Novel anticonvulsants for nerve agents and refractory status epilepticus
Active Cooperative Agreement Awarded Last action
- Award ID
- UG3NS138911
- Recipient
-
Texas A & M University System Health Science Center UEI HFT7XTHB6563
- Awarding agency
-
National Institute of Neurological Disorders and Stroke
National Institutes of Health, Department of Health and Human Services
- Obligated
- $1,071,121
Award facts
- Assistance listing
- 93.310 Trans-NIH Research Support
- Completion date 38% complete
- Funding agency
- Office of the Director National Institutes of Health, Department of Health and Human Services
- Place of performance
- Texas, USA
Award details come from USAspending.gov.
Description
- Abstract
- The overall goal of this proposal is to develop novel hydrophilic neurosteroids as anticonvulsants to control midazolam-refractory seizures and brain damage caused by nerve agent exposure. Acute exposure to nerve agents or organophosphate (OP) intoxication can result in refractory status epilepticus (RSE), and permanent brain damage or death. Benzodiazepine anticonvulsants (diazepam and midazolam) have often failed to be protective against RSE. Thus, there is an urgent need for new anticonvulsants that can increase midazolam efficacy and reduce benzodiazepine-resistant SE. Neurosteroids such as the ganaxolone (FDA-approved) have emerged as robust anticonvulsants for nerve agents and RSE. Recently, novel hydrophilic analogs ("super-ganaxolones") have been identified as promising anticonvulsants that can surpass the limitations of ganaxolone, which lack water-solubility and has limited absorption, half-life and dosing options. This project is designed to optimize new hydrophilic synthetic analogs of the ganaxolone (super-ganaxolones) as anticonvulsants for nerve agent-indued RSE and brain damage. This novel therapy is based on the proven efficacy of neurosteroids, targeting cellular changes involved in OP neurotoxicity and RSE. The central hypothesize is that super-ganaxolones enhance phasic and extrasynaptic tonic inhibition controls nerve agent-induced RSE and neuronal damage more effectively than benzodiazepines and thereby optimally mitigate long-term dysfunction. The primary emphasis is to optimize lead drugs with requisite biopharmaceutical traits, robust efficacy and acceptable safety profile and advance one lead drug for further development under the FDA "animal rule" pathway. These pilot studies shows that these drugs are formulated as dry powders for injection that offer an unprecedented shelf life of 10-years for stockpiling as medical countermeasures. Studies are organized as four specific aims to deliver a lead drug: (aim 1) to synthesize and optimize novel hydrophilic neurosteroids that can effectively activate synaptic and extrasynaptic gaba-AR-mediated tonic inhibition and elicit anticonvulsant effects with low risk of side effects. (aim 2) to determine the efficacy of top lead drugs against DFP-induced RSE and brain damage. (aim 3) to confirm the efficacy of a lead drug against soman-induced RSE and brain damage. (aim 4) to optimize PK and safety of a lead drug and file IND application. The project will be implemented as per the "go/no-go" milestones plan. Test drugs will be given by IM injection 40 min (in combination with midazolam) or 90 min (sequential) after OP exposures. The key outcome measures of drug effectiveness include: (i) tonic inhibition potency; (II) anticonvulsant efficacy, (III) side effects and off-target activity; (IV) neuroprotection; and (v) attenuation of neurological dysfunction, including SEX differences in efficacy and safety. Based on these pilot studies, test drugs are expected to be safe and efficacious for FDA approval for clinical use. The overall project's impact is high in delivering one well-characterized lead drug for advanced development for nerve agent exposure.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $532,121 | |
| Original award | $539,000 |
Quick answers
Who received award UG3NS138911?
UG3NS138911 was awarded to Texas A & M University System Health Science Center by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on September 1, 2025.
How much is award UG3NS138911 worth?
$1,071,121 has been obligated on UG3NS138911.
Which agency awarded UG3NS138911?
National Institute of Neurological Disorders and Stroke (National Institutes of Health) awarded UG3NS138911, with funding from Office of the Director (National Institutes of Health).
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