Gene Therapy Targeting Select Brain Cells May Treat Parkinson’s

UK team reports that therapy switches off after calming overactive neurons

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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An illustration of work into genes and DNA underway in a laboratory.

A gene therapy designed to track down and keep overactive brain cells in check was able to lower the number of seizures in a mouse study of epilepsy. This therapy is also notable in sparing healthy brain tissue by switching itself off after its work is done.

Should early work continue to show promise and it move into testing in people, the gene therapy might be used to treat other neurological diseases marked by specific brain cells altered in pathological, or disease related, ways, including Parkinson’s.

“This approach can be used to treat important neuropsychiatric diseases that do not always respond to medication. The gene therapy is self-regulated and can therefore be used without deciding a priori which brain cells need to be targeted,” Dimitri Kullmann, MD, PhD, who co-led the study, said in a university press release. Kullmann is a professor at University College London’s Queen Square Institute of Neurology in the U.K.

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‘Self-regulated’ therapy could be used for various neurologic diseases

“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,” Kullmann added.

The study, “On-demand cell-autonomous gene therapy for brain circuit disorders,” was published in the journal Science.

In the healthy brain, nerve cells work along circuits that allow them to fire electrical signals from one neuron to the next. One circuit can link a number of regions in the brain, which often act together to control functions such as movement.

In Parkinson’s and other neurological diseases, some of the neurons in a circuit can start to wither away and die while others become overly active.

People with these diseases often fail to respond well to medications, or they experience side effects that cause them to stop the treatment.

Gene therapy is seen as a possible treatment approach. But “a limiting factor is that they do not discriminate between neurons involved in circuit pathologies and ‘healthy’ surrounding or intermingled neurons,” the researchers wrote.

To get around this limitation, a team at University College London developed a gene therapy approach that quenches neuronal firing only for as long as brain cells are overactive.

“We invented a gene therapy that switches on only in overactive cells, and switches itself off if activity returns to normal,” said Gabriele Lignani, PhD, the study’s co-lead scientist.

The team placed the KCNA1 gene, which provides instructions for making part of a potassium channel called Kv1.1, under the control of a cfos promoter — a DNA sequence that’s switched on by intense neuronal firing. The flow of potassium ions into and out of neurons regulates their ability to pass along electrical signals. Kv1.1, in particular, transports potassium ions into neurons and reduces neuronal firing.

When packaged in a harmless viral vector for delivery into seizure-prone mice, the gene therapy calmed the brain cells that became overactive after a seizure was triggered. A seizure is a burst of uncontrolled electrical activity between brain cells.

The therapy also prevented spontaneous seizures from occurring, cutting their number by about 80% while leaving the animals’ behavior and cognitive function unaffected, the researchers reported.

“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,” Lignani said.

Similar observations were seen in miniature brains, a model created by growing skin-derived human stem cells in a lab dish.

Study results show that “activity-dependent gene therapy is a promising on-demand cell-autonomous treatment for brain circuit disorders,” the researchers concluded.