Restoration of the inverse gene activity of SCN1A in a mouse model | seizures stopped, further gains seen even after symptoms appear

recovery Scn1a The mouse type of gene that is often defective in humans Dravet syndrome Repressed seizures and normal behavior in mice, even after symptoms appear, a study shows.

Notably, improvements occurred in young mice as well as in adult mice with prolonged symptoms.

These findings may guide new therapeutic strategies for Dravet, such as genetic therapies, Scientists note. 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 syndrome“in the magazine Nature Connections.

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Understanding the role of SNC1A in Dravet

Up to 90% of cases of Dravet syndrome are in humans it causes with defects in SCN1A, a gene encoding NaV1.1 – a protein channel found on the surface of neurons that controls the influx of activated sodium ions into and out of cells. These defects lead to long-lasting epileptic seizures, usually beginning in the first year of life.

despite Available treatments Reducing the number and severity of seizures, they cannot fully control these seizures – or delay seizures symptoms Of the disease. As a result, new investigational therapies, including gene therapies, are being developed to restore SCN1A Gene activity or NaV1.1.

However, whether the symptoms are reversible after its success SCN1ANaV1.1 recovery, 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 deactivation. Scn1a Gene – The name in lowercase indicates that this is a genetic variant in mice. this is Scn1a The gene can be reactivated at any time, even after disease onset.

In Dravet mice with inactivation Scn1aThere was no difference in weight gain in the first 6 weeks of life compared to control mice. Still, with disabled Scn1a He started dying of sudden unexpected death in epilepsy known as SUDEP.

Early reactivation of Scn1abetween 1 and 12 days after birth, prevents sudden sudden death in 90% of infants Scn1a Mice up to 120 days (4 months) after injection. Early activation also stopped seizures caused by high temperatures.

Scn1a It was reactivated at 30 days of age to determine its effect after onset of symptoms, which occurs between 2-3 weeks of age in mice.

Molecular analysis confirmed a 50% reduction in Scn1a Genetic activity in the cerebral cortex, the outermost layer of the brain, in Dravet mice compared to reactivated activity Scn1a Mice and healthy controls. Similar results were seen for NaV1.1.

Scn1a Reactivation of Dravet mice that survived day 24 resulted in complete rescue of SUDEP in the following 4 months. Meanwhile, the rat dravet continued to die.

Moreover, spontaneous seizures, as measured by the electrical activity of the brain, were observed in most Dravet mice. At the same time, all those who have Scn1a The reactivation did not experience any spontaneous seizures,” indicating that Scn1a Reactivating the gene was able to protect against behavioral and/or electrical seizures,” the researchers wrote.

Consistently, all Dravet rats experienced temperature-induced seizures at day 60 Scn1a The reactivated mice were having seizures at this time.

Because Dravet is associated with neuropsychiatric problems — which typically include hyperactivity, attention deficit, anxiety-like behaviors, impaired social interactions, and severe cognitive deficits — the team exposed Scn1a He reactivated the mice for several behavioral tests.

normalization Scn1a Post-symptomatic activity rescued most of the behavioral deficiencies of the Dravet rats, including hyperactivity, social interaction, working memory, and memory defects.

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therapeutic ability

Basic behavioral characteristics, Drift rats were characterized by impaired excitability and high-frequency electrical signals of different subtypes of neurons in their brains. Scn1a Reactivation restores these signal defects.

Analysis of changes in the activity of other genes before and after Scn1a Reactivation, no differences were found between the reactivated mice and the healthy control mice. in comparison, Scn1a Reactivation mostly normalized changes in the activity of other genes seen in Dravet mice. Furthermore it, Scn1a Normalization rescued changes in genes associated with inflammation in dravite mice.

Finally, the team evaluated the effect of Scn1a Reactivation in 3-month-old Dravet rats after a prolonged period of symptoms is about 10 weeks, or about 2.5 months. Mice that experienced at least one seizure, assessed by brain electrical activity over a two-week period, were randomly selected Scn1a Reactivation or control.

Compared with pre-activation (baseline), 80% of inactive mice had more seizures, whereas all mice had more seizures. Scn1a The reactivated mice showed a significant reduction in the number of seizures in the first 8 days.

These attacks completely disappeared in the following days, with 100% of the mice showing a reduction in seizures compared to baseline. Similar results were observed in adult mice exposed to heat-induced seizures.

“Given that 3-month-old mice are roughly compatible with 20-year-old humans, the results of this trial help to look optimistically also at the treatment of adult patients,” the researchers noted.

“We have shown that the effective restoration of Scn1a Gene expression in A [Dravet syndrome] The mouse model, after the onset of symptoms, can stop seizures with associated severe behavioral changes, the team wrote.

They conclude that these findings “may be used to guide new therapeutic strategies” for Dravet.

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