A new therapeutic strategy for on-demand and cell-autonomous genes that can stop seizures in mice | selected by Science One Week

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The researchers report that a gene that can be expressed as needed to inhibit neuronal activity offers a new way to
reduce spontaneous seizures in mice.

In a new study, Yichen Qiu and colleagues introduced a closed-loop gene therapy for diseases of brain circuits in which only a subset of neurons is pathologically overactive
.
Spontaneous and intermittent seizures are characteristic of neurodevelopmental and neuropsychiatric disorders such as epilepsy.

Although these seizures can be reduced by using anti-epileptic drugs, nearly one-third of people with epilepsy do not respond to
these treatments.
Others respond well initially, but they later develop resistance
.

Beyond drug solutions, some gene therapy strategies have shown promise
.
However, these methods tend to indiscriminately target all neurons in specific brain regions, rather than those specific brain circuits that are problematic in connection with triggering seizures
.

To solve this problem, Qui et al.
developed a gene therapy strategy that selects pathologically overresponsive neurons on its own and down-regulates their excitability
in a closed-loop feedback system.
This method uses the Fos gene, whose expression can be upregulated by neuronal activity, including epilepsy, to control the Kcna1 gene, which encodes a suppressor gene that calms
neuronal activity.

Qiu et al.
transfected neurons
in a mouse model of epilepsy using adeno-associated viral vectors encoding the Fos promoter and Kcna1.
During intense neuronal activity, Fos promotes the expression of Kcna1, but this increase in expression occurs only in overactive neurons, and only when
these neurons appear to be abnormally active.

These findings suggest that neuronal excitability in these cells is inhibited by epilepsy-related activity, and as such, it provides a persistent anti-epileptic effect
that does not interfere with normal behavior.

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