An eight-month-old infant with a severe genetic epilepsy has become the first patient in the world to receive an experimental gene replacement therapy designed to restore the function of the WWOX gene directly in the brain.
The treatment, administered at Schneider Children’s Medical Center of Israel, represents a milestone in the development of precision genetic therapies for rare neurological disorders.
The therapy is based on more than a decade of research led by Rami Aqeilan of the Lautenberg Center for Immunology and Cancer Research at the Faculty of Medicine of the Hebrew University of Jerusalem. The effort brought together scientists, clinicians, and biotechnology leaders from Israel and the US, including Naama Orenstein and Dror Kraus of Schneider Children’s Medical Center and Yael Weiss, CEO of Mahzi Therapeutics.
The infant appeared healthy at birth but began experiencing severe epileptic seizures at six weeks of age. Genetic testing revealed a rare inherited defect in the WWOX gene, causing WOREE syndrome (WWOX-related epileptic encephalopathy), a disorder characterised by early-onset, drug-resistant epilepsy, profound developmental impairment, and a high risk of premature death.
While the specific mutation treated in this case is particularly prevalent among individuals of Yemeni Jewish ancestry, numerous disease-causing variants of the WWOX gene have been identified worldwide. These mutations similarly impair WWOX function and are associated with severe neurodevelopmental disorders, including WOREE syndrome.
Although WWOX was originally studied for its role in cancer biology, Aqeilan’s research revealed the gene is also essential for normal brain development and neurological function. Using genetically engineered mouse models lacking WWOX expression in the brain, his laboratory demonstrated loss of the gene causes severe neurological abnormalities, including epilepsy, developmental delay, defective myelination, and premature death—closely mirroring the symptoms observed in children with WOREE syndrome.
Building on these findings, the research team developed a gene replacement strategy using an adeno-associated viral vector (AAV9) to deliver a healthy copy of the WWOX gene to neurons. In preclinical studies, a single administration restored WWOX expression and improved seizures, neurological deficits, growth abnormalities, and survival in animal models, providing proof-of-concept for a therapeutic approach to WWOX-related disease.
“This moment represents the culmination of many years of basic and translational research,” Aqeilan said.
“What began as an effort to understand the biological function of a gene has evolved into a potential therapeutic strategy for children affected by one of the most severe forms of genetic epilepsy.”
Following years of academic research and development, the technology was licensed to Mahzi Therapeutics, which advanced the programme by manufacturing the clinical-grade gene therapy vector and supporting translational and regulatory activities. After Orenstein and her colleagues initiated a compassionate-use programme for the child, and following extensive preparation and regulatory approvals, the therapy was administered directly into the infant’s brain.
One month after treatment, the child remained clinically stable and was discharged from the hospital. No recurrence of the severe seizures that had previously threatened his development and survival had been reported during this initial observation period. Long-term clinical follow-up will be required to evaluate the safety and efficacy of the treatment.
“This achievement demonstrates the power of combining scientific discovery, clinical excellence, and international collaboration,” said Aqeilan.
“It highlights how fundamental research can advance from the laboratory toward potential new treatment options for patients with rare genetic diseases.”
The breakthrough builds upon a body of research from Aqeilan’s laboratory that established WWOX as a critical regulator of nervous system development and function. The work has helped lay the foundation for new therapeutic approaches to rare genetic neurological disorders and has received international support, including a European Research Council Proof-of-Concept grant aimed at advancing WWOX gene therapy toward clinical application.
While the infant will continue to be closely monitored, the treatment represents an important step in the development of personalised therapies for rare genetic epilepsies and offers hope for families affected by WWOX-related disorders worldwide.