Israeli ‘smart’ gene therapy activates only during epileptic seizures
Baku, June 23, AZERTAC
Israeli scientists have developed a gene therapy for epilepsy that activates only during seizures, introducing a self-regulating biological system designed to respond in real time to abnormal brain activity and potentially limit disease progression, according to TPS-IL. The approach marks a shift from continuous drug delivery to an adaptive treatment that switches on only under conditions of neurological stress.
Epilepsy affects more than 50 million people worldwide, and nearly one in three patients does not respond to existing medications. Current therapies can reduce seizure frequency and severity but do not address the underlying disease process or prevent its progression.
The key innovation is an activity-responsive genetic “switch” that remains inactive under normal conditions but becomes activated when neurons become hyperactive, as during a seizure. Unlike conventional gene therapies that act continuously after delivery, this system is designed to intervene only at moments of pathological activity.
At the center of the approach is Nrf2, a protein that helps protect cells from oxidative stress associated with seizures and brain injury. Because continuous activation of Nrf2 may interfere with normal brain function, researchers paired it with the cfos promoter, a genetic regulatory element that is naturally activated only in highly active neurons, enabling precise timing and location of the therapeutic response.
“Our goal was to create a treatment that works with the brain, not against it,” said Prof. Tawfeeq Shekh-Ahmed of the School of Pharmacy at The Hebrew University of Jerusalem, who led the research. “Instead of constant intervention, we wanted something that activates only during harmful activity.”
In preclinical studies, the therapy reduced seizure severity, lowered seizure burden, and increased seizure-free periods. It also improved memory, behavior, and overall brain function in epilepsy models, suggesting benefits beyond seizure suppression.
Importantly, the therapy remained effective even after epilepsy had already developed, including in models of long-standing or drug-resistant disease, indicating potential relevance for patients who do not respond to current treatments.
“This is a proof of concept for a smarter kind of therapy,” Prof. Shekh-Ahmed said. “One that is precise, adaptive, and minimizes unwanted side effects.”
While further research is required before human trials, the findings point toward a new generation of dynamic, self-regulating therapies designed to intervene at early stages of neurological disease. Because the therapy activates only during seizure activity, it may in the future reduce reliance on continuous medication and the systemic side effects associated with long-term anti-epileptic drug use.
Beyond seizure control, this targeted activation could potentially influence the course of epilepsy itself. By intervening at moments when abnormal neural activity emerges, the therapy may help slow or alter disease-related changes in brain networks over time. The preclinical improvements in memory and behavior also suggest possible broader neuroprotective effects, though these findings remain limited to experimental models.
More broadly, the same activity-triggered genetic design could, in principle, be adapted to other neurological conditions characterized by episodic or network-level abnormal brain activity. These include post-traumatic epilepsy following traumatic brain injury, seizure disorders after stroke, and other forms of acquired epilepsy linked to cortical injury. It may also have relevance for conditions involving abnormal neural firing or oscillations, such as migraine with aura and certain movement disorders, including Parkinson’s disease.
The study was published in the peer-reviewed Signal Transduction and Targeted Therapy.
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