Gene Therapy Decreases Seizures in a Model of Incontinentia Pigmenti

OBJECTIVE: Incontinentia pigmenti (IP) is a genetic disease leading to severe neurological symptoms, such as epileptic seizures, but no specific treatment is available. IP is caused by pathogenic variants that inactivate the Nemo gene. Replacing Nemo through gene therapy might provide therapeutic benefits.

METHODS: In a mouse model of IP we administered a single intravenous dose of the AAV vector AAV-BR1-CAG-NEMO delivering the Nemo gene to the brain endothelium. Spontaneous epileptic seizures and the integrity of the BBB were monitored.

RESULTS: The endothelium-targeted gene therapy improved the integrity of the blood-brain barrier. In parallel, it reduced the incidence of seizures and delayed their occurrence. Neonate mice intravenously injected with the AAV-BR1-CAG-NEMO vector developed no hepatocellular carcinoma or other major adverse effects 11 months after vector injection, demonstrating that the vector has a favorable safety profile.

INTERPRETATION: The data show that the blood-brain barrier is a target of antiepileptic treatment and more specifically provide evidence for the therapeutic benefit of a brain endothelial-targeted gene therapy in IP. This article is protected by copyright. All rights reserved.