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AAV-Kir4.1 astrocyte gene therapy reduces seizure frequency in rodent models of acute and chronic epilepsy

Y Gao(1,2) N Codadu(1) M Niu(2) M Dai(2) J Zulueta(2) M Lamptey(2) J P Cheung(2) S M Pastor(2) X Ban(2) K L Vera(1) R C Wykes(1,3) N D Mazarakis(2)

1:UCL; 2:Imperial College London; 3:University of Manchester

Kir4.1 is an ATP-sensitive inwardly-rectifying potassium ion channel encoded by the KCNJ10 gene. It is expressed exclusively in glial cells and plays a key role in regulating spatial K⁺ buffering of astrocytes. Kir4.1 loss-of-function results in increased extracellular K⁺ level and impaired glutamate uptake that can cause neuronal hyperexcitability and seizures. A functional decrease in Kir4.1 expression has been reported in human acquired and genetic epilepsies, and in rodent models of epilepsy. Thus, it is hypothesized that upregulation of Kir4.1 in astrocytes will counteract pathogenic rises in extracellular K⁺ and glutamate to prevent transition to seizures.

To investigate whether Kir4.1 over-expression could reduce seizure susceptibility, we injected unilaterally into the somatosensory and visual cortex with either AAV9-gfaABC1D-Kir4.1-tdTomato or AAV9-gfaABC1D-tdTomato vector. 2-3 weeks post-injection, electrographic recordings were performed in awake head-fixed mice and acute seizures induced by focal injection of chemoconvulsant (picrotoxin) to the transduced area of cortex. Mice over-expressing Kir4.1-tdTomato had fewer seizures than those expressing tdTomato alone.

Animals were made chronically epileptic by kainic acid injection into the right hippocampus. Telemetry devices were implanted to record baseline seizure frequency 2-3 weeks following acute status epilepticus. Animals were then treated with AAV-PHP.eB-gfaABC1D-EGFP-Kir4.1 or AAV-PHP.eB-gfaABC1D-EGFP vector injected into the right hippocampus. 2-4 weeks post-treatment, electrocorticography was recorded and analysed using a semi-automated program to quantify seizures. Kir4.1 over-expression significantly reduced seizure frequency normalised to baseline levels compared to GFP-treated mice. We conclude that AAV-Kir4.1 astrocyte gene therapy is effective in reducing seizure frequency in rodent models of acute and chronic epilepsy.

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