Delivery of Sodium Channel Subunits via Viral Vectors to Ameliorate Seizures in Dravet Syndrome Mice

Dravet Syndrome (DS) is caused primarily by impairment of the voltage-gated sodium channel alpha-1 subunit (Nav1.1) in inhibitory neurons. DS is characterized by febrile seizures, autistic behavior, and sudden unexpected death in epilepsy (SUDEP). Customized adeno-associated virus (AAV) serotype 9 vectors coding for AAV9-Gad1v1-Navβ1 and AAV9-Gad1v2-NaChBac were tested in Scn1a+/- mice, a mouse model of DS, to restore the activity of inhibitory neurons in Scn1a+/- mice. Neonatal injections with AAV9-Gad1v1-Navβ1 resulted in a partial improvement in the mortality of female Scn1a+/- mice and a reduction in the spontaneous seizure frequency in male Scn1a+/- mice, with no effect on the heat-induced seizures. Treatments with AAV9-Gad1v2-NaChBac did not induce inflammation in mouse brain and indicated that Gad1v2 promoter was more selective towards gamma aminobutyric acid (GABA)-ergic inhibitory neurons than the Gad1v1 promoter. The findings of this study demonstrated the capability of AAV as a useful tool in gene therapy for DS.M.Sc.2021-11-30 00:00:0