Epilepsy breakthrough: Experimental gene therapy cuts seizures by over 90% in first human trial

An experimental gene therapy that targets specific areas of the brain has reduced epileptic seizures by more than 90% in three patients with drug-resistant epilepsy, raising hopes for a new approach to treating the neurological disorder.

The early-stage clinical trial, reported in The New England Journal of Medicine and highlighted by Nature on November 4, tested a combination of gene therapy and an existing drug to control abnormal electrical activity in the brain.

The treatment was administered directly into the brain, targeting the small region responsible for triggering seizures. Researchers reported substantial reductions in seizure frequency among all three participants, without any serious side effects during the initial observation period.

However, scientists have cautioned that the findings are preliminary, given the extremely small number of participants and unanswered questions about the treatment's long-term safety.

What is the new gene therapy for epilepsy? 

The experimental treatment uses a technique known as chemogenetics, which combines genetic engineering with medication to control the activity of specific neurons.

Unlike conventional epilepsy treatments, which generally rely on medicines to suppress seizures across the brain, this approach attempts to regulate the activity of neurons in the precise area responsible for triggering them.

Researchers used a modified virus called adeno-associated virus 9 (AAV9) to deliver a specially engineered gene into the targeted brain tissue.

The gene instructs certain neurons to produce a particular receptor designed to respond to an anti-psychotic medication called clozapine.

Once patients receive clozapine, the drug activates these engineered receptors, reducing the activity of the targeted neurons.

This helps suppress the abnormal electrical signals that trigger epileptic seizures. An important feature of the approach is that the medication effectively acts as an adjustable switch, allowing researchers to regulate the activity of the genetically modified neurons.

How much did epileptic seizures decline? 

The initial results showed a dramatic reduction in seizure frequency among all three participants.

Before receiving the treatment, two participants experienced an average of 4.5 seizures per month, while the third experienced approximately four seizures monthly.

Around two months after treatment, the average monthly seizure frequency had declined to 0.5 for the first two participants and zero for the third.

According to the findings, the combined seizure frequency fell by more than 90%.

The results suggest that chemogenetic treatment could offer a potential alternative for patients whose seizures remain uncontrolled despite conventional medication.

However, the researchers designed the trial primarily to assess safety and feasibility, rather than establish definitive treatment effectiveness. There was no control group against which the results could be compared.

Why is this development significant? 

Epilepsy is a neurological disorder characterised by recurrent seizures caused by abnormal electrical activity in the brain.

According to the World Health Organization, around 50 million people worldwide live with epilepsy, making it one of the most common neurological conditions globally.

Although anti-seizure medications can control seizures in many patients, approximately one-third of people with epilepsy continue experiencing seizures despite available drug treatments.

For some patients, surgery to remove or destroy the seizure-generating brain tissue may be an option. However, this is not always possible, particularly when the affected region is close to areas responsible for essential brain functions.

Chemogenetics could potentially offer another route by modifying the activity of specific neurons without necessarily removing the affected brain tissue.

The latest research is particularly significant because it represents an early demonstration of this approach in human patients, after years of development primarily in laboratory and preclinical research.

What are the risks and limitations? 

Despite the encouraging results, researchers have warned against interpreting the findings as proof of a cure for epilepsy.

The biggest limitation is the trial's sample size. With only three participants, researchers cannot establish whether the treatment will work consistently across a larger and more diverse patient population. There are also questions about the long-term safety of the medication used in the treatment.

Matthew Walker, a neurologist at University College London who was not involved in the research, highlighted concerns about prolonged clozapine use.

The medication is an antipsychotic drug, and higher doses have been associated with cardiovascular complications and other adverse effects.

Walker also pointed out that it remains unclear whether the reduction in seizures resulted from the gene therapy, clozapine or the combination of both.

Further clinical trials involving more participants and longer follow-up periods will be necessary to establish the treatment's effectiveness, safety and durability.