A Targeted Small Molecule Reduces Seizure Burden in a Mouse Model of kcnt1-related Epilepsy
Abstract number :
3.057
Submission category :
1. Basic Mechanisms / 1D. Mechanisms of Therapeutic Interventions
Year :
2024
Submission ID :
572
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Goeun Jang, MS – Fralin Biomedical Research Institute at VTC
Jessica Urbanczyk, MD – Fralin Biomedical Institute
Sunil Sahdeo, PhD – Actio Biosciences
Shelby Gough, PhD – Actio Biosciences
Nick Stock, PhD – Actio Biosciences
Wayne Frankel, PhD – Columbia University Vagelos College of Physicians & Surgeons, New York, NY, USA
Pranav Mathkar, Ph.D. Student – Fralin Biomedical Institute
Amy Shore, PhD – FBRI
Matthew Weston, Ph.D. – Fralin Biomedical Institute
Rationale: Variants in the KCNT1 gene, which encodes a sodium-activated potassium channel (Slack, KNa1.1), cause early-onset seizure disorders such as epilepsy of infancy with migrating focal seizures (EIMFS) and sleep-related hypermotor epilepsy (SHE). All recurrent KCNT1 variants show gain-of-function (GOF) effects on ion channel function when expressed in heterologous cells, and in KCNT1 GOF mouse models. There are no effective treatments for KCNT1-related epilepsy, but evidence suggests that blocking the channel or reducing its expression may be a successful therapeutic strategy. We sought to determine if a novel small molecule with high potency and selectivity for KCNT1 could block the KCNT1 current, normalize action potential firing, and stop seizures in a KCNT1 GOF in a mouse model.
Methods: We created a mouse model of KCNT1-related epilepsy by introducing a highly recurrent human missense variant (R428Q) in C57Bl6/J mice and developed a new small molecule with nanomolar potency and high selectivity for the KCNT1 channel. Homozygous mice (Kcnt1RQ/RQ) exhibited multiple types of spontaneous seizures and impairments of action potential firing in cortical GABAergic neurons. We performed video-EEG monitoring of vehicle and drug-treated mice and compared seizure burden. We also applied the drug to mouse neurons and measured the K+ currents and action potential generation.
Results: Cellular electrophysiological assays in primary cultured neurons and acute brain slices showed that the small molecule suppressed an outward current and increased action potential generation by inhibitory neurons. In vivo, the small molecule strongly suppressed spontaneous seizures in a dose-dependent and reversible manner.
Conclusions: Our work reveals the therapeutic potential of a novel small molecule in the treatment of KCNT1-related epilepsy that may work by reducing the increased K+ currents caused by KCNT1 GOF and increasing actional potential generation in cortical GABAergic neurons.
Funding: NIH/NINDS project R01NS130042
Basic Mechanisms