Gwangju Institute of Science and Technology (GIST) and Korea Research Institute of Chemical Technology (KRICT) have developed a new drug candidate with a novel mechanism for treating Dravet syndrome (SMEI), a rare pediatric epilepsy that causes repeated seizures.
According to scientific sources on the 5th, GIST Chemistry Professor Ahn Jin-hee recently discovered the small molecule drug candidate "GM-91466" through joint research with KRICT researchers Bae Myung-ae and Kim Ki-young.
Dravet syndrome is a rare intractable epilepsy that develops within the first year of life. It begins with seizures accompanied by high fever and causes repeated convulsions and developmental delays during growth. The primary cause is dysfunction of the SCN1A gene, which regulates signal transmission in brain neurons.
The research team searched for candidate compounds using zebrafish and mouse models that replicated SCN1A dysfunction. GM-91466 significantly suppressed seizure-related abnormal behavior while not affecting movement in normal subjects. In mouse experiments, the compound showed superior efficacy compared to existing drugs, reducing seizure frequency and intensity while delaying seizure onset.
The team confirmed that the compound increases expression of TPH2, an enzyme that produces the neurotransmitter serotonin, thereby raising serotonin levels in the brain. Some existing drugs work by directly stimulating serotonin receptors. In contrast, GM-91466 represents a new approach that increases serotonin production itself to restore the excitation-inhibition balance in neural circuits.
The candidate compound also showed stable effects when administered orally. No abnormalities were observed in preclinical cardiac toxicity, genotoxicity, and repeated-dose toxicity evaluations. The research team expects potential for therapeutic development through future clinical trials.
"We confirmed that neural circuit hyperexcitability caused by SCN1A dysfunction can be regulated through a new mechanism," said Professor Ahn Jin-hee. "This has potential to expand beyond Dravet syndrome to various neurological diseases with similar mechanisms."
The research was published online in the Journal of Medicinal Chemistry on January 23. The study was supported by basic research programs from the Ministry of Science and ICT and National Research Foundation of Korea, as well as healthcare technology development programs from the Ministry of Health and Welfare and Korea Health Industry Development Institute.
