Restoring the activity of Scn1a — a mouse variant of the gene that is often defective in humans with Dravet syndrome — suppressed seizures and normalized behavior in mice, even after symptom onset, a study showed.
Notably, the improvements occurred in juvenile mice as well as in adult mice with prolonged symptoms.
These findings may potentially guide new therapeutic strategies for Dravet, such as gene therapies, the scientists noted. Current investigational treatments for this severe form of epilepsy oftentimes aim to restore gene activity.
the study,”Scn1a Gene reactivation after symptom onset rescues pathological phenotypes in a mouse model of Dravet syndrome,” was published in the journal Nature Communications.
Understanding the role of SNC1A in Dravet
Up to 90% of Dravet syndrome cases in humans are caused by defects in SCN1A, a gene that encodes NaV1.1 — a protein channel found on the surface of nerve cells that controls the flow of activating sodium ions in and out of cells. Such defects lead to episodes of prolonged epileptic seizures that typically begin in the first year of life.
Although available treatments reduce the number and severity of seizures, they cannot wholly control these convulsive attacks — or delay neurological symptoms of the disease. As a result, new investigational treatments, including gene therapies, are being developed to restore SCN1A gene or NaV1.1 activity.
However, whether symptoms are reversible following successful SCN1A/NaV1.1 restoration, especially after disease onset, remains unknown.
To find out, researchers based at the IRCCS San Raffaele Scientific Institute, in Italy, studied a Dravet mouse model with a deactivated Scn1a gene — the name in lowercase denotes that this is the gene variant in mice. This Scn1a gene can be reactivated at any time, even after disease onset.
In Dravet mice with a deactivated Scn1a, there was no difference in weight gain in the first six weeks of life compared with control mice. Still, those with a deactivated Scn1a started to die of sudden unexpected death in epilepsy, known as SUDEP.
Early reactivation of Scn1abetween one and 12 days after birth, prevented SUDEP in 90% of Scn1a mice up to 120 days (4 months) after injection. Early reactivation also stopped seizures induced by high temperatures.
Scn1a was reactivated at 30 days of age to determine its impact after symptom onset, which occurs between 2–3 weeks of age in mice.
Molecular analysis confirmed a 50% reduction of Scn1a gene activity in the cerebral cortex, the brain’s outermost layer, in Dravet mice compared with reactivated Scn1a mice and healthy controls. Similar results were seen for the NaV1.1 protein.
Scn1a reactivation in Dravet mice that survived past day 24 resulted in a complete rescue of SUDEP in the following four months. Meanwhile, the Dravet mice continued to die.
Further, spontaneous seizures, as measured by brain electrical activity, were observed in most Dravet mice. At the same time, all those with Scn1a reaction did not experience any spontaneous seizures, “suggesting that Scn1a gene reactivation was able to protect from behavioral and/or electrographic seizures,” the researchers wrote.
Consistently, all Dravet mice experienced temperature-induced seizures at day 60. None of the Scn1a reactivated mice had seizures at this time point.
Because Dravet is accompanied by neuropsychiatric problems—these usually include hyperactivity, attention deficit, anxiety-like behaviors, impaired social interactions, and severe cognitive deficits—the team subjected Scn1a reactivated mice to several behavioral tests.
Normalization of Scn1a Activity after symptom onset rescued most of the behavioral deficiencies of Dravet mice, including hyperactivity, social interaction, working memory, and memory defects.
Underlying behavioral characteristics, Dravet mice were marked by impaired excitability and high-frequency electrical signaling of different subtypes of nerve cells in their brains. Scn1a reactivation restored these signaling defects.
An analysis of changes in the activity of other genes, before and after Scn1a reactivation, found no differences between reactivated mice and healthy control mice. in comparison, Scn1a reactivation mostly normalized changes in other gene activity seen in Dravet mice. Moreover, Scn1a normalization rescued changes in inflammation-related genes in Dravet mice.
Finally, the team assessed the impact of Scn1a reactivation in 3-month-old adult Dravet mice after a prolonged symptomatic period of about 10 weeks, or approximately 2.5 months. Mice that experienced at least one seizure, assessed by brain electrical activity over two weeks, were randomly assigned to Scn1a reactivation or control.
Compared with before activation (baseline), 80% of non-activated mice had more seizures, whereas all Scn1a reactivated mice showed a significant reduction in the number of episodes in the first eight days.
Such attacks completely disappeared in the following days, with 100% of mice showing seizure reduction versus baseline. Similar results were observed in adult mice subjected to heat-induced seizures.
“Considering that 3-month-old mice correspond roughly to humans of 20 years of age, the results of this experiment help to look with optimism also to the treatment of adult patients,” the researchers noted.
“We showed that efficient restoration of Scn1a gene expression in a [Dravet syndrome] mouse model after symptom onset, can suppress seizures together with the associated severe behavioral alterations,” the team wrote.
These findings “may potentially be used to guide new therapeutic strategies” for Dravet, they concluded.