What percentage of epilepsy patients are refractory to available drugs?

Approximately 30–40% of epilepsy patients remain refractory to available pharmacotherapy, which affects roughly 1% of the global population.

What is the primary genetic cause of Dravet syndrome?

Dravet syndrome is primarily caused by SCN1A haploinsufficiency. Loss of Nav1.1 function impairs the firing capacity of parvalbumin-positive (PV+) GABAergic inhibitory interneurons, releasing uncontrolled excitatory activity.

How do sodium channel activators differ from conventional sodium channel blockers in epilepsy treatment?

Conventional sodium channel blockers inhibit channel activity to reduce neuronal excitability. Sodium channel activators, such as the pyridine derivatives developed by Xenon Pharmaceuticals, instead restore Nav1.1 channel activity in loss-of-function channelopathies like Dravet syndrome—a mechanistically opposite strategy where standard blockers may be contraindicated or paradoxically harmful.

What diseases are linked to KCNT1 gain-of-function mutations?

KCNT1 gain-of-function mutations are linked to epilepsy of infancy with migrating focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, Ohtahara syndrome, and Lennox-Gastaut syndrome.

What gene therapy approaches are being developed for Dravet syndrome?

Gene therapy approaches for Dravet syndrome include AAV-mediated delivery of SCN1A-encoding sequences restricted to inhibitory neurons (Allen Institute, Broad Institute), dCas9-mediated transcriptional activation of Scn1a (demonstrated in mouse models by Colasante et al., 2020), and microRNA modulation targeting sodium channel expression (Royal College of Surgeons in Ireland with miR-335-5p; Rockefeller University with miR-128).

What is eslicarbazepine's advantage over other sodium channel blockers in drug-resistant epilepsy?

Eslicarbazepine (eslicarbazepine acetate, BIA 2-093), developed by BIAL-Portela, is uniquely not a substrate for P-glycoprotein (P-gp) or multidrug resistance protein (MRP) efflux transporters, offering a mechanistic advantage in drug-resistant epilepsy where transporter-mediated efflux reduces drug brain exposure.