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Editors’ Choice: Self-sustained seizure inhibition


Dr Laura Andreae has recently published a review, selected as the Editors’ Choice in Science Translational Medicine, on the potential of gene therapy to inhibit focal seizures without affecting normal brain function. Laura highlights some of the current difficulties faced in the successful treatment of epilepsy: drugs can affect brain function globally whilst other, more recent, technological advances can have side effects and complications.

A recent paper by Lieb et al. describes a self-regulating antiepileptic gene therapy using neuronal inhibition in response to increases in extracellular glutamate. The therapy has been shown to be effective in a rat model of focal epilepsy with few side effects which is promising for clinical translation.

In her review, Laura describes how a channel found in C. elegans which allows chloride ions to enter the cell in response to elevated concentrations of the excitatory neurotransmitter glutamate (inhibiting neuronal firing) was used. The channel was engineered to become more sensitive to glutamate and, using a lentiviral vector, it was injected into the brains of rats. The modified channel was expressed long-term and importantly, the authors found the channel localised away from synapses (which means that the channel expression should not affect normal brain function). The really captivating aspect of their work however is the findings which suggest that the increase in glutamate levels activate the channel only in the immediate vicinity, significantly reducing seizure frequency in a model of focal epilepsy targeted to the visual cortex without affecting baseline ECG recordings or behaviour.

Although it will take significant further work to these findings clinically, Laura describes how the strategy offers hope for treatment-resistant focal epilepsy, particularly in cases where surgery is not viable because of the anatomical location of the focus of the seizures.

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