New epilepsy gene therapy

A new way to tackle epilepsy using gene therapy has been announced this week by scientists at UCL. Epileptic seizures or fits occur when a group of neurones in one region of the brain begin to fire inappropriate salvoes of nerve impulses. These spill over into other regions of the brain disrupting normal activity - and often causing unconsciousness - until the abnormal activity subsides. The condition can be controlled by drugs that damp down the activity to prevent fits occurring, but they can make users feel sleepy and struggle with concentration. The new approach, from Dmitri Kullmann, is, having identified where in the brain seizures are originating, to add to those nerve cells a small piece of DNA. This contains instructions that detect when a nerve cell is showing the electrical features of a fit, and switches on a gene that then damps down nerve activity in just those nerve cells. This means the treatment is only active when it’s needed and where it’s needed, minimising any side effects...

Dmitri - There are a lot of neurological diseases which are characterised by overactivity of populations of brain cells. The most obvious of these is epilepsy. So when people have seizures, it's a manifestation of a population of nerve cells firing excessively. And so we've have recently been trying to use gene therapy - using viruses to manipulate the genetic makeup of brain cells. Now you can target to some extent some of those viruses to the specific area of the brain where the seizures arise. But when you do that, you're still treating brain cells permanently and also both brain cells that are participating in the seizures as well as bystander brain cells that don't need to be treated. So that's the problem that we try to address using this on demand gene therapy, as we called it.

Chris - So tell us how that actually works then. What's going on that triggers it and how does it rein in the epilepsy,

Dmitri - There are ways of reducing the excitability of brain cells. So we know quite a lot about what makes cells fire and it's to do with the movement of electrically charged ions, these little atoms that go across the membrane and carry a charge. So we know what sorts of proteins underlie that. So we can simply increase the expression of some of these proteins that underlie normal inhibition of neurons. But what we wanted to do was to do it in a more refined way so that only those neurons that need to be treated are treated and only for as long as they need to be treated. So the treatment could switch itself off if it doesn't need to continue.

Chris - It's a bit like a sprinkler system in a supermarket. When the fire alarm goes off, you only turn the sprinklers on when you need to damp down a fire.

Dmitri - Absolutely. If we permanently express a protein that reduces the excitability of neurons, that's like having the hose on continuously. Now we could use another strategy which is to put in a receptor. So it's a protein that responds to a drug. In that way we could switch on this receptor by giving the drug and thereby reduce the excitability of those brain cells. So that's more like the equivalent of a hose with a tap on it. But what we wanted to do is to remove the need to give that additional drug to activate that protein. So the protein would only be produced in response to seizures. In the DNA you have something called a promoter, and the promoter is what tells a cell to produce that protein or not. So what we've decided to do was to use a promoter which has a special property that it can detect whether the cell is overactive. So when a seizure happens, this promoter switches itself on and that then leads to the production of the protein and the protein then reduces the firing of those brain cells.

Chris - And you know, this works. How did you demonstrate that you could actually get the promoter to register the overactivity of a nerve cell with activity akin to an epileptic discharge so that it would turn on your therapeutic gene?

Dmitri - So we started in brain cells grown in a dish. And so we verified that these promoters could indeed switch on the expression of a protein in response to conditions where the cells are firing too much. And then we moved on to a way of recording the activity of a whole population of brain cells in a dish where they can be made to fire in such a way that you're starting to mimic something a little bit more like a seizure. And then we tested this in mice, which were spontaneously epileptic. And then we verified that the treatment would indeed suppress the seizures. And then we found that indeed this treatment was highly effective and we could completely suppress all the seizures in some of the mice and in other mice the seizures were reduced in frequency without any deleterious side effects.

Chris - In summary, you put into the region of the brain where we know the epilepsy stems from this construct. It sits there doing nothing until the cell starts to describe the sort of electrical activity that we know is associated with an overactive nerve cell in epilepsy that then recruits this promoter and says, "Make this therapeutic gene", which then turns on temporarily, damps down the seizure and then the cell goes back to normal?

Dmitri - Yes. Now of course people always ask the question, "Well surely the seizure happens so quickly that this treatment won't have time to stop that seizure." And indeed this treatment typically switches on we think within about half an hour and then will gradually switch itself off over a few days unless it's reactivated. So we won't be able to stop the first seizure, but we can certainly reduce the likelihood of a second seizure occurring. Now a lot of people with drug resistant epilepsy have clusters of seizures, so they may have several seizures in the space of a day or so. So the time scale of the expression of this protein that we're making to reduce the excitability of neurons is entirely consistent with a sort of clustering of seizures that people have. So we hope that this, if and when we get it into the clinic, would have a very powerful effect in stopping those clusters.