A new drug has been shown to reduce seizures in children with a rare and severe form of epilepsy called Dravet syndrome by up to 90% by addressing the underlying genetic mutation that causes the disease.
This finding came from an early-stage trial that was not designed to show efficacy, so it is not yet clear whether the results will hold up in larger trials. But if realized, it would be the first drug that could change the trajectory of a disease that carries delayed neurodevelopment and a high risk of sudden death.
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Results from a clinical trial published March 4 in the New England Journal of Medicine showed that the drug, called zolevnersen, can be safely given to children with Dravet syndrome, reducing the number of seizures and improving overall quality of life.
Although the study’s main goal was to test the drug’s safety and find the optimal dose, Cross’s team also investigated whether the treatment led to reduced seizures, improved neurodevelopment, and quality of life.
“We saw improvements in all of these areas, especially at the higher doses,” he told Live Science.
Addressing the root causes
In addition to frequent seizures, people with Dravet syndrome also have developmental delays, coordination problems, behavioral problems, and other symptoms. Approximately half of patients with Dravet disease die suddenly and prematurely due to this disease. All of these symptoms are caused by problems with interneurons, a type of cell that relays messages in the central nervous system. Antiepileptic drugs and implants can reduce the number of seizures to some extent, but they do not improve developmental delays.
A gene called SCN1A controls the formation of sodium channels required for interneuron signaling. Most people have two copies of this gene, but in many people with Dravet syndrome, a change in the gene causes one of these copies to no longer function properly. Dr. Zorebnersen solved this problem by increasing the amount of protein produced by the other working copy of the SCN1A gene. The drug is a type of molecule called an antisense oligonucleotide that works by increasing the messenger RNA that directs a functional version of the SCN1A protein.
To ensure that the zorebnersen reached the brain, a lumbar puncture, an injection into the spine that injected the drug into the cerebrospinal fluid that bathes the brain, was performed. The treatment requires clinic visits for each dose, but studies have shown that the effects last for several months.
A total of 81 children aged 2 to 18 took part in this early-stage study, which took place in hospitals in the UK and US. Cross and his colleagues were particularly interested in knowing which dose of zorebnersen would produce the best results, so they tried several different doses. Some received one treatment, while others underwent repeated lumbar punctures every few months. Thereafter, 75 of the study participants continued to receive zolevnersen treatment every four months. Participants were followed for a total of 3 years.
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After 20 months of treatment, seizures were reduced by 59% to 91% in children who received the highest dose at the start of the trial.
Some children in the study had mild side effects from the lumbar puncture, such as headaches, vomiting, or increased protein levels in their cerebrospinal fluid. But overall, the trial showed that the drug was safe for children.
This study has some limitations. Only a small group of children were studied and there was no placebo group.
In a large clinical trial already underway, researchers are looking at an additional 170 children to see if the treated children actually showed more improvement than the control group.
“We’re targeting the actual root cause of the problem, so not only are we reducing seizures, but we’re also improving other aspects of the disease,” Cross said.
The trial is scheduled to be completed in October 2028, so even if the results are positive, it will be several years before this treatment is available to all children with Dravet syndrome.
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