Novel 1-time treatment cuts seizures by over 95% in Dravet mice
Gene-targeting therapy also shown to boost animal's survival
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A one-time treatment designed to boost the activity of a gene deficient in most people with Dravet syndrome significantly reduced seizures — both fever-triggered and spontaneous — in a mouse model of the rare condition, a severe form of epilepsy that typically begins in infancy.
Specifically, treated mice saw a reduction of more than 95% in spontaneous daily seizures over two weeks compared with untreated mice. In another experiment, when the animals’ body temperatures were raised, the proportion of mice experiencing fever-triggered seizures fell from more than 70% to about 15% in the treatment group.
Use of the investigational therapy, which aims to increase expression of the SCN1A gene, also improved survival among the animals, the researchers found. The treatment, the team noted, uses a modified, harmless adeno-associated virus type 9 (AAV9) to deliver a molecule called AntagoNAT, which ultimately activates SCN1A.
“In this proof-of-concept study, we have demonstrated for the first time the delivery of AntagoNAT via an AAV9 [carrier],” the scientists wrote. “Thus, offering the possibility of a one-time treatment for [Dravet syndrome] patients.”
The study, “AAV9-mediated targeting of natural antisense transcript as a novel treatment for Dravet syndrome,” was published in the journal Molecular Therapy Nucleic Acids by a research team in the U.K.
In people, Dravet usually begins during the first year of life. Most cases are caused by mutations in the SCN1A gene, which provides instructions for making a part of the sodium channel called NaV1.1. This sodium channel is essential for proper electrical signaling in the brain.
The resulting lack of working NaV1.1 contributes to frequent and often prolonged seizures, including those triggered by fever, as well as other Dravet symptoms. Those with Dravet also have increased rates of premature death, including from sudden unexpected death in epilepsy, known as SUDEP.
Given this, researchers have hypothesized that increasing production of the protein encoded by the SCN1A gene may represent a therapeutic strategy for Dravet.
Scientists set out to create more potent gene-targeting therapy
To test this, a team led by scientists at University College London used small molecules called AntagoNATs, which block a naturally occurring RNA molecule known as a natural antisense transcript (NAT).
Because NAT normally suppresses SCN1A gene activity, blocking this molecule would be expected to increase levels of SCN1A’s messenger RNA (mRNA), an intermediate molecule derived from DNA that cells use as a template to make proteins.
Previous experiments in a mouse model of Dravet showed that repeated AntagoNAT treatment directly into the fluid that surrounds the brain and spinal cord had the ability to reduce seizures.
Now, the researchers set out to design more potent AntagoNATs and package them into an AAV9 to explore whether the approach could provide sustained effects after a single administration.
A total of 18 new AntagoNATs were screened in lab-grown mouse cells for their ability to increase SCN1A’s mRNA levels. Two of the most promising candidates, AntagoNAT-H and AntagoNAT-K, were then packaged into AAV9 vectors and tested in a mouse model of Dravet, with AntagoNAT-H showing the strongest overall effects.
Fever triggered seizures drop from over 70% to 15% with treatment
The therapies were administered to newborn mice either directly into fluid-filled spaces in the brain or through a combination of brain and intravenous, or into-the vein, injections. With the combined approach, 84.2% of mice treated with AAV9-AntagoNAT-H survived to 100 days of age, compared with 50% of untreated Dravet mice. Treatment was also associated with fewer cases of SUDEP.
The one-time gene therapy also strongly protected against fever-triggered seizures. When researchers gradually raised the animals’ body temperature, the proportion of mice experiencing such a seizure fell from 73% in untreated mice to 15.4% in treated mice, the data showed.
The researchers noted that the fever-triggered seizures that did occur in animals treated with AntagoNAT-H also were significantly shorter and less severe than those in the untreated animals.
Continuous monitoring of brain activity over 15 days after gene therapy showed a similar, if not stronger, effect on spontaneous seizures. Treated mice averaged 0.03 seizures per day, compared with 1.12 in untreated mice — a reduction of 97.3%. Again, and seizures were also significantly shorter with treatment (2.56 vs. 25.14 seconds).
The AAV9-AntagoNAT strategy provides great promise as a genetic therapy for [Dravet syndrome].
Consistent with the therapy’s intended mechanism, AAV9-AntagoNAT-H significantly increased SCN1A mRNA levels in the animals’ brains. However, the researchers did not detect a significant increase in NaV1.1 sodium channel, that they said that may partly reflect technical difficulties in accurately measuring the protein.
When the treatment was tested in older mice, dose proved important. In 14-day-old mice — a developmental stage that roughly corresponds to that of a 1- to 2-year-old child — the dose used in newborn mice caused inflammation in the brain and liver and poorer survival. A total of 14% of treated mice survived to 100 days, compared with 60% of untreated mice, the data showed.
Lowering the dose produced a markedly different result: 87.5% of treated mice survived to 100 days, compared with 60% of untreated mice. Further, SCN1A mRNA levels in the brain also increased, the reseachers noted
More studies will be needed to fully assess the treatment’s safety and effectiveness, the researchers stressed. Still, the team wrote that “the AAV9-AntagoNAT strategy provides great promise as a genetic therapy for [Dravet syndrome].”
Encoded Therapeutics’ ETX101, a similar AAV9-based therapy designed to activate the SCN1A gene in specific brain cells, is being tested in children with Dravet in a pivotal Phase 1/2 clinical trial called ENDEAVOR (NCT05419492). Pivotal trials are those designed to produce robust results that, if positive, may support an application seeking a therapy’s approval.
Preliminary data from the first part of ENDEAVOR and other trials have shown that the one-time gene therapy is generally safe and reduces seizures for up to one year in children with Dravet.
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