Sexually Divergent Mortality and Partial Phenotypic Rescue After Gene Therapy in a Mouse Model of Dravet Syndrome

Hum Gene Ther. 2020 Mar;31(5-6):339-351. doi: 10.1089/hum.2019.225. Epub 2020 Jan 16.


Dravet syndrome (DS) is a neurodevelopmental genetic disorder caused by mutations in the SCN1A gene encoding the α subunit of the NaV1.1 voltage-gated sodium channel that controls neuronal action potential firing. The high density of this mutated channel in GABAergic interneurons results in impaired inhibitory neurotransmission and subsequent excessive activation of excitatory neurons. The syndrome is associated with severe childhood epilepsy, autistic behaviors, and sudden unexpected death in epilepsy. Here, we compared the rescue effects of an adeno-associated viral (AAV) vector coding for the multifunctional β1 sodium channel auxiliary subunit (AAV-NaVβ1) with a control vector lacking a transgene. We hypothesized that overexpression of NaVβ1 would facilitate the function of residual voltage-gated channels and improve the DS phenotype in the Scn1a+/- mouse model of DS. AAV-NaVβ1 was injected into the cerebral spinal fluid of neonatal Scn1a+/- mice. In untreated control Scn1a+/- mice, females showed a higher degree of mortality than males. Compared with Scn1a+/- control mice, AAV-NaVβ1-treated Scn1a+/- mice displayed increased survival, an outcome that was more pronounced in females than males. In contrast, behavioral analysis revealed that male, but not female, Scn1a+/- mice displayed motor hyperactivity, and abnormal performance on tests of fear and anxiety and learning and memory. Male Scn1a+/- mice treated with AAV-NaVβ1 showed reduced spontaneous seizures and normalization of motor activity and performance on the elevated plus maze test. These findings demonstrate sex differences in mortality in untreated Scn1a+/- mice, an effect that may be related to a lower level of intrinsic inhibitory tone in female mice, and a normalization of aberrant behaviors in males after central nervous system administration of AAV-NaVβ1. The therapeutic efficacy of AAV-NaVβ1 in a mouse model of DS suggests a potential new long-lasting biological therapeutic avenue for the treatment of this catastrophic epilepsy.

Keywords: SCN1A; SCN1B; adeno-associated virus; autism; cerebral spinal fluid; epilepsy; neurodevelopmental disorder.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autistic Disorder / genetics
  • Autistic Disorder / therapy
  • Dependovirus / genetics
  • Disease Models, Animal
  • Epilepsies, Myoclonic / genetics*
  • Epilepsies, Myoclonic / therapy*
  • Epilepsy / genetics
  • Epilepsy / therapy
  • Female
  • Genetic Therapy*
  • Genetic Vectors / therapeutic use
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • NAV1.1 Voltage-Gated Sodium Channel / genetics*
  • Phenotype
  • Seizures / genetics
  • Seizures / therapy
  • Sex Factors
  • Transgenes
  • Treatment Outcome
  • Voltage-Gated Sodium Channel beta-1 Subunit / genetics*


  • NAV1.1 Voltage-Gated Sodium Channel
  • Scn1a protein, mouse
  • Scn1b protein, mouse
  • Voltage-Gated Sodium Channel beta-1 Subunit