CNS-targeted antioxidant gene therapy for treating epilepsy

Epilepsy is a common neurological disorder that affects 1% of the global population and significantly burdens patients and society. Many epilepsies are acquired following brain injury and no effective prophylaxis or cure exists. Accumulating evidence suggests that oxidative stress plays a critical role in the development of epilepsy, and that pharmacological targeting of oxidative stress can prevent spontaneous seizures. However, non-specific antioxidant therapies may disrupt the physiological balance of oxidants/antioxidants, highlighting the need for targeted intervention. Here, we used AAV vectors to drive the expression of the Nrf2-encoding gene, which promotes endogenous antioxidant systems, under the control of a constitutive cell-type-specific promoter for targeting excitatory neurons.We used the Kainic Acid-induced Status Epilepticus (KA-SE) rat model. Rats were treated with AAVs before SE for the anti-epileptogenic effect, or 10-12 weeks following SE after confirming chronic epilepsy.We demonstrated that AAV-Nrf2 vectors significantly decreased neuronal cell death induced by kainic acid-SE in the hippocampus. When injected before KA-SE, AAV-Nrf2 vectors dramatically reduced seizure frequency over 12 weeks and significantly decreased the total number of seizures compared with control rats. Additionally, 60% of the animals remained seizure-free for 12 weeks after SE induction, and only 20% of the animals became epileptic after treatment with the AAV-Nrf2 vector, compared to 100% of the animals in the control group.Our cell type-specific approach for the targeted delivery of antioxidant therapies offers a promising strategy for combating oxidative stress following brain injury and modifying the development of epilepsy.