Enhancement of Glutamate Uptake as Novel Antiseizure Approach: Preclinical Proof of Concept
Krzysztof Kamiński, Katarzyna Socała, Michał Abram, Marcin Jakubiec, Katelyn L. Reeb, Rhea Temmermand, Mirosław Zagaja, Maciej Maj, Magdalena Kolasa, Agata Faron‐Górecka, Marta Andres‐Mach, Aleksandra Szewczyk, Mustafa Q. Hameed, Andréia CK Fontana, Alexander Rotenberg, Rafał M. Kamiński
Annals of Neurology 2025, 97(2):344–357. doi: 10.1002/ana.27124
The paper describes advanced preclinical studies of the compound ( R )-AS-1 (iQ-007, iQure Pharma) developed by the team of prof. Krzysztof Kamiński from the Faculty of Pharmacy, Jagiellonian University Medical College in Krakow. This compound has a unique mechanism of action, previously undescribed for antiepileptic drugs. ( R )-AS-1 was identified as the first-in-class small-molecule, highly selective positive allosteric modulator of the EAAT2 (GLT-1) transporter for glutamate. The compound ( R )-AS-1 was characterized by a broad spectrum of anticonvulsive activity, which was assessed using a number of animal models of seizures and epilepsy within the ETSP (Epilepsy Therapy Screening Program) NINDS, NIH, USA (https://www.ninds.nih.gov/current-research/focus-disorders/epilepsy-research/epilepsy-therapy-screening-program-etsp). In vitro studies ( R )-AS-1 increased glutamate uptake, but after repeated administration in vivo no effect on GLT-1 expression was observed. The compound was well tolerated and had a favorable safety profile.
The EAAT2 (GLT-1) transporter, present primarily in the central nervous system, is the major transporter for the removal of excess glutamate from the synaptic space. Pathological accumulation of glutamate in the synaptic space leads to excitotoxicity, which is a common feature of epilepsy, as well as many other neurological, neurodegenerative, and psychiatric diseases. Normalization of glutamate levels by ( R )-AS-1 may therefore represent a novel therapeutic approach in the treatment of epilepsy and many other diseases of the central nervous system.
Research groups from domestic institutions (including the Jagiellonian University Medical College, Maria Curie-Skłodowska University, the Institute of Rural Medicine in Lublin, the Medical University of Warsaw, the Medical University of Lublin, the Institute of Pharmacology of the Polish Academy of Sciences in Krakow) and from foreign institutions (Rheinische Friedrich-Wilhelms-Universität Bonn, University of Oslo, Drexel University College of Medicine, University of Pittsburgh - School of Medicine, University of Utah Health, Harvard University - Harvard Medical School) and the National Institute of Neurological Diseases and Stroke participated in the studies on ( R )-AS-1.
It is also worth mentioning that in January 2025, the US Food and Drug Administration (FDA) granted the iQ-007 molecule orphan drug status for the treatment of Dravet syndrome, a severe genetic epileptic encephalopathy that appears in early childhood.
