Could optogenetics cure epilepsy?
Could optogenetics be implemented in humans? If we consider some of the major conditions that might well be treated using this technique - one of them is epilepsy. Andrew Jackson is leading a project called CANDO at Newcastle University, and he spoke to Chris Smith…
Andrew - What the CANDO project to do is it’s a combined therapy that involves a gene therapy to render neurons sensitive to light using optogenetic technology. And also a brain implant and that brain implant has the capability to both record electrical signals from the brain and send light into the brain to control neurons. The aim of this is to develop a therapy that will prevent seizures that arise from epileptic conditions.
Chris - Now when a person has epilepsy, what is actually going on in their brain to produce the manifestations that people are probably familiar with - fits and seizures.
Andrew - The particular type of epilepsy that we’re talking about here is focal epilepsy and that’s where a small part of the brain is behaving abnormally and the neurons become excessively synchronised and start firing in a very rhythmic manner. This abnormal activity then starts propagating through the brain network leading a seizure which is then associated with uncontrolled movements, loss of consciousness, and things like that.
Chris - How do we currently control epilepsy in patients who have this?
Andrew - Obviously, the frontline treatment would be drugs and there are a variety of drugs that can be offered but, in quite a large proportion of cases, those drugs are not effective without unacceptable side effects. So there’s actually quite a large population of people who have seizures that are not being controlled by the existing drugs.
Now the other solution then, in the case of focal epilepsy, is for a surgeon to go in effectively with a scalpel blade and remove the part of the brain that is abnormal and is generating these seizures. But obviously, when we’re talking about resecting part of the brain, that also has potential side effects and there are certainly some parts of the brain which can’t be removed like that without a really severe side effects.
Chris - So, if your project comes to fruition, how will it surmount those problems?
Andrew - The hope would be by using this implant and using the optogenetics technology, we could control that part of the brain but without destroying its function. So allowing that part of the brain to operate normally but preventing this abnormal activity from developing and causing a seizure.
Chris - Talk us through what would be involved then? How would you if you had a patient in front of you with epilepsy they can’t control with drugs and the drugs that they do take have horrible side effects, and they say right I’m desperate. I want some other alternative and I don’t want surgery - what would happen?
Andrew - What we would so is the first step, we would inject a viral vector. So this is derived from a virus but it’s a virus that can’t replicate so it’s safe. But that virus would be used to deliver the opsin gene to specific neurons in the region of the seizure focus.
The second step would be implanting the brain implant, which we’re envisaging is about the size of a drawing pin, that get’s put into the seizure focus. Now this drawing pin has the capability of listening to the electrical activity in the area of brain surrounding it. As these abnormal patterns start developing, this implant then delivers light to control specific cells in the vicinity in order to suppress the seizure activity and prevent it developing.
Chris - It’s rather like these automatic implantable cardiac defibrillators that people with heart problems have fitted. As soon as they tune into a heart signature that suggests you might be about to have a cardiac arrest it then kicks in with a shock and sorts the heart rhythm out, yours kicks in with a pulse of light which resets the nerve firing rhythm?
Andrew - That’s right. It’s worth pointing out that there are already quite a number of successful devices that are used quite widespread in clinical conditions that use electrical stimulation to activate the nervous system. Perhaps the best example of the would be deep brain stimulation which is a very good and established therapy for treating the symptoms of Parkinson’s disease.
Now there are also attempts to treat epilepsy with electrical stimulation but they only have partial success. Part of the reason for this is that electrical stimulation is rather like trying to play a musical instrument by hitting it with a sledgehammer, you sort of play all the notes at once. What optogenetics allows us to do is to use promotores to express the opsins (these light sensitive proteins) in only specific cell types and then we can activate particular cell types within the brain network.
The other thing I’ve got to say is because we’re stimulating with light we can also, at the same time, record the electrical systems from the brain. If you electrically stimulate, then those currents that you are using are much larger than the currents that the brain produces and so you can’t record at the same time. So, in principle, what this close loop optogenetics allows us to do is to listen to what’s going on in the brain and stimulate at the appropriate time. So that’s rather like playing your musical instrument, not only are you playing the right notes, but also being able to listen to what the instruments around you and the rest of the orchestra are playing, and play the appropriate thing at the right time.
Chris - What evidence have you got, so far, that were you to go down this path and put this into a person’s brain who has epilepsy, you have a good chance of controlling their disease for them?
Andrew - There’s been some promising studies in animal models that have this optogenetic technique to control epilepsies. We are also working with extensive computer simulations that allow us to simulate the effect of the optogenetic stimulation on the epileptic networks.
Then the other line of evidence which we’re working on, but is currently very encouraging, is that we can take… as you said to you one of the main treatments, at the moment, for some of these epilepsies is to resect that part of the brain from the patient. Here at Newcastle my colleague, Mark Cunningham, with the patient’s consent can take that tissue after it’s been resected and start studying it in the dish in the laboratory. So we’re beginning now to get data from actual human tissues having seizures and being able to look at the effect of optogenetics on that activity.