Self-Regulated Gene Therapy Only Affects Overactive Brain Cells

Researchers at University College London have successfully tested a new gene therapy that selectively alters overactive brain cells and leaves cells functioning normally alone. The technique could form the basis of new treatments for neurological and psychiatric diseases like epilepsy that are caused by excessive activity by a small number of brain cells. Such disorders don’t respond well to drug treatment, mainly because drugs affect the whole brain.

Outlined in a recent issue of Science, the mouse tests are the first gene therapy to distinguish between overactive and normal brain cells. “We invented a gene therapy that switches on only in overactive cells, and switches itself off if activity returns to normal,” says corresponding author Dr. Gabriele Lignani, of the UCL Queen Square Institute of Neurology.  “We harnessed the ability of certain DNA sequences to control gene expression in response to metabolic signals. By re-directing this activity-sensing mechanism to drive the production of molecules that stop brain cells from firing, we showed that epileptic seizures can be suppressed."

To create the gene therapy, the team screened several genes known to “switch on” in response to stimulation and coupled their promoters—DNA sequences that determine whether the DNA is copied to RNA—to potassium channels chosen for their ability to reduce the firing of nerve cells. The promoter-potassium channel combinations were tested both in mice and in miniature brain-like structures grown in dishes from skin-derived human stem cells.

They found that the immediate early gene cfos promoter, in combination with the KCNA1 potassium channel gene, proved to be highly effective in calming neuronal excitability following an induced seizure, and also in suppressing spontaneous seizures without having negative effects on cognition. The treatment was also more effective than previous gene therapies or anti-seizure drugs tested in the same model, with around an 80% reduction in spontaneous seizures in epileptic mice.

Researchers say the gene therapy could theoretically be used for other disorders where some brain cells are overactive, such as Parkinson’s.

 “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,” says co-corresponding author Professor Dimitri Kullmann from the UCL Queen Square Institute of Neurology. “The gene therapy is self-regulated and can therefore be used without deciding a priori which brain cells need to be targeted. Importantly, 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.”