Infant receives first-in-human gene therapy for severe genetic epilepsy

A new experimental gene therapy has shown early success in treating a rare genetic epilepsy syndrome.

WWOX-related epileptic encephalopathy (WOREE syndrome) is a rare neurodevelopmental disorder that results in drug-resistant seizures, intellectual disability and high likelihood of premature death. Clinicians have now delivered a first-in-human experimental gene therapy to an infant with the condition at the Schneider Children's Medical Centre of Israel in Petah Tikvah, with the child showing early improvements following treatment.

Professor Rami Aqeilan from the Hebrew University of Jerusalem, Israel, whose team has been leading the work, said: 'What began as a scientific effort to understand the biological function of a gene has now become a potential treatment for children suffering from one of the most severe forms of epilepsy.'

WOREE syndrome occurs when a person inherits two pathogenic variants of the WWOX gene, one from each parent. Those with a single altered copy of the gene do not develop symptoms but can pass the variant on to their children. To date, only 60 to 90 cases have been described in the medical literature, making it an ultra-rare condition.

First investigated for its role in cancer, WWOX was later shown to play a critical role in brain development. Mouse models lacking WWOX gene function develop defects that closely resemble those seen in children with WOREE syndrome, including seizures and severe neurological abnormalities. In preclinical studies, a single dose of gene therapy restored gene expression, reduced seizures and improved survival in the animals.

The gene therapy was approved under a compassionate-use framework, which allows experimental treatments to be given outside clinical trials due to the severity of certain conditions. Clinicians, biotechnologists and researchers from Israel and the USA collaborated to develop an adeno-associated viral vector designed to deliver a healthy copy of WWOX directly to the central nervous system. The vector specifically targets neurons rather than all brain cells, as these appear to be the most affected cell type in the disease. The team is now planning to submit an application for regulatory approval in the USA.

The approach 'gives hope to many patients who not only have this syndrome, but also other neurodevelopmental problems,' said Professor Aqeilan. 'Gene therapy can be the answer to many of these diseases. We must continue working to promote it.'

One month after treatment, the infant has remained in a stable condition and has not experienced severe seizures. This trial represents an important early milestone in the development of therapeutic approaches for WOREE syndrome. However, long-term follow-up will be needed to confirm the safety and efficacy of this experimental gene therapy.