![]() Furthermore, our data shows that the activity-dependent gene therapy is self-regulated, it is switched-off when seizures were fully rescued. In vivo results showed that cfos-KCNA1 reduces network activity and seizures in a mouse model of intractable epilepsy (intra-amygdala kainic acid). Result: In vitro results showed that activity-dependent gene therapy is efficient in decreasing neuronal activity using different combinations of promoters and transgenes. We also performed behaviour experiments to assess the effect of our innovative treatment on memory and learning. Then, as proof-of-principle, we used the promoter of an extensively characterised IEGs, cfos, to drive the expression of KCNA1 in an animal model of intractable epilepsy. Method: 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). Self-time-limited expression of the transgene and specificity for over-active neurons argue that the treatment should be better tolerated. Once seizures resolve, the gene therapy tool automatically turns off. Here, we use activity-dependent promoters to drive a therapeutic transgene that attenuates neuronal excitability only in pathologic hyperactive neurons. However, current experimental gene therapies do not discriminate between neurons involved in seizure generation and ‘healthy’ surrounding neurons. Gene therapy is currently the most promising candidate replacement for surgical treatment of pharmaco-resistant focal epilepsy. 30% of people with epilepsy are refractory to pharmacological treatment, and surgical resection of the focal brain area remains the best option. Purpose: Epilepsy remains one of the commonest serious neurological diseases. Walker 1 Stephanie Schorge 2 Dimitri Kullmann 1 Gabriele Lignani 1ġUCL Queen Square Institute of Neurology, Clinical and Experimental Epilepsy, London 2UCL, Neuroscience, Physiology and Pharmacology, London Yichen Qiu 1 Nathanael O'Neill 1 Amanda Almacellas Barbanoj 1 Thomas James Turner 1 Irina Zalavina 1 Steffan Jones 1 Jenna Carpenter 1 Matthew C. 34th International Epilepsy Congress 28 August – 1 September 2021 Oral Presentations Basic Sciences Sunday, 29 August 2021 882 Activity-dependent gene therapy for intractable epilepsy ![]()
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