08 Jun Hebrew University: First WWOX Gene Replacement Therapy Administered to Child With Hereditary Seizures
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
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.
MedicalResearch.com: How was replacement of the gene accomplished?
Response: The therapeutic strategy was based on delivering a healthy copy of the WWOX gene directly to neurons in the central nervous system using an adeno-associated viral (AAV) vector. This approach was designed to restore long-term WWOX expression in cells that lack a functional copy of the gene.
The foundation for this therapy came from extensive preclinical studies in our laboratory demonstrating that AAV-mediated WWOX replacement could rescue the neurological phenotype of WWOX-deficient mice. Following these successful proof-of-concept studies, the technology was licensed by Yissum, the technology transfer company of the Hebrew University of Jerusalem, to Mahzi Therapeutics. Mahzi subsequently advanced the program by developing a clinical-grade gene therapy product suitable for human administration.
The opportunity for clinical translation arose when Dr. Naama Orenstein, a physician at Schneider Children’s Medical Center, diagnosed an infant with a severe WWOX loss-of-function disorder. Given the devastating nature of the disease and the lack of effective treatment options, the clinical team, together with regulatory authorities and Mahzi Therapeutics, pursued a compassionate-use pathway to administer the therapy. The gene therapy was delivered directly into the brain through a cisterna magna (ICM) injection, allowing broad distribution of the therapeutic vector throughout the central nervous system. The procedure was well tolerated, and the child is currently clinically stable with encouraging early signs of improvement. While these initial observations are promising, it is important to emphasize that long-term follow-up will be required to fully evaluate the safety, durability, and therapeutic benefit of the treatment across the broad spectrum of neurological symptoms associated with WWOX deficiency.
MedicalResearch.com: What are the main findings? Might this therapeutic approach be used for other genetic disorders?
Response: The recent treatment represents the first known clinical use of WWOX gene replacement therapy in a child with WOREE syndrome. Early observations following treatment have been encouraging and support continued clinical development of this approach. However, it is important to emphasize that conclusions regarding efficacy will require longer-term follow-up and evaluation in additional patients.
More broadly, this work demonstrates that severe monogenic neurodevelopmental disorders may be amenable to precision gene replacement strategies when the disease is caused by loss of function of a single gene. Similar approaches are already being explored for a growing number of rare neurological diseases, and we believe that lessons learned from the WWOX program may help accelerate the development of therapies for other devastating pediatric disorders.
According to the National Institute of Neurological Disorders and Stroke, gene therapy approaches targeting the central nervous system represent one of the most promising frontiers in treating inherited neurological diseases, with AAV-based delivery systems increasingly showing durable results in both preclinical and early clinical studies.
MedicalResearch.com: What else should readers take away from your report?
Response: One important message is that transformative therapies often begin with fundamental scientific discovery. The path to this treatment started more than twenty years ago with basic research aimed at understanding the biological functions of WWOX. Over time, this work expanded from molecular biology to animal models, patient-derived cellular systems, brain organoids, translational development, and ultimately clinical application.
This achievement reflects the contributions of many students, postdoctoral fellows, collaborators, clinicians, industry partners, regulatory agencies, and, most importantly, the families who participated in and supported this research effort.
MedicalResearch.com: Is there anything else you would like to add? Any disclosures?
Response: While the early clinical observations are highly encouraging, it is important to proceed with scientific rigor and caution. Additional studies and long-term follow-up will be required to establish the safety, durability, and clinical benefit of WWOX gene replacement therapy.
One of the most exciting aspects of this achievement is that it demonstrates how decades of fundamental research can ultimately be translated into a potential treatment for patients with previously untreatable diseases. This milestone was made possible through the combined efforts of academic researchers, clinicians, regulatory authorities, industry partners, and, most importantly, the patients and families who have supported and participated in this journey.
Looking ahead, Mahzi Therapeutics is actively advancing the program toward formal regulatory development and plans to initiate IND-enabling studies in the near future. The goal is to generate the additional safety and efficacy data required to support clinical trials and, ultimately, broaden access to this therapy for other patients affected by WWOX-related disorders.
I would also like to acknowledge the WOREE patient community. Their resilience, advocacy, and trust have been instrumental in driving progress and maintaining momentum toward meaningful therapeutic advances.
Disclosure: Prof. Aqeilan is the academic researcher whose laboratory pioneered much of the preclinical work underlying WWOX gene replacement therapy. The technology was licensed through Yissum, the technology transfer company of the Hebrew University of Jerusalem, to Mahzi Therapeutics, and he serves as a scientific consultant to the company.
For more on advances in gene therapy and neurological disease research, see MedicalResearch.com’s genetic research coverage.
Citations
Obeid M, Wang J, Abudiab B, Akkawi R, Aqeilan RI. WWOX in brain development and disease: Molecular mechanisms and therapeutic opportunities. Neurobiol Dis. 2026 Jul;225:107446. doi: 10.1016/j.nbd.2026.107446
Obeid M, Akkawi R, Repudi S, Singh PK, Abudiab B, Berent A, Brennan T, Weiss Y, Shekh-Ahmad T, Aqeilan RI. Neuron-Specific WWOX Gene Therapy Produces Dose-Dependent, Durable Rescue in a Model of WWOX-Related Epileptic Encephalopathy. bioRxiv 2026.03.11.710995. https://doi.org/10.64898/2026.03.11.710995
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Last Updated on June 8, 2026 by Marie Benz MD FAAD