There are many different types of epileptic seizures, but all of them spur from batches of overactive neurons. While gene therapies have shown promise in treating epilepsy, most of those developed so far tend to impact cells across an entire region of the brain rather than selecting for pathologically excited neurons. Other strategies such as medication and electrographic seizure detectors have limits, too.

Enter a new potential treatment: a highly targeted gene therapy that affects only hyperactive neurons, stops when the seizures go away and doesn’t impair cognitive function. The therapy was developed and tested on seizure-prone mice and human brain organoids by a team at University College London that reported its results in a paper published Nov. 4 in Science Translational Medicine. The mice’s seizures declined by 80% on average—with some of them becoming seizure-free—and the therapy quashed overactive neurons in the organoids.

Though it’s too soon to tell whether the treatment will translate to the clinic, the results in mice are quite promising, co-corresponding author Dimitri Kullmann, Ph.D., a neurologist and University College London professor, told Fierce Biotech Research. Seizures in rodents tend to be difficult to treat; other types of gene therapies have cut the seizure rate in mice somewhere between 35% and 50%. “The seizure reduction was very impressive compared to what has been achieved in gene therapy so far,” Kullmann said.

The project built on the previous work of Kullmann and collaborator Gabriele Lignani, Ph.D., both of whom research gene therapies for seizure disorders. Kullmann’s lab had been looking into how an engineered potassium channel dubbed EKC could inhibit overactive neurons, while the Lignani lab was studying the therapeutic potential of cFos, a gene that is expressed in response to active cells. They wondered whether pairing cFos’ promotor region with a gene altered to express EKC could work as a treatment that detected and then inhibited seizure activity.

To find out, the researchers first expressed the cFos-EKC combination in cell cultures containing mouse neurons that were prone to hyperactivity. Seeing that it was able to temper them, they moved on to live mice. Using a mouse model of a common type of focal epilepsy affecting the temporal lobe of the brain, the team injected a viral vector containing the gene therapy directly into their hippocampi, a prominent site of seizure activity.

The therapy had a marked anti-epileptic effect in all treated mice. And unlike other gene therapies that permanently alter the expression of specific genes, the expression of EKC is designed to stop if and when the hyperactivity stops. How, then, was it able to lower the frequency of seizures over the course of six weeks? 

The answer likely lies in another component of epilepsy: frequent bursts of neurons firing all at the same time, also known as “spikes” for the activity they display on an EEG. The spikes were enough to induce expression of the gene therapy, the scientists found, even though over time, treated mice had significantly fewer spikes than epileptic mice treated with a control viral vector. This might explain why the treatment was ultimately able to reduce seizure activity, Harvard epilepsy researcher Kevin Staley, M.D., who was not involved in the project, wrote in a commentary published in Science.

“Spike-driven [EKC] expression could unlink its expression from seizures, providing a more consistent inhibition of epileptic neurons,” Staley wrote.

While the therapy had clearly worked, there was another hurdle to tackle. Previous experiments by scientists working on learning and memory had shown that cFos expression in the hippocampus was involved in learning from experiences. Thus, it would be important to ensure that the therapy wouldn’t interfere with cognition.

To do so, the researchers pulled from the experimental playbook of those same scientists. Two weeks after treating a group of mice with the gene therapy, they replicated the memory researchers’ experimental conditions to test whether the mice could still develop a fear response. To the researchers’ relief, mice who had been treated with the therapy had the same memory capabilities as controls. There was also no difference in their working memory, scent discrimination or anxiety levels.

“There was a precedent for using [cFos expression] to manipulate behavior,” Kullmann said. “The animals behaved perfectly normally.”

Armed with the knowledge that the therapy could indeed reduce seizures in mice without inhibiting learning, there was one more box to check: its potential viability in human neurons. For this, the team applied the gene therapy to cell cultures containing human “mini brains,” organoids grown from human stem cells. They then stimulated cell hyperactivity by applying a convulsant chemical cocktail twice. The gene therapy successfully expressed EKC on the first round and stopped seizure-like activity on the second, as it had in the mice.

The researchers’ gene therapy doesn’t tackle the genetic cause of seizures, as is the case with those that are used for rare disorders. Instead, it works downstream, making it applicable to virtually all types of seizures. That includes patients whose seizures aren’t linked to a specific part of the brain, a particularly difficult type to treat.

Looking even further out, it’s possible that the treatment could be applied to other types of neuropsychiatric conditions, too.

“Extrapolating from epilepsy, we could potentially apply this to Parkinson’s disease and other disorders where neurons are overactive, at least in theory,” Kullmann said.


Source:, Helen Floersh