Restoring the activity of Scn1a – a murine variant of the gene that is often defective in humans with Dravet syndrome – suppressed seizures and normalized behavior in mice, even after symptoms appeared, a study has shown.
Notably, the improvements occurred in juvenile mice as well as adult mice with prolonged symptoms.
These findings could potentially guide new therapeutic strategies for Dravet, such as gene therapies, the scientists noted. Current experimental treatments for this severe form of epilepsy often aim to restore gene activity.
The study, “Scn1a gene reactivation after symptom onset rescues pathological phenotypes in a mouse model of Dravet syndromewas published in the journal Nature Communication.
Understanding the role of SNC1A in Dravet
Up to 90% of cases of Dravet syndrome in humans are caused by defects in SCN1A, a gene that codes for NaV1.1 – a protein channel found on the surface of nerve cells that controls the flow of activating sodium ions into and out of cells. Such defects lead to episodes of prolonged seizures that usually begin within the first year of life.
Although available treatments reduce the number and severity of seizures, they cannot completely control these seizures or delay the neurological symptoms of the disease. As a result, new experimental treatments, including gene therapies, are being developed to restore SCN1A NaV1.1 gene or activity.
However, if the symptoms are reversible after a SCN1AThe restoration of /NaV1.1, 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 Scn1a gene – the lowercase name indicates that this is the mouse variant of the gene. This Scn1a The gene can be reactivated at any time, even after the onset of the disease.
In Dravet mice with a Scn1a, there was no difference in weight gain during the first six weeks of life compared to control mice. However, those who have a disabled device Scn1a started dying a sudden and unexpected death due to epilepsy, known as SUDEP.
Early reactivation of Scn1abetween one and 12 days after birth, prevented SUDEP in 90% of Scn1a mouse 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 and 3 weeks in mice.
Molecular analysis confirmed a 50% reduction in Scn1a gene activity in the cerebral cortex, the outermost layer of the brain, in Dravet mice compared to reactivated mice Scn1a mice and healthy controls. Similar results were observed for the NaV1.1 protein.
Scn1a reactivation in Dravet mice that survived beyond day 24 resulted in complete rescue of SUDEP over the next four months. Meanwhile, the Dravet mice continued to die.
In addition, spontaneous seizures, measured by brain electrical activity, were observed in most Dravet mice. At the same time, all those who have Scn1a reactivation did not experience any spontaneous seizures, “suggesting that Scn1a gene reactivation may have protected behavioral and/or electrographic seizures,” the researchers wrote.
Consistently, all Dravet mice exhibited temperature-induced seizures by day 60. None of the Scn1a reactivated mice had convulsions at this time.
Because Dravet comes with neuropsychiatric issues — these typically include hyperactivity, attention deficit, anxious behaviors, impaired social interactions, and severe cognitive deficits — the team submitted Scn1a mice reacted to several behavioral tests.
Normalization of Scn1a activity after symptom onset rescued most of the Dravet mice’s behavioral impairments, including hyperactivity, social interaction, working memory, and memory defects.
Underlying behavioral characteristics, the Dravet mice were marked by impaired excitability and high-frequency electrical signaling from different nerve cell subtypes in their brains. Scn1a reactivation restored these signaling faults.
An analysis of changes in the activity of other genes, before and after Scn1a reactivation, found no difference between reactivated mice and healthy control mice. In comparison, Scn1a reactivation mainly normalized changes in the activity of other genes seen in Dravet mice. In addition, 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 about 2.5 months. Mice that experienced at least one seizure, as assessed by brain electrical activity for two weeks, were randomly assigned to Scn1a reactivation or control.
Compared to before activation (baseline), 80% of non-activated mice had more seizures, while all Scn1a reactivated mice showed a significant reduction in the number of episodes during the first eight days.
Such attacks disappeared completely within days, with 100% of mice showing seizure reduction from baseline. Similar results were observed in adult mice subjected to heat-induced convulsions.
“Since 3-month-old mice roughly correspond to 20-year-old humans, the results of this experiment provide optimism for treating adult patients as well,” the researchers noted.
“We have shown that effective restoration of Scn1a gene expression in a [Dravet syndrome] mouse model after symptom onset, can suppress seizures as well as associated severe behavioral alterations,” the team wrote.
These findings “could potentially be used to guide new therapeutic strategies” for Dravet, they concluded.