From Gene to Therapy: Translating WWOX Biology into a Gene Therapy for WOREE Syndrome

WOREE syndrome (WWOX-related epileptic encephalopathy) is a devastating neurodevelopmental disorder caused by biallelic loss-of-function mutations in the WWOX gene. Affected children develop severe drug-resistant epilepsy, profound developmental delay, intellectual disability, and significant motor impairment, with no disease-modifying therapies currently available.

Over the past two decades, our laboratory has investigated the biological functions of WWOX in cancer and neurological disease. Through studies in genetically engineered mouse models, patient-derived iPSC cells, and human brain organoids, we demonstrated that neuronal loss of WWOX is a key driver of disease pathogenesis and that restoration of WWOX expression can reverse major disease-associated phenotypes.

These findings formed the basis for the development of an AAV-based gene replacement therapy designed to restore WWOX expression in the central nervous system. Following successful preclinical studies demonstrating rescue of seizures, neurological deficits, and survival in WWOX-deficient mice, the technology was translated into a clinical-grade therapeutic product. Recently, the first patient with WOREE syndrome received WWOX gene therapy under a compassionate-use protocol, representing an important milestone in the translation of fundamental gene discovery into a potential treatment for a devastating pediatric neurological disorder.

This presentation will describe the scientific journey from gene discovery and disease mechanism to therapeutic development, highlighting the opportunities and challenges of translating rare disease biology into first-in-human gene therapy.