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New closed-loop gene therapy approach for the treatment of cerebral circulation disorders
On-demand expression of a gene that inhibits neuronal activity offers a way to reduce spontaneous seizures in mice, researchers report. In a new study, Yichen Qiu and colleagues present a closed-loop gene therapy approach to treat cerebral circulation disorders in which only a subpopulation of neurons are problematically overactive, including epilepsy. Spontaneous and intermittent seizures characterize neurodevelopmental and neuropsychiatric disorders such as epilepsy. Although these episodes can be reduced with anti-seizure medications, nearly a third of epilepsy patients do not respond to these treatments. Others who initially respond positively may later develop tolerance. Outside of pharmacological solutions, several gene therapy strategies have shown promise. This …
New closed-loop gene therapy approach for the treatment of cerebral circulation disorders
On-demand expression of a gene that inhibits neuronal activity offers a way to reduce spontaneous seizures in mice, researchers report. In a new study, Yichen Qiu and colleagues present a closed-loop gene therapy approach to treat cerebral circulation disorders in which only a subpopulation of neurons are problematically overactive, including epilepsy.
Spontaneous and intermittent seizures characterize neurodevelopmental and neuropsychiatric disorders such as epilepsy. Although these episodes can be reduced with anti-seizure medications, nearly a third of epilepsy patients do not respond to these treatments. Others who initially respond positively may later develop tolerance. Outside of pharmacological solutions, several gene therapy strategies have shown promise. However, these methods tend to indiscriminately target all neurons in a specific brain region, rather than the specific problematic circuits responsible for triggering the episode.
To address this, Qui et al. developed a gene therapy strategy that self-selects pathologically overreactive neurons and downregulates their excitability in a closed feedback system. The approach uses the Fos gene, whose expression is upregulated by neuronal activity, including seizures, to control the Kcna1 gene, which encodes an inhibitory gene that calms neuronal activity.
Qiu et al. used an adeno-associated virus vector encoding the Fos promoter and Kcna1 to transfect neurons in a mouse model of epilepsy. During periods of intense neuronal activity, Fos promoted Kcna1 expression, but only in hyperactive neurons and only as long as they showed abnormal activity. According to the results, neuronal excitability in these cells was reduced by seizure-related activity, providing a sustained antiepileptic effect that did not affect normal behavior. In a related perspective, Kevin Staley discusses the new approach in more detail.
Source:
American Association for the Advancement of Science (AAAS)
Reference:
Qiu, Y., et al. (2022) On-demand cell autonomous gene therapy for cerebral circulation disorders. Science. doi.org/10.1126/science.abq6656.
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