Abstracts

Rationale: Epilepsy remains one of the commonest serious neurological diseases. 30% of people with epilepsy are refractory to pharmacological treatment, and surgical resection of the focal brain area remains the best option. Gene therapy is currently the most promising candidate replacement for surgical treatment of pharmaco-resistant focal epilepsy. However, current experimental gene therapies do not discriminate between neurons involved in seizure generation and ‘healthy’ surrounding neurons. Here, we use activity-dependent promoters to drive a therapeutic transgene that attenuates neuronal excitability only in pathologic hyperactive neurons. Once seizures resolve, the gene therapy tool automatically turns off. Self-time-limited expression of the transgene and specificity for over-active neurons argue that the treatment should be better tolerated.

Methods: We initially tested different immediate early genes (IEG) driving either the potassium channels KCNA1 or KCNJ2, in vitro (using MEA) and ex vivo (using patch-clamp). Then, as proof-of-principle, we used the promoter of an extensively characterised IEGs, cfos, to drive the expression of KCNA1 and KCNJ2 in an animal model of intractable epilepsy. We also performed behaviour experiments to assess the effect of our innovative treatment on memory and learning.

Results: In vitro results showed that activity-dependent gene therapy is efficient in decreasing neuronal activity using different combinations of promoters and transgenes. In vivo results showed that cfos-KCNA1 reduces network activity and seizures in a mouse model of intractable epilepsy (intra-amygdala kainic acid). Furthermore, our data shows that the activity-dependent gene therapy is self-regulated, it is switched-off when seizures were fully rescued. We also observed no behaviour deficits with mice treated with the activity-dependent gene therapy.