Genetic Research, Neurology, Pediatrics / 08.06.2026
Hebrew University: First WWOX Gene Replacement Therapy Administered to Child With Hereditary Seizures
[caption id="attachment_74143" align="aligncenter" width="500"] Conceptual illustration of AAV9-mediated delivery of the WWOX gene to neurons, representing the first clinical use of a gene replacement therapy designed to restore WWOX function in the brain of an infant with WOREE syndrome.Credit: Hebrew University of Jerusalem / AI-generated illustration[/caption]
MedicalResearch.com Interview with:
Prof. Rami Aqeilan
Jacob M. Eisenberg and Thomas W. Baylek Chair for Medical Research in the field of Genetic Engineering
Lautenberg Center for Immunology and Cancer Research
Faculty of Medicine
Hebrew University of Jerusalem
Jerusalem, Israel
This therapy is based on more than a decade of research led by Prof. Rami Aqeilan, brought together with scientists, clinicians, and biotechnology leaders from Israel and the United States, including Dr. Naama Orenstein and Dr. Dror Kraus of Schneider Children's Medical Center and Dr. Yael Weiss, CEO of Mahzi Therapeutics.
MedicalResearch.com: What is the background for this study? Would you briefly explain the functions of the WWOX gene? Response: WWOX (WW domain-containing oxidoreductase) is a highly conserved gene that plays essential roles in brain development, neuronal function, and cellular stress responses. Nearly two decades ago, our laboratory and others began studying WWOX because of its involvement in cancer biology. However, over the past decade it became increasingly clear that WWOX is also critical for normal brain development. Inherited loss-of-function mutations in WWOX cause a devastating neurological disorder known as WOREE syndrome (WWOX-Related Epileptic Encephalopathy). Affected children typically develop severe, treatment-resistant epilepsy during infancy, profound developmental delay, intellectual disability, and significant motor impairment. Unfortunately, there has been no disease-modifying therapy available for these patients. The foundation for this therapeutic approach came from years of fundamental research in our laboratory aimed at understanding the biological role of WWOX in the nervous system. Using genetically engineered mouse models, we discovered that deleting WWOX specifically in neurons was sufficient to reproduce the major neurological features observed in mice lacking WWOX throughout the entire body. This finding demonstrated that neuronal WWOX deficiency is a primary driver of the disease and suggested that restoring WWOX function in neurons might be sufficient to achieve therapeutic benefit. Based on this insight, we developed a gene replacement strategy designed to restore WWOX expression selectively in neurons using an adeno-associated viral (AAV) vector. In preclinical studies, delivery of this vector into the brains of WWOX-deficient mice resulted in remarkable rescue of the disease phenotype. Treated animals exhibited normal behavior, elimination of seizures, and substantial correction of the neurological abnormalities associated with WWOX deficiency. These findings provided the critical proof-of-concept that neuronal gene replacement could effectively reverse key features of the disease and laid the scientific foundation for translating this approach toward clinical application in patients with WOREE syndrome.
Conceptual illustration of AAV9-mediated delivery of the WWOX gene to neurons, representing the first clinical use of a gene replacement therapy designed to restore WWOX function in the brain of an infant with WOREE syndrome.Credit: Hebrew University of Jerusalem / AI-generated illustration[/caption]
MedicalResearch.com Interview with:
Prof. Rami Aqeilan
Jacob M. Eisenberg and Thomas W. Baylek Chair for Medical Research in the field of Genetic Engineering
Lautenberg Center for Immunology and Cancer Research
Faculty of Medicine
Hebrew University of Jerusalem
Jerusalem, Israel
This therapy is based on more than a decade of research led by Prof. Rami Aqeilan, brought together with scientists, clinicians, and biotechnology leaders from Israel and the United States, including Dr. Naama Orenstein and Dr. Dror Kraus of Schneider Children's Medical Center and Dr. Yael Weiss, CEO of Mahzi Therapeutics.
MedicalResearch.com: What is the background for this study? Would you briefly explain the functions of the WWOX gene? Response: WWOX (WW domain-containing oxidoreductase) is a highly conserved gene that plays essential roles in brain development, neuronal function, and cellular stress responses. Nearly two decades ago, our laboratory and others began studying WWOX because of its involvement in cancer biology. However, over the past decade it became increasingly clear that WWOX is also critical for normal brain development. Inherited loss-of-function mutations in WWOX cause a devastating neurological disorder known as WOREE syndrome (WWOX-Related Epileptic Encephalopathy). Affected children typically develop severe, treatment-resistant epilepsy during infancy, profound developmental delay, intellectual disability, and significant motor impairment. Unfortunately, there has been no disease-modifying therapy available for these patients. The foundation for this therapeutic approach came from years of fundamental research in our laboratory aimed at understanding the biological role of WWOX in the nervous system. Using genetically engineered mouse models, we discovered that deleting WWOX specifically in neurons was sufficient to reproduce the major neurological features observed in mice lacking WWOX throughout the entire body. This finding demonstrated that neuronal WWOX deficiency is a primary driver of the disease and suggested that restoring WWOX function in neurons might be sufficient to achieve therapeutic benefit. Based on this insight, we developed a gene replacement strategy designed to restore WWOX expression selectively in neurons using an adeno-associated viral (AAV) vector. In preclinical studies, delivery of this vector into the brains of WWOX-deficient mice resulted in remarkable rescue of the disease phenotype. Treated animals exhibited normal behavior, elimination of seizures, and substantial correction of the neurological abnormalities associated with WWOX deficiency. These findings provided the critical proof-of-concept that neuronal gene replacement could effectively reverse key features of the disease and laid the scientific foundation for translating this approach toward clinical application in patients with WOREE syndrome.
Dr. Schaffner[/caption]
William Schaffner, MD
MedicalResearch.com: What roles do a decrease in US immunization rates and/or increased immigration from under-vaccinated area play in this increase?
Response: The substantial majority of unimmunized children in the US were born and raised in this country. They usually are members of middle- or upper-income families. The most frequent importers of measles into the US are our own unimmunized children who travel abroad, encounter measles virus and bring it back to their homes where the virus then spreads among the child’s schoolmates and playmates, creating an outbreak.
Samson Nivins PhD
Postdoctoral Researcher, specializing in Perinatal and Pediatric Neurology
[caption id="attachment_71834" align="alignleft" width="92"]
Clubfoot
Clubfoot
Dr. Casale[/caption]
Thomas B. Casale, M.D.
Professor of Medicine and Pediatrics
Chief of Clinical and Translational Research
Division of Allergy and Immunology
USF Health Morsani College of Medicine
University of South Florida
Tampa, Florida
MedicalResearch.com: What is the background for this study?
Response: The data leading to FDA approval of neffy came from extensive pharmacokinetic and pharmacodynamic studies. As with previous epinephrine delivery devices, the FDA asked for data showing that after delivery of neffy the epinephrine blood levels and expected changes in pulse and blood pressure were similar to those achieved with injectable formulations of epinephrine. neffy performed as expected with blood levels of epinephrine bracketed by those achieved with EpiPen and a needle and syringe along with increases in pulse and blood pressure compatible with the epinephrine levels measured.
Additionally, clinicians are interested in whether neffy would perform similarly in real clinical situations. The data from the neffy experience program provides real-world assurance that neffy can effectively treat acute allergic reactions. Given the large number of patients and the similar findings to those achieved with injectable epinephrine in previous studies, the data should provide assurance that neffy can be an effective substitute for injectable epinephrine in patients that desire a needle-free option.
Dr. Dunbar[/caption]
MedicalResearch.com Interview with:
Michael S. Dunbar, PhD
