Science: Novel gene therapies targeting overactive brain cells hold promise for treating neurological disorders

In a new study, researchers from University College London in the United Kingdom have developed a new treatment for neurological and psychiatric disorders, and the cover method works
by reducing the firing of overactive brain cells.
The results of the study were published in the Nov.
4, 2022 issue of Science as "On-demand cell-autonomous gene therapy for brain circuit disorders.
"

Many brain disorders, such as epilepsy, are caused
by the overactivity of a small number of brain cells.
These diseases tend to respond poorly to drug treatment, mainly because the drugs used affect the entire brain
.
While gene therapy may be a promising class of treatments for these diseases, current approaches to this type do not distinguish between overactive brain cells and normal brain cells
.

However, in the new study, the new method developed by the authors used a technique
that only alters overactive brain cells without affecting those that act normally.

Dr Gabriele Lignani, co-corresponding author of the paper from the Queens Square Institute of Neuroscience at University College London, said: "We have invented a new gene therapy that works only by turning on in overactive brain cells and shutting itself down
if they return to normal.
We harnessed the ability of certain DNA sequences to control gene expression in response to metabolic signals
.
By redirecting this active sensing mechanism to drive the production of molecules that prevent brain cells from firing, we found that seizures can be suppressed
.
”

To develop the new gene therapy, the authors screened several genes known to be activated in response to stimuli and coupled their promoters to potassium channels selected for reducing nerve cell firing
.
This combination of promoter-potassium channels was tested in mice and in miniature brain-like structures (known as brain organoids) cultured in petri dishes, which are made from skin-derived human stem cells
.

They found that the combination of the immediate early gene CFOS promoter and the KCNA1 potassium channel gene was shown to be highly effective in inhibiting neuronal firing after seizure induce, as well as inhibiting spontaneous seizures without any negative effects
on cognitive performance.

In vitro characterization
of CFOS activity-dependent activation.
Image from Science, 2022, doi:10.
1126/science.
abq6656
.

The new treatment, which was more effective than gene therapy or anti-epileptic drugs previously tested in the same model, reduced spontaneous seizures in mice with epilepsy by about 80 percent
.
The authors say the new gene therapy could also theoretically be used to treat other diseases in which brain cells are overactive, such as Parkinson's disease
.

Professor Dimitri Kullmann, co-corresponding author of the paper and from the Queens Square Institute of Neurology at University College London, said: "Our findings suggest that overactivity of brain cells can return to normal, and that this new approach can be used to treat important neuropsychiatric disorders
that do not always respond to drugs.
This new gene therapy is self-regulating, so it can be used
without predeciding which brain cells need to be targeted.
Importantly, in principle, it may extend to many other diseases where some overactive brain circuits exist, such as Parkinson's disease, schizophrenia, and pain disorders
.
(Biovalley Bioon.
com)

Resources:

Yichen Qiu et al.
 On-demand cell-autonomous gene therapy for brain circuit disorders, Science, 2022, doi:10.
1126/science.
abq6656.