Dravet syndrome is a genetic disorder causing a severe form of epilepsy. Many people living with Dravet syndrome have neurodevelopmental problems, including cognitive delay and autism-like behaviours, and have an increased risk of sudden unexpected death in epilepsy (SUDEP). In the majority of Dravet syndrome cases, there is a mutation in the SCN1A gene. The SCN1A gene codes for a sodium channel that is required for some brain cells to function properly. A SCN1A mutation may cause the channel to be inactive or under-active. Dravet syndrome is currently treated with diet therapy (e.g. ketogenic diet) and/or medication; however, there is still a large number of people with the syndrome who do not respond to these treatment options.

Given this need for better treatments, Dr. David R. Hampson and his lab at the Leslie Dan Faculty of Pharmacy, University of Toronto, tested the effects of increasing the number of auxiliary sodium channel subunits (i.e. over-expression of a sodium channel subunit) to determine if this would improve brain function and reduce seizure activity. To do this, they used viral vector-based gene therapy administration in both male and female Dravet syndrome mice. Viral vectors are viruses used to introduce new genetic material (DNA) into cells. Mice that received the functional gene were the ‘treated’ group, and mice injected with same type of viral vector but not carrying the sodium channel subunit served as the control group.

The effects were studied in both Dravet and typically developing juvenile mice (3-8 weeks old), and the number of tonic seizures was measured using video monitoring. In addition, behavioural testing was carried out on both Dravet and normal adult mice (2-3 months old). Using established tests, they assessed autism-like behaviours in the mice, including motor hyperactivity, anxiety/fear, and learning and memory function.

The results revealed that untreated Dravet mouse males and females have different susceptibilities to SUDEP; untreated female Dravet mice were more susceptible to SUDEP than male mice1.  Importantly, the male Dravet mice treated with the functional genes had fewer seizures compared to the female mice. Moreover, treated male Dravet mice showed partial behavioural improvements, such as reduced motor hyperactivity, compared to treated female Dravet mice.

These findings suggest that gene therapy may help to reduce autism-like behaviours in mice with Dravet syndrome. Moreover, for human with Dravet syndrome, gene therapy may improve seizure outcomes and lower their risk of SUDEP.

The findings of this study may have a wider clinical impact, as it helps to contribute to our understanding of gene therapy and how it could translate into a longer-lasting and alternative treatment to taking drug-resistant, anti-seizure medications for Dravet patients.

This research was funded, in part, by Katie’s Run for Epilepsy (www.katiesrun.ca).

  1. Niibori Y, Lee SJ, Minassian BA, Hampson DR (2020) Sexually Divergent Mortality and Partial Phenotypic Rescue After Gene Therapy in a Mouse Model of Dravet Syndrome. Hum Gene Ther 31(5-6): 339-351

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