KCNQ2 Channel as a Druggable Epilepsy Target: Advances in Pharmacological Modifiers.

Abstract

KCNQ2 encodes the Kv7.2 channel, which mediates the M-current and regulates neuronal excitability. Pathogenic variants of KCNQ2 are associated with a spectrum of neonatal epilepsies, ranging from self-limited familial neonatal epilepsy to severe Developmental and Epileptic Encephalopathy (DEE), characterized by early seizure onset within the first week after birth, seizure clustering, and poor long-term neurodevelopment. Despite advances in molecular diagnosis, current treatment options remain limited and are not specific to Kv7.2 modulation, underscoring the need for therapies that target the underlying KCNQ2 channel dysfunction. Pharmacological modifiers of Kv7- mediated currents, such as retigabine, have demonstrated the restoration of impaired M-currents, but safety concerns limit their clinical application. Recent progress has led to the development of nextgeneration Kv7 activators, such as XEN1101, as well as other investigational compounds with improved potency, selectivity, and tolerability. These agents have shown promise for the treatment of epilepsy in adults in both preclinical and clinical studies, but evidence in children remains limited. Indirect modulators acting through sodium channels, GABAergic pathways, or network-level mechanisms may provide seizure control but are less likely to address the underlying channel dysfunction or improve neurodevelopmental outcomes. Challenges persist in translating in vitro efficacy into treatable clinical outcomes, particularly in neonates with DEE. Safety considerations, biomarkers of treatment responsiveness, and neurodevelopmental effects require careful evaluation. Nonetheless, the evolving pharmacological landscape highlights KCNQ2 channels as attractive and druggable targets in epilepsy, offering opportunities for mechanism-based therapies that could transform the management of this rare but devastating DEE.