Design and development of glutamate transporter activators for disease modifying and symptomatic treatment of epilepsy - epilepsy is a complex neurological disorder characterized by recurrent,…

The National Institute of Neurological Disorders and Stroke (NINDS), a division of the Department of Health and Human Services National Institutes of Health, awarded a cooperative agreement worth $576,788 to Drexel University on March 15, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853).

Drexel University is designing and optimizing GTS467, a novel activator of the excitatory amino acid transporter 2 (EAAT2), a glutamate transporter responsible for clearing more than 80 percent of glutamate from the synapse. The work targets disease-modifying and symptomatic treatment of drug-resistant epilepsy and rare genetic forms of epilepsy such as Dravet syndrome. GTS467 demonstrates good drug-like properties and oral bioavailability and has reduced seizure burden and promoted disease modification in murine models of epilepsy. Under the UG3 optimization phase and UH3 IND-enabling studies phase, Drexel will further develop GTS467 toward clinical translation.

Performance occurs in Philadelphia, Pennsylvania, with a period of performance from the award date through February 28, 2027. The obligated amount is $576,788.

The Children's Hospital of Philadelphia Research Institute serves as a sub-grantee, conducting in vivo seizure testing in genetic mouse lines and induced-seizure models using video and EEG monitoring. The sub-award was made on April 21, 2026. CHOP will determine median seizure frequency, identify minimal effective doses and maximum tolerated doses across series-dosed treatments, and compare active seizure activity between drug-treated and placebo-control cohorts across pilocarpine chronic-epilepsy, flurothyl acute-seizure, and spontaneous-seizure genetic-line models.

Design and development of glutamate transporter activators for disease modifying and symptomatic treatment of epilepsy - epilepsy is a complex neurological disorder characterized by recurrent, unprovoked seizures affecting around 50 million people worldwide. There are over 30 marketed drugs to treat the symptoms of epilepsy, however, these drugs do not work in nearly a third of the patients leading to drug resistant epilepsy. In addition, there are various forms of genetic epilepsy and rare forms of epilepsy that do not respond to the existing drugs. Nearly 85 genes have been identified in genome wide association studies as causal for childhood and genetic epilepsy such as dravet syndrome. The SLC1A2 encoding the excitatory amino acid transporter 2 or EAAT2 has been noted as a risk gene with at least three mutants in epilepsy patients and animal models have demonstrated that loss of EAAT2 induces neuronal hyperexcitability and recurrent epileptic seizures, while genetic or pharmacological upregulation of EAAT2 reduced epileptic seizures. EAAT2 is a glutamate transporter localized to the astrocytes and responsible for clearing >80% of glutamate from the synapse is downregulated in epilepsy leading to glutamate accumulation and excitotoxicity. In this study, we utilized the hybrid structure-based screening platform to design GTS467, a novel activator of EAAT2 to not only suppress seizures but to promote neuroprotection by restoring normal glutamate neurotransmission. GTS467 has good drug-like properties and high oral bioavailability in plasma and brain tissue was chosen as the lead candidate for in vivo studies at ninds-epilepsy therapy screening program. GTS467 was tested in various murine models of epilepsy and results from the studies have shown that GTS467 not only reduces seizure burden but can also promote disease modification. In this proposal we aim to further optimize GTS467 (UG3 phase) and in IND enabling studies (UH3 phase) with a goal to deliver a clinical candidate as a disease modifying agent to treat acute and drug-resistant forms of epilepsy which is a significant unmet need.