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

Abstract

Dravet syndrome (DS) is a neurodevelopmental genetic disorder caused by mutations in the SCN1A gene encoding the a 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 b1 sodium channel auxiliary subunit (AAV-NaVb1) with a control vector lacking a transgene. We hypothesized that overexpression of NaVb1 would facilitate the function of residual voltage-gated channels and improve the DS phenotype in the Scn1a +/mouse model of DS. AAV-NaVb1 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-NaVb1-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-NaVb1 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-NaVb1. The therapeutic efficacy of AAV-NaVb1 in a mouse model of DS suggests a potential new long-lasting biological therapeutic avenue for the treatment of this catastrophic epilepsy.

Modelling epilepsy in the mouse: challenges and solutions

“…Conventional gene therapy, in which loss of function of a specific gene is corrected by delivery of a viral vector encoding the missing product, is already being tested in monogenic epilepsy models (e.g. Niibori et al, 2020 ). Further developments include the use of antisense oligonucleotides to upregulate expression of the sodium channel Na v 1.1, leading to a reduction in seizure frequency and severity in a mouse model of Dravet syndrome ( Han et al, 2020 ).…”

A systematic review of adults with Dravet syndrome

“…They also successfully upregulated SCN1A expression using an engineered transcription factor, ultimately reversing multiple phenotypic characteristics. Another AAV study targeted increases in the multifunctional B1 sodium channel auxiliary subunit (AAV-NaVB1) to increase NavB1 in SCN1A haplosufficient mice [89]. The observed males had normalization of motor activity and improved in tests examining anxiety, fear, learning and memory.…”

Nucleic Acid–Based Therapeutics in Orphan Neurological Disorders: Recent Developments

“…Overexpression of NaVβ1, an auxiliary subunit of the NAv1.1 channel using an AAV vector (AAV-NaVβ1), could facilitate the function of residual channels and improve the DS phenotype. A single AAV-NaVβ1 injection into the cerebral spinal fluid of neonatal male Scn1a ± mice led to increased survival, reduced spontaneous seizures, normalization of motor activity, and performance on the elevated plus maze test ( Niibori et al, 2020 ).…”