Voltage-gated sodium channel (persistent current)

Class

small molecule; preferential/selective inhibitor of persistent (late) sodium current (INa) over peak INa, giving improved selectivity for hyperexcitable/disease-state sodium channels relative to standard-of-care sodium channel blockers

Pathway

Reduces pathological persistent sodium current associated with SCN2A/SCN8A gain-of-function mutations, which drive neuronal hyperexcitability in developmental and epileptic encephalopathies (DEEs).

Voltage-gated sodium channels are proteins in the membranes of neurons that generate the rapid electrical signal, or action potential, underlying nerve firing. Normally these channels open briefly and then close, producing a short burst of current. A small number of channels, however, can reopen or fail to close fully, creating a low-level but continuous "persistent" or "late" sodium current. Certain inherited mutations in the genes encoding neuronal sodium channels, particularly SCN2A and SCN8A, increase this persistent current, making neurons chronically closer to firing threshold. The result is neuronal hyperexcitability that manifests as seizures and broader developmental impairment, as seen in developmental and epileptic encephalopathies. Because the transient current is essential for normal nerve signaling, a compound that blocks sodium channels indiscriminately risks impairing healthy neural and cardiac function. Selectively targeting the abnormal persistent current, while largely sparing the transient current, offers a way to reduce pathological excitability without broadly suppressing normal electrical activity. This selectivity distinguishes such agents from older, nonselective sodium channel blockers and represents a mechanism-based strategy aimed at the specific molecular defect driving these genetic epilepsies.