Inside the future of epilepsy therapy

The earliest descriptions are on ancient clay tablets from Mesopotamia. “His neck turning left, hands and feet are tense, and his eyes wide open, and from his mouth froth is flowing without him having any consciousness.” This man was almost certainly suffering what modern doctors would call an epileptic seizure.

Today, almost 3000 years later, epilepsy is still a devastating disease for the 65 million people living with the condition globally. For many, modern medication and lifestyle changes can control the seizures. But a third of sufferers have a drug-resistant form of epilepsy. For them, the condition is much more serious and the outlook less certain.

However, the science behind treating epilepsy is moving in exciting directions.
A growing understanding of the fine-grained details of how and why seizures happen is opening up new areas of research. “In the last three or four years, we have been at a tipping point that has triggered a different way of thinking about epilepsy,” says Stefanie Dedeurwaerdere, head of epilepsy research at UCB, a global biopharmaceutical company.

“It’s very early, but we hope there is more we can do for people living with, and impacted by, the spectrum of epilepsy disorders. Something completely innovative,” she says.

There are many different types of epilepsy, but the main characteristic is recurrent seizure. Seizures manifest in various ways, many of which are more subtle than the stereotypical description described in Mesopotamian clay. Seizure types vary from a very brief lapse in attention or muscle jerk to severe and prolonged convulsions. Seizures can also vary in frequency, from less than one a year to several per day. In addition, doctors have identified over one hundred different epilepsy syndromes which are characterised by specific signs and symptoms.

Each seizure occurs when neurons in the brain begin to fire abnormally, producing bursts of electrical signals.

Anti-seizure medication has proven to be effective in preventing these electrical bursts in many sufferers by damping down the excitability of neurons.

However, anti-seizure medication treats the symptoms of epilepsy, not the underlying cause. “If we are going to change this, we need to do something dramatically different: we need to move further upstream to treat the root cause,” Dedeurwaerdere says.

This focus is now becoming possible thanks to “omics” technologies. These are molecular sensing techniques capable of revealing the molecular-level changes of genes, proteins, metabolites and other molecules that cause neurons to over-fire in parts of the brain.

These changes turn out to be hugely complex, involving labyrinthine networks of interactions. As researchers are piecing together how this happens, it is opening the door on a new way to approach treatment. “We can think about it as a whole cascade of pathways that eventually lead to seizures,” Dedeurwaerdere says. “This different way of thinking is the key to disease modification: it means not just looking at seizure suppression  but modifying the pathways that bring them on. In this way, you could impact more than just seizures.”

Researchers had initially thought, for instance, that epilepsy’s electrical network abnormality stemmed from ion channel defects leading to “hyperexcitable” neurons. However, large-scale genetic investigations pointed to many different molecular pathways that take part — those involved in signalling, energy metabolism, protein synthesis, axon guidance and so on.

“All of the pathways involved lead to the fundamental problem in epilepsy, which is hyperexcitability,” says Annapurna Poduri, Associate Professor of Neurology at Harvard Medical School and the director of the Epilepsy Genetics Program at Boston Children’s Hospital.

This new understanding will help guide treatment — although, Poduri warns, success will depend on the specific molecular cause for each group of patients. “I am not sure if we can modify disease in all cases, but I am hopeful that we can improve the course for each patient, perhaps limiting or preventing some symptoms by addressing a precise molecular cause and hopefully making an impact on seizures and cognitive function in as many patients as possible,” she says.

One route forward is “regenerative medicine”, which uses stem cells that can be induced to form any of the various kinds of cells in the body — muscle, neurons, skin, blood and so on. Stem cells can be turned into “inhibitory” neurons, or interneurons, which secrete chemicals called GABA inhibitory neurotransmitters that “turn off” other neurons, halting their abnormal electrical activity.

In pre-clinical trials, stem cells have been induced to form interneurons that, once transplanted, significantly reduced seizures in epilepsy models. This work raises the possibility of similar treatments in humans.

Some rare forms of epilepsy are caused by defects in a single gene. This makes them potentially treatable by replacing or repairing that gene. In this way, gene therapy could have the potential to improve outcomes.

Although such techniques are potentially important, they are still in the early stages of development. “The concept is great but the implementation will require a lot of thought and perseverance,” Dedeurwaerdere says. Mike Cousin, Chair of Epilepsy Research UK’s Scientific Advisory Committee, and a professor at the Muir Maxwell Epilepsy Centre in the University of Edinburgh, agrees. “At present there are still many unanswered questions to be addressed before this becomes widely employed,” he says. But, he adds, there is “a significant possibility” that it might provide hope for those for whom the current range of treatments don’t offer any improvement. “It will be exciting to see developments over the next few years.” Perhaps one day, accounts of seizures will truly become things of the past.

More information at: www.ucbpharma.co.uk

UCB commissioned, funded and
collaborated in the preparation of this article.
UCB also reviewed it for medical accuracy.
EU-N-DA-EPI-2200010.
Date of preparation: November 2022