Editors' ChoiceEpilepsy

Self-sustained seizure inhibition

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Science Translational Medicine  01 Aug 2018:
Vol. 10, Issue 452, eaau7381
DOI: 10.1126/scitranslmed.aau7381

Abstract

Gene therapy with a glutamate-sensitive chloride channel allows effective local inhibition of focal seizures without affecting normal brain function in rats.

Almost a third of those affected by epilepsy still suffer seizures despite treatment. Part of the problem is that most drugs only have a narrow safe dose range, as increasing concentrations lead to impairment of normal brain function. If we could design the perfect drug to treat epilepsy, we would want it to dampen excitability only in those neurons that are involved in the seizure itself, leaving the rest unaffected. Recent technological advances such as optogenetics and chemogenetics offer promise in this regard, but they involve either the insertion of physical devices into the brain or administration of systemic drugs, both likely to produce complications or side effects.

Now, Lieb et al. have developed an ingenious gene therapy–based strategy to address this problem. They focused on a channel found in worms (Caenorhabditis elegans) which allows chloride ions to enter the cell in response to elevated concentrations of the excitatory neurotransmitter glutamate, thereby inhibiting neuronal firing. This was engineered to become more sensitive to glutamate and incorporated into a lentiviral vector to allow transduction of neurons. Injection of the construct into the brain of normal rats resulted in long-term expression. In preliminary tests, they found that the channel localized away from synapses. They therefore reasoned that the channel expression should not affect normal brain function, but that during a seizure, the increase in glutamate levels would activate the channel only in the immediate vicinity. In a series of proof-of-principle experiments in rats, they then confirmed that this “autoregulatory” loop did indeed occur, significantly reducing seizure frequency in a model of focal epilepsy targeted to the visual cortex without affecting baseline electrocorticogram recordings or various behavioral tests.

Although these findings will need to be translated into human studies, this strategy offers hope for treatment-resistant focal epilepsy, especially where the focus is not amenable to surgical approaches due to its location in inaccessible regions of the brain.

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