggesting altered protein processing and clearance that resulted in improved synaptic integrity and function. These findings highlight the complex relationship between sleep and autophagy, in regulating protein homeostasis, and the neuroprotective potential of sleep-enhancing therapeutics to slow the progression or delay the onset of neurodegeneration."

CNS Disorders • Sleep Disorder

Regulation of proteostasis by sleep through autophagy in Drosophila models of Alzheimer's disease. (PubMed, Life Sci Alliance) - "In contrast, sleep induction using gaboxadol led to reduced toxic Tau accumulation in neurons as a result of modulated autophagic flux and enhanced clearance of ubiquitinated Tau, suggesting altered protein processing and clearance that resulted in improved synaptic integrity and function. These findings highlight the complex relationship between sleep and regulation of protein homeostasis and the neuroprotective potential of sleep-enhancing therapeutics to slow the progression or delay the onset of neurodegeneration."

Journal • Alzheimer's Disease • CNS Disorders • Sleep Disorder • Targeted Protein Degradation

Therapeutic efficacy of the BKCa channel opener chlorzoxazone in a mouse model of Fragile X syndrome. (PubMed, Neuropsychopharmacology) - "Chlorzoxazone was more efficacious in alleviating these phenotypes than gaboxadol and metformin, two repurposed treatments for FXS that do not target BKCa channels. Systemic administration of chlorzoxazone modulated the neuronal activity-dependent gene c-fos in selected brain areas of Fmr1-KO mice, corrected aberrant hippocampal dendritic spines, and was able to rescue impaired BKCa currents recorded from hippocampal and cortical neurons of these mutants. Collectively, these findings provide further preclinical support for BKCa channels as a valuable therapeutic target for treating FXS and encourage the repurposing of chlorzoxazone for clinical applications in FXS and other related neurodevelopmental diseases."

Journal • Preclinical • CNS Disorders • Developmental Disorders • Fragile X Syndrome • Genetic Disorders • Mood Disorders • Psychiatry • FOS

Sex differences in motor learning flexibility are accompanied by sex differences in mushroom spine pruning of the mouse primary motor cortex during adolescence. (PubMed, Front Neurosci) - "We assessed α4GABAR expression using immunohistochemical and electrophysiological techniques (whole cell patch clamp responses to 100 nM gaboxadol, selective for α4βδ GABARs)...Although motor learning was similar for all groups, only female wild-type mice (low mushroom spine density) learned the accelerating rotarod task after the constant speed task (P = 0.006), a measure of motor learning flexibility. These results suggest that optimal motor learning flexibility of female mice is associated with low baseline levels of post-pubertal mushroom spine density in L5M1 compared to male and female α4 -/- mice."

Journal • Preclinical

Extrasynaptic δGABAA receptors mediate resistance to migraine-like phenotype in rats. (PubMed, J Headache Pain) - "Our study introduced a rat strain resistant to migraine-provoking agents and signified a critical involvement of extrasynaptic δGABAergic receptors. Extrasynaptic δ GABAA receptors, by mediating constant background inhibition on the excitability of neurons, stand as a novel drug target with a therapeutic potential in migraine."

Journal • Preclinical • Absence Seizure Disorder • CNS Disorders • Epilepsy • Migraine • Pain

Impact of Abl2/Arg Deficiency on Anxiety and Depressive Behaviors in mice. (PubMed, Behav Brain Res) - "The expression of Gabbr2 was significantly reduced in the hippocampus of arg-/- compared to WT mice, and intraperitoneal treatment of GABA receptor agonist Gaboxadol normalized anxiety/depression-related behaviors of arg-/- mice. These findings underscore the potential role of Abl2/Arg in influencing anxiety and depressive-like behaviors, thereby contributing valuable insights into its broader physiological and pathological functions."

Journal • Preclinical • CNS Disorders • Depression • Oncology • Psychiatry • ABL2 • GABBR2

Manipulation of α4βδ GABAA receptors alters synaptic pruning in layer 3 prelimbic prefrontal cortex and impairs temporal order recognition: Implications for schizophrenia and autism. (PubMed, Brain Res) - "Pubertal injection (14 d) of the GABA agonist gaboxadol, at a dose (3 mg/kg) selective for α4βδ, reduced L3 spine density by half (P < 0.0001), while α4 knock-out increased spine density ∼ 40 % (P < 0.0001), mimicking spine densities in SCZ and ASD, respectively...These data suggest that altering α4βδ GABAR expression/activity alters spine density in L3 mPFC and impairs temporal order memory to mimic changes in ASD and SCZ. These findings may provide insight into these disorders."

Journal • Autism Spectrum Disorder • CNS Disorders • Genetic Disorders • Psychiatry • Schizophrenia

Extrasynaptic GABAA receptors in central medial thalamus mediate anesthesia in rats. (PubMed, Eur J Pharmacol) - "The present study investigated the role of extrasynaptic GABAA receptors in the central medial thalamic nucleus (CM) in anesthesia induced by gaboxadol (THIP) and diazepam (DZP) in rats. Moreover, the rats with declined expression of GABAA receptor δ-subunit in the CM were less responsive to THIP or DZP. These findings explained a novel mechanism of THIP-induced loss of consciousness and highlighted the role of CM extrasynaptic GABAA receptors in mediating anesthesia."

Journal • Preclinical • Anesthesia • CNS Disorders • Depression • Psychiatry

Placebo-Controlled, Single-Dose Challenge Study of Gaboxadol in Adult Males With Fragile X Syndrome (FXS) (clinicaltrials.gov) - P2 | N=10 | Recruiting | Sponsor: Craig Erickson

New P2 trial • Fragile X Syndrome • Genetic Disorders

Auditory brainstem responses are resistant to pharmacological modulation in Sprague Dawley wild-type and Neurexin1α knockout rats. (PubMed, BMC Neurosci) - "First, we probed how different commonly used anesthetics (isoflurane, ketamine/xylazine, medetomidine) affect ABRs. In the next step, we assessed the effects of different pharmacological compounds (diazepam, gaboxadol, retigabine, nicotine, baclofen, and bitopertin) either under isoflurane or medetomidine anesthesia...Significant modulation was observed with (i) nicotine, affecting the late ABRs components at 90 dB stimulus intensity under isoflurane anesthesia in both genotypes and (ii) retigabine, showing a slight decrease in late ABRs deflections at 80 dB stimulus intensity, mainly in isoflurane anesthetized Nrxn1α KO rats. Our study suggests that ABRs in anesthetized rats are resistant to a wide range of pharmacological modulators, which has important implications for the applicability of ABRs to study auditory brainstem physiology."

Journal • Preclinical • Anesthesia • NRXN1

Mutation of novel ethanol-responsive lncRNA Gm41261 impacts ethanol-related behavioral responses in mice. (PubMed, Genes Brain Behav) - "Behaviorally, mutant mice had reduced ethanol, gaboxadol and zolpidem-induced loss of the righting response and reduced tolerance to ethanol in both sexes...In C57BL6/J mice, TX2 within the cortex was cytoplasmic and largely present in Rbfox3+ neurons and IBA1+ microglia, but not in Olig2+ oligodendrocytes or in the majority of GFAP+ astrocytes. These data support the hypothesis that TX2 mutagenesis and dysregulation impacts ethanol drinking behavior and ethanol-induced behavioral responses in mice, likely through alterations in the GABAergic system."

Journal • Preclinical • Addiction (Opioid and Alcohol) • Solid Tumor • GFAP • OLIG2

ROCKET: A Study of OV101 in Individuals With Fragile X Syndrome (clinicaltrials.gov) - P2 | N=36 | Completed | Sponsor: Ovid Therapeutics Inc. | N=23 ➔ 36

Enrollment change • Fragile X Syndrome • Genetic Disorders • FMR1

A novel combination treatment for fragile X syndrome predicted using computational methods. (PubMed, Brain Commun) - "This work demonstrates for the first time that by targeting multiple pathways, with a combination treatment, we were able to rescue more phenotypes in a fragile X syndrome mouse model than either ibudilast or gaboxadol could achieve as monotherapies. This combination treatment approach holds promise for addressing the wide spectrum of diverse symptoms in this heterogeneous patient population and may have therapeutic potential for idiopathic autism."

Journal • Autism Spectrum Disorder • CNS Disorders • Cognitive Disorders • Developmental Disorders • Fragile X Syndrome • Genetic Disorders • Mood Disorders • Psychiatry