Precision medicine approach for in vitro modeling and computational screening of anti-epileptic drugs in pediatric epilepsy patients with SCN2A (R1629L) mutation

Abstract

This study aimed to develop personalized anti-epileptic drugs for pediatric patients with an SCN2A (R1629L) mutation, which is unresponsive to conventional sodium channel blockers. The mutation was identified using genomic DNA sequencing, and patient-derived induced pluripotent stem cells (iPSCs) were differentiated into the neuronal network to mimic seizure activity. A total of 1.6 million compounds were screened using computational methods, identifying five candidates with high affinity to the mutant SCN2A protein, low potential toxicity, and high blood–brain barrier permeability. These compounds were pharmacologically evaluated using the patient-derived in vitro seizure model, which replicated the abnormal electrophysiological characteristics of epilepsy. Two of the five candidate compounds effectively modulated electrophysiological activities; moreover, these compounds were 100 times more potent than phenytoin. Therefore, this study demonstrates the feasibility of precision medicine in epilepsy treatment, emphasizing the benefits of patient-derived in vitro seizure models and computational drug screening. Additionally, this study highlights the potential of targeted therapeutic development for patients unresponsive to conventional therapies, showcasing a promising approach for personalized medical interventions in epilepsy. © 2025 Elsevier Ltd