Gene Therapy Cures Epilepsy

New research from University College London this week shows that gene therapy can potentially cure epilepsy in rats.  Epilepsy affects around 50 million people worldwide.  It’s a chronic disorder of the brain where patients can suffer seizures and loss of consciousness.  These seizures are caused by out-of-control electrical activity in the brain. Dr Stephanie Schorge from University College London, co-author of this paper, published in Science Translational Medicine, explains why gene therapy was an attractive proposition...

Stephanie -   Although we now have a set of drugs that can treat epilepsy, there is an incredibly large subset of patients that don’t respond to any of the drugs.  In fact, there are people who have epilepsy with seizures that are recurring regularly and this is a risk of death.  It’s roughly 1 in 100 per year so this is a life-threatening thing. One of the treatments is to remove the bit of brain that causes seizures.  That’s not your first choice for treatment, but for some people, even removing the bit of the brain isn’t a great possibility because there are bits of your brain that you can't just cut out without stopping use of an arm or speech. So, for those people for whom drugs don’t work and you can't cut out the piece of brain because it’s so important, they have no choice but to live with these seizures.  And so, we’re looking for a completely new approach to treating epilepsy and we decided to take this avenue of gene therapy.  You can use genetically modified viruses to deliver little bits of DNA directly to neurons, only in that little piece of brain that is triggering the seizure and you express maybe one gene that just slows them down.  It doesn’t silence them, it doesn’t turn them off, but it just stops them from triggering seizures.

Ben -   So, what actually is the biological basis of epilepsy?  What's happening in that part of the brain that then leads to what's been called an electrical storm throughout the rest of the brain?

Stephanie -   That’s a fabulous question and I wish there was an answer.  There's this theory that there's an imbalance between excitation and inhibition, and that generally speaking, you have more excitation than you want and less inhibition than you want.  That means that excitation gets out of hand and you get the feedback, a buzz, a seizure, a storm, and the underlying genetics of that were really quite mysterious.  But now, through these families who show up in clinic who will have epilepsy running very strongly in their family, in the last 10, 15 years, genes have been coming out and we’ve been learning from these patients that if you have a mutation that destroys one gene, that can lead to epilepsy. So our thought is, if we replace that gene or if we give more of that gene to those cells, maybe we can dampen epilepsy. And actually, the gene that we’re working with that we’re really, really most excited about, it’s from a boy who showed up in a clinic in Scotland a little more than a decade ago.  He was 3 years old and his family had epilepsy.  He had this very rare, only a dozen families in the world or so have this disease, and we went and looked in his family and sequenced the DNA and found a mutation of one gene called the Shaker Potassium Channel.  It’s called the Shaker Potassium Channel because in Drosophila, the fruit fly, when you have a mutation in this gene, they shake.  They have little epilepsy-like seizure things.  Of course, they're flies so it’s hard to say it’s really epilepsy, but in this family, they had a mutation in this gene and they were also having seizures.  The thing that this channel does, it’s a potassium channel.  When a potassium channel opens, it allows positively charged potassium ions to leave the neuron and that makes the inside of the neuron relatively more negative and more negative neurons are less excitable, so maybe, less likely to trigger a seizure.

Ben -   So, adding these potassium channels means that the nerves are less likely to fire off, so you're less likely to get this uncontrolled activity.  How do you actually go about adding it?

Stephanie -   We used a virus.  It’s a virus that’s derived from HIV.  All the bits that make HIV have been stripped out and instead, it’s been replaced with this Shaker Potassium Channel gene and we’re using a rat model of epilepsy that is like the human epilepsy.  It’s really resistant to drugs and has a very sharp focus, a small area of the brain that is triggering the seizures and so, we’re injecting a tiny amount of virus into that exact tiny little focus.  And when we first tried it, we were a little anxious because there's not that many neurons that are affected and we said, “Oh, it’s not going to be enough” but sure enough, after watching over a period of – it took about a week and a half.  The seizures that were well-established in these animals just went away, and went away, and went away, and were effectively cured.

Ben -   And once you’ve added this gene, is there any way to control its expression?

Stephanie -   The viruses we use, once they go in, they seem to stay in.  The gene that we chose is one that normally, when a cell is just sitting quietly, it’s not going to do anything. If somebody decides after 10 years that they want the gene out, the model that we used in this trial, you couldn’t do that.  There are several other possible viruses that you can use that you could switch things on and off, but those are a little further downstream. We’re really interested in moving this to the clinical trials and doing pre-clinical trials, and all the challenges that lie therein.  One advantage we think we have is that this is a human protein and it’s a human protein that normally occurs in human neurons.  So we’re not adding something that isn’t there already.  We’re just slightly changing the amount of something that’s there already in a very small subset of cells.