2023 Fiscal Year Final Research Report

Fundamental Research for an Innovative Drug Discovery Based on the Molecular Pathomechanisms of Refractory Epilepsy Using a Multidimensional Approach.

Research Project

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Project/Area Number	20H03651
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Review Section	Basic Section 52050:Embryonic medicine and pediatrics-related
Research Institution	Fukuoka University
Principal Investigator	Hirose Shinichi 福岡大学, 医学部, 教授 (60248515)
Co-Investigator(Kenkyū-buntansha)	荻原郁夫日本医科大学, 医学部, 准教授 (30373286) 石井敦士国際医療福祉大学, 福岡保健医療学部, 教授 (90568825)
Project Period (FY)	2020-04-01 – 2024-03-31
Keywords	てんかん / iPS細胞 / 遺伝子改変動物 / ハイスルーブットスクリーニング / 創薬
Outline of Final Research Achievements	In human epilepsy, numerous genetic mutations were identified, and simultaneously, genes believed to be responsible for naturally occurring epilepsy in animals were also identified. Based on this information, model animals for Dravet syndrome were created, revealing abnormalities in synaptic function and the relationship between brain development and the onset of symptoms. Furthermore, stem cells established from epilepsy patients were differentiated into neurons, elucidating their molecular pathology. Building on this, drugs and compounds capable of intervening in the pathology were explored from multiple angles. Two candidate compounds were identified, and analyses were conducted on their blood-brain barrier permeability and other properties to serve as seeds for antiepileptic drugs. Additionally, it was found that these compounds improve epilepsy symptoms and reduce mortality in genetically modified animal.
Free Research Field	てんかん分子病態研究
Academic Significance and Societal Importance of the Research Achievements	てんかんの遺伝子が最初に同定されたのは1995年で、2003年からは次世代シークエンスにより、多くの遺伝子が同定されるようになった。最近になって、ようやくてんかんの分子病態が明らかになってきた。このため、分子病態に基づく創薬の試みは、海外で緒に就いたばかりであり、国内で我々以外にない。加えて、多手法を用いて多目的に実施しようとするのは本研究以外に未だ見当たらない。分子病態に基づく治療が開発できれば、てんかんの根治療法となり、現在3割程度存在する難治性てんかんへの大きな光明となる。