Gene therapy targets overactive brain cells in mice, potential neurological treatment

By Greg Slabodkin, ScienceBoard Editor in Chief

November 4, 2022 -- University College London (UCL) researchers have developed a gene therapy for neurological and psychiatric diseases that reduces the excitability of overactive brain cells. Tested in mice, the scientists contend the treatment could potentially be used in human brain diseases, such as epilepsy, caused by excessive activity of a small number of brain cells.

In a study published November 3 in the journal Science, the UCL researchers report that the novel treatment was more effective than previous gene therapies or anti-seizure drugs tested in the same model, with an approximate 80% reduction in spontaneous seizures in epileptic mice.

The authors note that about one-third of epilepsy patients do not respond to currently available anti-epileptic drugs and while several gene therapy approaches have been proposed, these techniques tend to indiscriminately target all neurons in the brain and do not distinguish between overactive and normal brain cells.

However, the study's authors say they have come up with a method that only alters overactive brain cells and spares those that are acting normally. In addition, the gene therapy is "self-regulated" and can be administered without the need to decide a priori which brain cells to target.

The gene therapy "self-selects neurons that are pathologically overactive and down-regulates their excitability in a closed loop," according to the authors, who screened several genes known to "switch on" in response to stimulation and tested them in mice and in miniature brainlike structures grown in dishes -- which were created using skin-derived human stem cells.

The researchers describe how they "put the KCNA1 gene, which encodes a potassium channel, under the control of an immediate early gene promoter with activity that is switched on by intense neuronal firing" and that the treatment "switches itself off once brain circuit activity has returned to baseline." They demonstrated that the immediate early gene c-fos promoter -- in combination with the KCNA1 potassium channel gene -- proved to be highly effective in calming neuronal excitability following an induced seizure, and in suppressing spontaneous seizures without having any negative effects on cognition.

"Our findings indicate that the activity of brain cells can be normalized, and that this approach can be used to treat important neuropsychiatric diseases that do not always respond to medication," co-corresponding author Dimitri Kullmann, professor of neurology in the UCL Queen Square Institute of Neurology, said in a statement. "It could in principle, be extended to many other disorders such as Parkinson's disease, schizophrenia, and pain disorders, where some brain circuits are overactive."

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