SCN1A as a therapeutic target for Dravet syndrome

ABSTRACTIntroduction 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 NaV1.1, 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.Areas covered We discuss the potential to treat Dravet syndrome by targeting NaV1.1 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 NaV1.1. Some of these interventions have encouraging pre-clinical data from in vitro and animal models.Expert opinion Increasing functional NaV1.1 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.KEYWORDS: Developmental and epileptic encephalopathyDravet syndromeGene therapySCN1AAdeno-associated virusAntisense oligonucleotide Article highlights Dravet syndrome is a severe early infancy-onset developmental and epileptic encephalopathy caused by mutations in SCN1A, a gene encoding the sodium channel subunit NaV1.1.Patients with Dravet syndrome typically have drug-resistant epilepsy and developmental impairment, and are at high risk for sleep disturbance, gait abnormalities, and early death.Sodium channel inhibiting anti-seizure medications are typically ineffective and may actually exacerbate seizures.Antisense oligonucleotides and adeno-associated virus-based interventions can increase functional NaV1.1, reduce seizures, and reduce mortality in mouse models of Dravet syndrome.Gene therapy interventions that target SCN1A are a promising therapeutic avenue for Dravet syndrome, with the potential to address co-morbidities as well as improving seizure control; however, data from human clinical trials are necessary to assess safety and clarify the true therapeutic potential.Declaration of InterestKA Myers receives or has received research funding from Fonds de Recherche du Québec – Santé (282228, 295639), Savoy Foundation, Dravet Canada, Research Institute of the McGill University Health Centre, Citizens United for Research in Epilepsy (439534), Koolen-de Vries Foundation, Liam Foundation, Epilepsy Canada, and Grand Défi Pierre Lavoie Foundation; he is the site principal investigator for trials sponsored by LivaNova and Ultragenyx.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Additional informationFundingThis manuscript funded by the Fonds de Recherches du Québec – Santé (282228, 295639).