Design and development of Glutamate transporter activators for disease modifying and symptomatic treatment of Epilepsy

About This Grant

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.