Researchers are making progress on a new “on demand” epilepsy pill which can be taken when people feel a seizure starting. The pill has been developed by a team at University College London, UK, led by Professor Dimitri Kullmann.
They explain that about one percent of people worldwide, or 65 million individuals, have epilepsy. About a quarter are resistant to normal treatments, drugs that suppress the excitability of all brain cells and cause side effects.
But the new pill to suppress seizures may help this group, as it works by genetically modifying brain cells, making them sensitive to a compound which is normally inactive. Kullmann described the process. “First, we inject a modified virus into the area of the brain where seizures arise,” he said.
“This virus instructs the brain cells to make a protein that is activated by clozapine-N-oxide, or CNO, a compound that can be taken as a pill. The activated protein then suppresses the overexcitable brain cells that trigger seizures, but only in the presence of CNO.”
He added, “At the moment, severe seizures are treated with drugs that suppress the excitability of all brain cells, and patients therefore experience side effects. Sometimes the dose required to stop seizures is so high that patients need to be sedated and taken to intensive care.
“If we can take our new method into the clinic, which we hope to do within the next decade, we could treat patients who are susceptible to severe seizures with a one-off injection of the modified virus, and then use CNO only when needed.
“CNO would be given as a pill in the event that patients could predict when seizures were likely to occur. For example, many people with treatment-resistant epilepsy experience clusters of seizures, where severe seizures are preceded by smaller ones. Seizure risk is also high when people are ill, sleep deprived, or at certain times of the menstrual cycle, so these would all be good times to take the pill as a preventative measure.
“In urgent situations, the compound could be given as an injection. We could even consider a fully automatic delivery system, where CNO was given by a pump, as is done for insulin in some people with diabetes.”
Full details of the treatment are outlined in the journal Nature Communications. The team has tested the pill on rodents and are planning future trials on human volunteers.
Dr. John Williams, a neuroscientist and head of clinical activities, neuroscience and mental health at the UK-based charity The Wellcome Trust, commented, “Epilepsy is a debilitating condition with limited treatment options. We look forward to seeing how this innovative approach for targeted control of seizure activity might translate into new treatment options for managing and controlling seizures in humans.”
Currently, individuals with epilepsy are often prescribed daily anticonvulsant drugs. Nevertheless, about 30 percent still have seizures, and adverse effects such as mood changes and drowsiness occur in up to 90 percent of those taking the drugs.
On the other hand, CNO is broken down in the body after a few hours, and affects only specific parts of the brain rather than the whole brain, as with seizure-suppressing drugs.
“This method is more attractive than alternative forms of targeted therapy such as surgery to remove the brain region where seizures arise, or gene therapy that permanently alters the excitability of brain cells,” said Kullmann.
“Although there is currently no evidence that permanently suppressing excitability in a small area affects brain function, we cannot be sure that it would have no impact long-term. Our new method is completely reversible, so if there were any side effects then people could simply stop taking the CNO pill.”
Kullmann’s team is also working on optogenetics, a method of on-demand seizure suppression which uses light pulses to activate seizure-suppressing receptors in the “epileptogenic zone,” a small brain region that can usually be located with imaging techniques. An implanted device delivers light of the appropriate wavelength, intensity and duration to this brain area, where seizures begin.
Recent tests on rodents indicate that optogenetic seizure suppression is feasible in principle. But one of its main limitations in humans is the need for implantation of optical devices.
The researchers said the new drug/genetics method “is a promising approach to achieve region- and cell-type specific attenuation of neuronal excitability to suppress seizures.”
They add, “The pathway to translation is likely to be more direct than for optogenetics.”
Katzel, D. et al. Chemical-genetic attenuation of focal neocortical seizures. Nature Communications, 27 May 2014 doi:10.1038/ncomms4847