SCN1A as a therapeutic target for Dravet syndrome

Dravet syndrome is a severe early infancy-onset developmental and epileptic encephalopathy. Patients have drug-resistant seizures, as well as significant co-morbidities, including developmental impairment, crouch gait, sleep disturbance, and early mortality. The underlying cause is mutations in SCN1A, encoding the sodium channel subunit Na_V1.1, in >90% of patients. At present, approved Dravet syndrome treatments are symptomatic, primarily aimed at reducing seizure frequency, but having little to no effect on co-morbidities.

We discuss the potential to treat Dravet syndrome by targeting Na_V1.1 directly. Anti-seizure medications that act as sodium channel inhibitors are generally minimally effective and can actually exacerbate seizures. However, other interventions are currently under investigation, including gene therapies that increase the amount of functional Na_V1.1. Some of these interventions have encouraging pre-clinical data from in vitro and animal models.

Increasing functional Na_V1.1 via antisense oligonucleotides or virus-borne vectors is the most promising avenue for meaningful improvement in Dravet syndrome treatment, with the potential to not only reduce seizures but also address the multiple co-morbidities associated with this disease. However, human clinical trial data are necessary to determine safety and to clarify if, and to what extent, these interventions modify the natural history of Dravet syndrome.