Stem cells, the cells in the body that provide the blueprint for the creation of all other specialized cells (e.g., nerve, cardiac, blood cells, etc.), have generated significant interest in the research community over the past decade. Stem cells can help regenerate or repair tissues in individuals that have been affected by certain disorders and are being assessed for the ability to reduce seizures in people with epilepsy.
This webinar will discuss a pioneering neural cell therapy approach that could provide a novel treatment for drug-resistant focal epilepsy. Viewers will learn about the promising new data supporting this approach which will be presented by Dr. Robert Beach from the State University of New York (SUNY) Upstate Medical University.
Q&A Transcript
Will this approach only be useful for epilepsy located in the temporal lobe or any drug-resistant epilepsy? Where do you see this going?
Well, if it is successful in this well-studied area of the brain, it will probably be useful in other focal epilepsies. As long as you can localize the seizures and target them with the cells, it has the potential to be beneficial. We’re starting with the best studied and most frequently treated surgically part of the brain as a starting point because it’s far and away the best understood and the most likely to provide us with realistic estimates as how it might work elsewhere.
Do you think it will eventually help people with Lennox-Gastaut syndrome or genetic disorders?
Well, most genetic disorders are not focal. Some of them, like tuberous sclerosis for example, have multiple foci, and it might be useful in that sort of setting because it’s very hard to necessarily know which is the active focus. If you’re not damaging the area as you would with surgery or something, you may be able to treat more than one focus. But many of the genetic disorders are too diffuse and not well-localized enough to likely benefit from this kind of stem cell implant.
Can stem cell therapy be used in a patient who has a deep brain stimulator?
Well, not at this point, but it could be, theoretically. Deep brain stimulation is often used for less well-localized epilepsies, and some of those probably do not have a focal area that could be treated. Some of them have multiple focal areas of which you’ve … concurrently with the responsive neurostimulator or RNS, treat two of them, but not multiple ones. This could potentially have the ability to treat these area parts epilepsies where there are more than two foci or two focus that aren’t easily addressed by the RNS.
Are the cells manipulated in any way? Are they grown to increase their number
or cultured in any way? Selected in any specific ways?
Yes, all of the above. They are put into culture and they’re differentiated using a variety of growth factors and other things that influence distill differentiation. Then they’re tested to be these inhibitory GABAergic neurons, and then they’re expanded and tested for purity, and then they’re frozen in small amounts to be used in a particular implantation, and that you have multiple samples of the cells that can be used over a longer period of time with the frozen cells.
This isn’t actually coming from the person who’s having the surgery, but these are cells that were generated some time ago?
Yes. I don’t know exactly when they were generated, but they were generated from stem cells that have been obtained from, not from an embryo or not from a fetus, I should say. I don’t know exactly where they’re obtained from. Theoretically, you might be able to generate stem cells from the individual, which would have immense advantages in terms of not needing the immune suppression. That is one of the more complicated parts of this kind of approach, and I think that that’s potentially doable. It may be that cord stem cells may be more versatile and require less immune suppression. These are things that I don’t have a lot of information on, but are potential.
So, this person has a daughter with epilepsy, but an SCN1A mutation. They have stem cells saved from birth via the cord stem cell banking, and they’ve saved it from both of their children. Do you think this type of stem cell can come in handy for treating epilepsy?
That’s a very good question. I think there probably is a potential for those stem cells for this person, but I don’t think it’s going to be necessarily this kind of stem cells delivered focally, and it may not be primarily GABAergic neurons. It may be something that might introduce a different or correction of a different deficit that would be seen in SCN1A. But at this point, I really don’t know exactly how that would work.
How long does it take to see improvement, for example, a reduction in seizures after cell implantation?
Well, we don’t know. We were pretty surprised that this person did as well as he did in terms of seizures. So, the hypothesis that we are operating under is that the benefit of the cells would come mostly after they integrated with the other cells, and form new connections and new networks, which would take time. The plan was to assess this over a year, basically, be looking at six months, but expecting to find some realistic estimate over a year. This is, being the first patient, I think it’s premature to say that this is going to be a characteristic of everybody getting these cells, but it’s very encouraging.
If somebody has a VNS and can’t have an MRI, is it still possible to be assessed for this?
Well, a person with a VNS, as long as they don’t have it slipped way down below their chest or in the lower part of their chest, can have an MRI. There’s a, you require certain things in the MRI to be able to get, in the scanner, be able to get an MRI in somebody who has a VNS. There’s an absolute area of exclusion where if it exists, you can’t do it. But for the most part, they are coils that are used that go around the head and localize the flow of the changes of magnetic fields that keep it from interfering and keep it from damage the VNS. The VNS has to be turned off during the MRI. One obvious reason is if somebody has their magnet on and they go through the MRI, they’re going to be exposed to rapidly fluctuating magnetic fields, which will trigger it on and off multiple times, which would be intolerable very quickly. But most people with a VNS can get an MRI. If they have a focal abnormality that is likely to be the source of their seizures, or a couple maybe in the future, they may be candidates, but for now we’re looking at one focus.
So, back to the GABAergic interneurons, will they only work in the hippocampus or could they work in other areas?
Well, these are neurons that come from an area of the brain that spreads out throughout the cortex. The cells are formed in the median ganglia eminence, and then they migrate to various parts of the cortex. The reason it’s being tested in the hippocampus is because it’s a well-studied model, and we know that there’s GABAergic cell loss. They should potentially work in many other areas if there is a loss of GABAergic input and they can be replaced, which if there’s a loss of GABAergic cell loss, and it’s an area that can be, well almost in the area can be accessed using stereotactic implantation. So, probably, as long as there’s a focal area that can be identified as a seizure source, and there’s a good reason to think there’s GABAregic cell loss, it does have potential again, in the future.
How long do you think it will take to get a good readout from this clinical trial and know what the next steps will be? We’re getting a lot of questions about the future of this and where it could be used, but clearly, we’ve got to complete this trial first. Talk about this trial and how long it might go.
The way the trial’s set up now is the first two patients had to be separated by I think, three months. So, second patient was implanted about three months ago, who I don’t know much about their seizure effects or side effects. But I note, they’ve had no major side effects, and the cells were implanted a very similar way as to what I demonstrated with our patient in approximately on, well, actually as of now, there’s been several things that the Data Safety Monitoring Board has allowed us to do that’s going to facilitate getting patients in faster. One of them is to open it up for additional studies in this preliminary group of patients who are really getting a low dose, and there’ll be five people in that initial cohort that should probably be all implanted within the next six months, I would hope. Approximately a year after those five people go through, we should have some idea as to whether this effect on epilepsy is real, and whether there are side effects that we haven’t yet seen that are going to be an issue.
We also may have an idea, because they’ve opened it up now, so we can do non-dominant hemisphere patients, I’m sorry, dominant hemisphere patients as well as the non-dominant hemisphere patients. We may get an idea as to whether the most important benefit for this, it may be realized, and that is if you’re treating the dominant hemisphere temporal lobe epilepsy, in somebody who has relatively normal verbal memory and function, you’re going to get a decrement on surgery, because you’re going to be taking out areas important for that. But it is very possible, and it’s been shown with the less you take out, the more likely you are to have less effect on memory and language function. It’s very likely that with this kind of approach that you’ll have even less effect, or we hope that there’s even less effect on the language and verbal memory, and that we might have some information on that within the next year. I’m not really sure.
It might take longer than that, but it’s going to take larger numbers to really get a good sense for how likely various things are. I think we’re definitely seeing some very promising results, but it’s very early to know.
So, we’ve got a question about eligibility, and you’ve been talking about unilateral mesial temporal lobe epilepsy in the non-dominant side, and you just shared that there’s been a loosening of restrictions to also now allow the dominant side. It sounds like that might be because of the lack of concern around changes in some function.
Well, it’s because there doesn’t appear to be any major risk showing up from what we’ve done so far. It’s the dominant hemisphere of patients who this is most likely to be the most attractive approach for, because of that potential for sparing language function or even getting improvement potentially. So, as long as somebody has unilateral at this point, unilateral left or right mesial temporal sclerosis and seizures coming from that area, and no progressive degenerative diseases, and various other minor or unusual restriction criteria, they would be a candidate for this. But it’s basically, think of it as somebody who might be a candidate for epilepsy surgery on one temporal lobe, may be a candidate for this. There are some details beyond that, but that’s a good starting point.
Are there any discussions about trying this in children? I know that’s a difficult question, I’m sure.
Yeah. I think there will be plans to do that, because temporal lobe epilepsy is fairly common in children. But I think that there are some differences in, I would guess that’s going to take a while before we have a good handle on anything that’s going to actually try that. If it’s very successful, maybe a no-brainer to go forward with children, but it’s a little unclear at this point.
Do immunosuppressants have any effect on seizures themselves?
Not that I know of. I mean, they have side effects that can be somewhat systemic, but I’m not aware that any of them are actually anti-convulsant. Now, there are drugs that reduce proliferation that are in some ways related to the immune suppressants that can affect development of some of the epilepsies that require things like tuberous sclerosis, where you get growth of cell populations as tubers or as giant cell astrocytomas, where they suppress that. But that’s not truly an immune suppressant. I’d have to look to see what data there is. I’m not aware of any, but there might be some data on that.
Here’s somebody who is asking about autoimmune epilepsy and its impact on the hippocampus. The autoimmune epilepsy appears to have shrunk or changed their hippocampus. So, is somebody like this a candidate?
So, autoimmune epilepsy should first be treated to reduce the impact of the molecule causing the autoimmune response and the autoimmune response itself. If that is unsuccessful, and there’s residual long-term epilepsy, then they may be a candidate for this, but autoimmune epilepsy is usually a monophasic course where if you can remove the inciting antigen, which might be in some cases related to a tumor or an abnormal cell growth, or if you can suppress the response adequately, you can get control of those seizures in most people. And, if they are treated quickly enough and aggressively enough, they’re likely to get enough of a benefit. So, long-term epilepsy is not likely to occur, but for some people it does, and I think those people, if it’s in the hippocampus, would be candidates. I don’t think they’d be candidates for this study because that’s probably a restriction, but because autoimmune is not really a clearly defined stimulus that ends at a given time, but I think that they would be candidates for this kind of approach.
So why do the cells have to be injected into the brain? Why couldn’t they be injected into the bloodstream?
So, there are immune therapies to which are largely for blood cells where there can be replacement or treatment directly into the blood, and there may be epilepsies which are widespread and without a focus that might benefit from some blood cell treatments in the future. But for the effect of the GABAergic cells to be beneficial without causing widespread suppression of activity, you want to be able to put them where the abnormality is, where the hyperexcitability is, and that requires injecting them into the brain. There might be some genetic cases where that would be different, but not at this point.
Are there any outwardly visible components of implanting stem cells in long term?
Outwardly visible? Well, I guess if you palpated their skull, you might find a small little burr hole in the back where the burr hole is made. If the person is on long-term immunosuppressants, there might be some side effects that could last over a longer period of time, and of course, being on immunosuppressants does increase the risk for infections, but that’s not really a marker. That’s just a risk, I’d say.
You’ve talked about long-term immunosuppressants. It’s likely that people would have to be on immunosuppressants for their lifetime or do we know?
Probably on some level for lifetime. The aggressive approach initially is much more, all of, I think he was at one point on three strong immunosuppressants, and is now on a single low dose of Tacrolimus, which is one of the more common immunosuppress use for tissue transplants, which is probably not causing significant side effects at this point. Does have the increased risk of possible infection though.
Do you see this being used for any other kinds of neurological disorders?
Yes. I don’t think the, there’s probably ones where I think GABAergic cells may be beneficial, but I do think that stem cell of particular kinds will be useful in some other diseases, perhaps even in something like Parkinson’s disease where we now do stimulation, there might be potential to use certain kinds of cell implants to benefit there, but that’s something that I really don’t know for sure, and it’s in the future for sure.
So, you’ve talked about, you mentioned these people who are being enrolled are on a low dose. So, is the anticipated that the next steps in the clinical trial will try different levels of stem cell infusion or different numbers of stem cell infusions?
Yeah, the plan was to try a higher dose with the second cohort, which would be after these five people have gotten adequate results, which would be roughly a year from now or maybe slightly more. I’m not sure if the results are particularly impressive with the low dose. That may be modified.
Would be useful for generalized genetic epilepsies, and generalized epilepsies in general?
Well, I think most of the generalized epilepsies don’t have a focus where we could inject GABAergics neurons and expect to get a benefit. There may be particular subtypes of GABAergic cells that might be useful in some of the generalized epilepsies, but that’s very theoretical, because you’d have to be able to figure out which subtype and where to inject it. Theoretically, with some of the generalized epilepsies, it might be in the internuclear or reticule thalamic nuclei, which is part of the relay for some of the so-called spike-wave epilepsy, which are often called primary generalized. But I think that’s highly theoretical at this point.
The information contained herein is provided for general information only and does not offer medical advice or recommendations. Individuals should not rely on this information as a substitute for consultations with qualified healthcare professionals who are familiar with individual medical conditions and needs. CURE Epilepsy strongly recommends that care and treatment decisions related to epilepsy and any other medical condition be made in consultation with a patient’s physician or other qualified healthcare professionals who are familiar with the individual’s specific health situation.