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

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.