Sharona Ben-Haim, MD, Neurosurgeon at UC San Diego Health, and Jerry Shih, MD, Neurologist and Director of Comprehensive Epilepsy Center at UC San Diego Health, talk about regenerating cells to stop epileptic seizures
Interview conducted by Ivanhoe Broadcast News in 2024.
What is the regenerative brain cell therapy procedure?
Ben-Haim: It’s a really unique treatment that is for patients who have refractory epilepsy. Not all patients with epilepsy would qualify for this.
What is a refractory?
Ben-Haim: Lucily, the majority of patients with epilepsy do really well with medications. But there is a percentage, about 30 or so percent of patients, that don’t have a meaningful reduction in their seizures after the first medication and don’t have that reduction after the second medication. Once they’ve failed two medication therapies and they’re still having seizures that are significantly impairing their quality of life, that’s when we consider them for something like a surgical workup to see if there is an area in the brain where we can intervene to help their seizures slow down, or ideally, go away completely.
Typically, would you do an ablation surgery almost to get rid of it, is it always caused by a tumor, would you do that?
Ben-Haim: No, in fact, the majority of patients that we see have perfectly normal MRIs. Our job as a surgical epilepsy center is really to ask the question, can we figure out where these seizures are coming from in the brain? If we can figure that out and once we figure that out, then we tailor a specific treatment for that patient. We have really great technology now where we can pinpoint the seizure focus, like minimally invasive laser ablation surgeries. That’s something that’s just come online in the last seven or eight years. There are other therapies that we can do when it’s not safe to perform an ablation, or it’s not safe to perform a resection. Those types of therapies usually involve things like neuromodulation, where we’re placing electrodes in the brain and trying to quiet the seizures. The problem with those neuromodulation therapies is that we’re not expecting to render the patient seizure-free after these treatments. Those really are therapies that attempt to improve quality of life by significantly reducing either the duration, or severity, or number of seizures patients experience. And what we consider success with those types of therapies is reducing seizures by at least 50 percent.
Would regenerative brain cell therapy be as close to cures what you’re going to get?
Ben-Haim: What’s so exciting about that therapy is that in theory, we could potentially get the best of both worlds here. Our goal there is to actually achieve seizure freedom. But right now, we don’t have a meaningful way to do that without actually destroying that part of the brain where seizures are coming from. So with this type of therapy, we have the hope of being able to meaningfully intervene in that area. Really, also what’s exciting about it is that we’re trying to correct what actually is going on with epilepsy, which is where we have too much excitation of those cells, and that’s what we think causes spontaneous seizures. Here, we’re inserting something into the brain with the goal of calming that region down without affecting the underlying function of the brain in that area.
Tell me how it works. What is it?
Ben-Haim: What we’re doing is we’re inserting cells into the region of the brain where seizures are coming from. So this does require us to have some sense of where seizures are coming from. But instead of going in there with laser ablation, or with resection, like we’ve done in the past, we’re actually going in and in a very targeted way under MRI guidance, inserting cells that came from stem cells that are secreting a substance, a neurotransmitter called GABA. GABA is an inhibitory neurotransmitter, and the goal of injecting the GABA into that region of brain is to quiet that activity, quiet that hyper activity that’s happening in a place in the brain where seizures are coming from.
Would you say you’re replacing unhealthy, or abnormal cells in the brain with healthy cells?
Ben-Haim: We do know that oftentimes, the region where seizures are coming from is in fact unhealthy. Sometimes, we see that there’s been cell death there. Sometimes, what we do know is that there is deranged metabolic activity there, often times with increased excitation and not enough inhibition, or that’s what we think causes that part of the brain to form spontaneous seizures, which often times start in one area and then can spread to other parts of the brain and sometimes even involve the whole brain. So what we’re doing is we’re inserting cells that can hopefully restore that balance of excitation and inhibition in that part of the brain, and therefore calm, or ideally, completely stop the seizures.
You’re using human stem cells. Are they from anything in particular?
Ben-Haim: There are lots of different ways now to have stem cells that then can differentiate into these type of GABA-producing cells. These particular stem cells that we’re using in this trial are of embryonic origin. There are other ways to induce a person’s own cells derived from their own skin cells and then induce those cells into GABAergic cells. This particular trial currently is using that, but we can foresee hopefully lots of different ways to be able to produce these cells.
Do you have to have a match when it comes to stem cells? Would it be best if they use their own stem cells?
Ben-Haim: I don’t think we really know the answer to that question at this point. What we do know is that there’s been really rigorous safety data because that’s of course, the number one thing we’re concerned about. We want to make sure that what we’re doing is safe. Now we have really a lot of data that shows us that these cells stay where they’re supposed to stay, do what they’re supposed to do, and do not differentiate into something dangerous. That was the basis of the FDA approval for this type of therapy. How we’re going to use that kind of technology in the future? I think there’s a lot of different things we can do with it. Now, one downside to this trial is that at least for now, and really, because it’s become protocol in a lot of trials that use differentiated stem cell therapy, patients do have to be on immunosuppressants at this point after the surgery for a set period of time. And so I don’t want to quote because I’m not 100 percent sure, but I believe it’s on the order of one year. It’s can be a tough therapy. It’s one that involves getting blood levels to make sure you’re not having too much immunosuppressants, not having too little, and it’s something that we monitor pretty closely for the first year after the trial.
For you, you’re the surgeon, how did you do? Was it an open brain surgery?
Ben-Haim: No. That’s probably the best part about it. It’s a minimally invasive surgery. It’s similar in the approach that we use, for example, for a laser ablation procedure where we make a very small incision that allows us to reach our target, and then we insert the cannula that allows us to then very slowly insert the stem cells over time. We actually do this under real time MRI guidance, which is a really cool advancement in technology that we’ve been fortunate enough to have for the last eight years here at UC San Diego. And that allows us to actually see where the stem cells are precisely, where we’re depositing them in our target region.
I would think that ablations have a lot of risk to it because you can damage some tissue around and a lot of times, it’s in areas that control speech, or comprehension, or whatever. Does this hold the same risk?
Ben-Haim: That’s exactly why we’re so excited about it because what we’re seeing, what we saw in pre-clinical testing and what we’re seeing now in the several patients that have already been treated is that we’re not actually inhibiting the underlying function of that tissue. That’s a game changer in epilepsy surgery. That means we could potentially intervene, could potentially restore some balance in that part of the brain and yet maintain the function of that part of the brain.
It’s really exciting, right? There are hundreds of thousands of people that can’t get the help that they need.
Ben-Haim: It’s really exciting because it will allow us to treat patients we weren’t able to treat before. The results are still yet to be determined, but if this therapy can really do what we hope it can do, this could potentially change the way we think about treating patients with epilepsy. Right now, we think about surgical patients as having a focus where their seizures start from. Some patients have what we call multi focal epilepsy, so they have seizures coming, let’s say for both hippocampi, for example, and we realize that the way we’re thinking about epilepsy is simplified in a sense, it’s not exactly that straightforward. And that really what we’re finding with research and just our clinical practice is that it’s pretty clear that epilepsy pathophysiology really involves networks in the brain and not just these foci, not just these specific individual regions, so with a therapy that allows us to intervene in multiple targets safely, we can possibly target other bigger picture epilepsy networks and do so safely.
This man that you operated on, how many different targets did you put?
Ben-Haim: So right now, the trial is only for one focal target. And so really until we see the results of that, I don’t think we’re going to think about multifocal targets, but that’s something that’s clearly potentially in the future for a therapy like this, which is really what makes it exciting.
Can you tell me a little bit about the patient?
Shih: So the patient that we have recruited was actually referred to us from one of my outside colleagues outside of UCSD. Because we are a Level 4 center, National Association of Epilepsy Center we get referred to a number of patients who are interested in treatments above and beyond the usual general standard therapy. So this is a patient who has referred to us and this patient has a condition called drug resistant temporal lobe epilepsy. This is a condition in which medications don’t fully control the seizure disorder and so this patient was looking at other options.
Can you go into a little bit more in depth? Like how was he? Was he having seizures five times a day, two times a week?
Shih: This gentleman is in his mid 30s and he was having seizures probably about 5-8 times per month. People think, oh, you know, 5-8 times per month that’s really not a whole lot. But when you think about it when you have seizures at that frequency you can’t legally drive in California and holding down a job that requires you to be there all the time makes it also difficult. So he wasn’t gainfully employed for long.
Was this something that he experienced his entire life?
Shih: He actually started having seizures in his late 20s. So he’s only had it for about seven or eight years. And the thing is as I was saying, a seizure typically lasts 30 seconds to two minutes. When you think 30 seconds to two minutes, 5, 6, 7 times, that’s what? 15, 18 minutes out of a person’s month? But they go for the rest of that 99% of the month unable to drive, scared to go out to the mall, unable to establish solid relationships oftentimes unfortunately for many of these patients and unable to be gainfully employed in certain types of jobs that they may want to do. So it really is problematic.
Why were you interested in this particular therapy?
Shih: This is the first in human clinical trial of injecting cells that are human cells into the temporal lobe. So again, first ever in history of mankind of injecting human cells into a humans temporal lobe. I think it’s important to back up a little bit and understand that the traditional therapy for people who don’t respond to medications is we try to pinpoint the seizure focus and then we either surgically remove it. Dr. Ben-Haim will surgically remove it or we’ll laser ablation and burn it. We’re destroying tissue. That’s standard therapy. This therapy offers us the opportunity to not destroy tissue but to actually rehabilitate it and recover it. Basically injecting healthy cells and letting those cells establish connections within that damaged brain and try to make it more whole again.
For this patient we’ve talked about the surgery itself with your colleague. After this patient did this, how long was this? How long was the surgery?
Shih: A little over three-and-a-half months ago.
What has been his response?
Shih: His response has been excellent.
Is it something that takes time? It’s just not injected and it’s healed, right?
Shih: Right. His response has been excellent. He’s had better than a 95% reduction in his seizures which is tremendous. And the seizures that he now has are very brief and they don’t affect his awareness. So he gets that funny feeling what we call an aura but it doesn’t go to where he’s confused, disoriented. So people may not even know when he’s got that feeling. So he can actually work through it and be much more functional. The other thing is that- well, I forgot my train of thought.
How long did it take for him to see a difference?
Shih: So typically at least we thought that it would take months because you inject the cells in there, they take a little while to migrate and move around and then to establish connections with other cells. The thought was always that it might take six months. With him as well as the other two people before him in this trial it took a matter of 1-2 months where we started seeing very dramatic and noticeable improvements.
Do you think it’ll continue to improve?
Shih: I’m certainly hoping so. I think that looking at the experiences of the very first patient who had this done, who was implanted in New York that patient has been implanted for over a year and that patient is essentially seizure free. And that was a patient who had like 30 seizures a month.
Is this the closest thing to cure that we’ve gotten to epilepsy?
Shih: There are ways to cure epilepsy, but in patients who have not responded to medication we do have to do those destructive procedures that does give us about seven out of 10 people get their seizures cured but it’s a destructive form of therapy. Again our goal is to see if we can have a rehabilitative or recovery type procedure that’s going to have a really high success rate and no side effects. That’s the goal.
Would this be something that could, one day, if it continues to move forward, replace medications because there’s always side effects of medications, there are always downsides?
Shih: That clearly is a possibility. There are going to be some philosophical issues because this is brain surgery and so there are some risks involved. And our standard procedure is that if medications work that we really don’t offer surgery so that will have to be a philosophical discussion at some point in time.
What’s next for this?
Shih: So currently the study is looking just at seizures coming from what we call the temporal lobe which is actually the most common type of drug resistant epilepsy. What comes next is that once we are able to demonstrate that, that’s effective and it’s safe then we can look at seizures coming from other parts of the brain.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
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