Science: Gene therapy that targets overactive brain cells can treat neurological disorders

Researchers at University College London have developed a new treatment for neurological and psychiatric disorders that works
by reducing the excitability of overactive brain cells.

Many brain disorders, such as epilepsy, are caused
by the overactivity of a small number of brain cells.
These conditions usually do not respond well to medication, mainly because the drug affects the entire brain
.

While gene therapy may be a promising treatment for these diseases, current methods cannot distinguish between overactive brain cells and normal brain cells
.

However, the new therapy, outlined in the journal Science and tested in mice, uses a technique
that changes only the overactive cells and preserves those that are normally active.

Corresponding author Dr Gabriele Lignani (Queens Square Institute of Neurological Research, University College London) said: "We have invented a gene therapy that only starts in overactive cells and automatically shuts down
when activity returns to normal.
"

"We use the ability of certain DNA sequences to control gene expression in response to metabolic signals
.
By redirecting this activity-sensing mechanism to drive the production of molecules that prevent brain cells from firing, we demonstrate that seizures
can be suppressed.
”

To create this gene therapy, the team screened several "on" genes known to respond to stimuli and bound their promoters (the DNA sequence that determines whether DNA is copied to RNA) to potassium channels to reduce nerve cells' ability to
fire.
The promoter-potassium channel combination was tested in miniature brain-like structures grown in mice and in a Petri dish created with skin-derived human stem cells
.

They found that the immediate early gene cfos promoter, which binds to the KCNA1 potassium channel gene, proved to be very effective at calming neuronal excitability and suppressing spontaneous seizures after inducing epilepsy — without any negative effect
on cognition.

The new treatment was more effective than previous gene therapies or anti-epileptic drugs tested in the same model, and spontaneous seizures were reduced by about
80 percent in epileptic mice.

The researchers say gene therapy could eventually theoretically be used for other diseases in which brain cells are overactive, such as Parkinson's
.

Co-corresponding author Professor Dimitri Kullmann (Queenssquare Institute of Neurological Research, University College London) said: "Our findings suggest that brain cell activity can be normalised and that this approach can be used to treat important neuropsychiatric disorders that often do not respond to
medications.
"

"Gene therapy is self-regulating, so it can be used without having to predetermine which brain cells need to be targeted
.

"Importantly, in principle, it can be extended to many other diseases such as Parkinson's, schizophrenia and pain disorders, where some brain circuits are overactive
.
"

The study was funded by the UK Epilepsy Research Centre and funded
by the Medical Council and the Wellcome Foundation.
UCL academics have also received funding
from the TAS Award (TRO) and the UCL Technology Fund.