A new treatment for drug-resistant epilepsy with the potential
to suppress seizures 'on demand' with a pill, similar to how you
might take painkillers when you feel a headache coming on, has been
developed by UCL researchers.
The treatment combines genetic and chemical approaches to
suppress seizures without disrupting normal brain function. The
technique was demonstrated in rodents but in future we could see
people controlling seizures on-demand with a simple pill.
Epilepsy affects around 50 million people worldwide including
600,000 in the UK and around a quarter of cases are resistant to
conventional treatments. Many of these cases could be addressed by
the new treatment method, which relies on genetic modification of
brain cells to make them sensitive to a normally inactive
compound.
"First, we inject a modified virus into the area of the brain
where seizures arise," explained Professor Dimitri Kullmann of the
UCL Institute of Neurology. "This virus instructs the brain cells
to make a protein that is activated by CNO (clozapine-N-oxide), a
compound that can be taken as a pill. The activated protein then
suppresses the over-excitable brain cells that trigger seizures,
but only in the presence of CNO.
"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."
As CNO has a half-life of about a few hours and only affects the
pre-treated epileptic parts of the brain, the new method avoids the
need to permanently alter the brain or treat the whole brain with
seizure-suppressing drugs. It builds on similar work by Professor
Kullmann's group using gene therapy to 'calm down' brain cells, or
using light pulses to activate seizure-suppressing receptors in the
brain. The new technique works in a similar way but is reversible
and avoids the need for invasive devices to deliver light to the
brain.
"After the one-off injection into affected areas of the brain,
our new technique would require nothing beyond CNO, administered as
an injection or a pill, to suppress seizures when required," said
Professor Kullmann. "This makes it 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.
"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."
The paper, Chemical-genetic attenuation of focal neocortical seizures, is
published in Nature Communications.