08 Jun 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.
L. Levi[/caption]
Liran Levi, PhD student
Faculty of Medicine at Hebrew University
MedicalResearch.com: What is the background for this study?
Response: Motivated behavior is driven by a group of brain regions called collectively the reward system. This neural system is at the heart of every decision we make about our actions - it integrates information about the world and decides whether to perform a behavior or not based on the predicted reward/benefit. The key molecule in this process is dopamine - whenever we perform a behavior that provides a reward dopamine is released in the reward system and reinforces this behavior. Drugs of abuse exploit this system - they cause abnormally high levels of dopamine, and thus force the reward system to seek drugs constantly, even after prolonged withdrawal. From a neurobiological perspective, that is how we view substance dependence - the reward system drives people to seek for the reward.
Shani Vaknine[/caption]
Shani Vaknine, Ph.D. candidate
Brain and Behavioral Sciences
The Hebrew University
MedicalResearch.com: What is the background for this study?
Response: We’ve long known that maternal stress during pregnancy can affect her baby’s development, but the molecular mechanisms behind this remained unclear. In our study, we explored how psychosocial stress experienced by the mother in late pregnancy influences tiny molecular fragments in the newborn’s blood. These fragments, called transfer RNA fragments or tRFs, were considered for many years to be disposable, but have recently been shown to have important biological functions.
Prof. Monsonego Ornan[/caption]
Efrat Monsonego Ornan, Ph.D
Head of School of Nutritional Sciences
Institute of Biochemistry and Nutrition
The Robert H. Smith Faculty of Agriculture,
Food and Environment
The Hebrew University of Jerusalem
MedicalResearch.com: What is the background for this study?
Response: Food supplies in recent decades have been dominated by heavily processed, ready-to-eat products. Essentially, 75% of all world food sales are of processed foods. Over the past 30 years, children’s ultra-processed food intake has increased markedly, with 50% of the children in the US consuming these foods. Only in the US does UPF comprise 58% of energy intake, of which 90% is derived from added sugars. This reflects children’s excessive consumption of food and drink that are high in fat and refined sugars but do not provide appropriate levels of the proteins, vitamins and minerals required for growth.
The negative health outcomes of excessive consumption of Ultra-processed food are well known, include obesity, metabolic syndrome and diabetes, and considered as the current world epidemic; the fact that children, during their postnatal development period (birth to adolescent), are the target of the Ultra-processed food industry is very disturbing in terms of public health. Bone development and growth are the characteristic phenomena of the childhood period. Yet, in spite of the huge importance of nutrition to bone development, the impact of Ultra-processed food consumption on skeleton development during childhood has never been studied directly, and this was the purpose of our study.
To this end, we used young rats which are an excellent pre-clinical model for growth and fed them with either the recommended diet for their age or a diet comprised of a typical Ultra-processed meal (a roll, hamburger, tomatoes, lettuce, ketchup and French fries) and a caloric soft drink.