Gene Therapy for Temporal Lobe Epilepsy

Podcast Transcript

Neuro Pathways Podcast Series

Release Date: September 15, 2024

Expiration Date: September 15, 2025

Estimated Time of Completion: 31 minutes

Gene Therapy for Temporal Lobe Epilepsy

Imad Najm

Description

Each podcast in the Neurological Institute series provides a brief, review of management strategies related to the topic.

Learning Objectives

• Review up to date and clinically pertinent topics related to neurological disease
• Discuss advances in the field of neurological diseases
• Describe options for the treatment and care of various neurological disease

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Physicians and Advanced Practice providers in Family Practice, Internal Medicine & Subspecialties, Neurology, Nursing, Pediatrics, Psychology/Psychiatry, Radiology as well as Professors, Researchers, and Students.

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Participants claiming CME credit from this activity may submit the credit hours to the American Osteopathic Association for Category 2 credit.

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Podcast Series Director

Imad Najm, MD
Epilepsy Center

Additional Planner/Reviewer

Cindy Willis, DNP

Faculty

Imad Najm, MD
Epilepsy Center

Host

Glen Stevens, DO, PhD
Cleveland Clinic Brain Tumor and Neuro-Oncology Center

Agenda

Gene Therapy for Temporal Lobe Epilepsy

Imad Najm, MD

Disclosures

In accordance with the Standards for Integrity and Independence issued by the Accreditation Council for Continuing Medical Education (ACCME), The Cleveland Clinic Center for Continuing Education mitigates all relevant conflicts of interest to ensure CME activities are free of commercial bias.

The following faculty have indicated that they may have a relationship, which in the context of their presentation(s), could be perceived as a potential conflict of interest:

The following faculty have indicated they have no relationship which, in the context of their presentation(s), could be perceived as a potential conflict of interest: Cindy Willis, DNP.

CME Disclaimer

The information in this educational activity is provided for general medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options of a specific patient's medical condition. The viewpoints expressed in this CME activity are those of the authors/faculty. They do not represent an endorsement by The Cleveland Clinic Foundation. In no event will The Cleveland Clinic Foundation be liable for any decision made or action taken in reliance upon the information provided through this CME activity.

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Introduction: Neuro Pathways, a Cleveland Clinic podcast exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neurorehab, and psychiatry.

Glen Stevens, DO, PhD: The Centers for Disease Control and Prevention estimate that approximately 3.5 million Americans are living with epilepsy, and of those, only 2/3 have their epilepsy controlled by anti-seizure medications. This percentage is even lower for individuals with temporal lobe epilepsy. For epileptologists, the goal is 100% seizure freedom and driving today's research is the desire to achieve 100% seizure freedom for all patients. In this episode of Neuro Pathways, we're specifically exploring the treatment options for patients with medically refractory temporal lobe epilepsy and the dawn of gene therapy.

I'm your host, Glen Stevens, neurologist, neuro-oncologist in Cleveland Clinic's Neurological Institute, and I'm very pleased to have Dr. Imad Najm join me for today's conversation. Dr. Najm is a neurologist and director of the Epilepsy Center in Cleveland Clinic's Neurological Institute. Imad, welcome to Neuro Pathways.

Imad Najm, MD: Thank you, Glen.

Glen Stevens, DO, PhD: So Imad, I've known you for over 30 years, but for those that don't know you tell us how you made your way to Cleveland and what you do on a daily basis.

Imad Najm, MD: Yes, we've been together actually since our internship and residency back in the 1990s. I came here directly from Los Angeles, California where I did the four-year postdoctoral research training in molecular biology of epilepsy. And before that, I spent some time in France and I was born and raised and went to medical school in Beirut, Lebanon.

Glen Stevens, DO, PhD: And your practice today is what?

Imad Najm, MD: Well, I am a neurologist, but my practice is almost 100% now focused on diagnosis and treatment of patients with epilepsy, in particular, those complex epilepsies or what we call medically intractable, pharmacoresistant epilepsies.

Glen Stevens, DO, PhD: Good. Well, I will tell the audience out there that when I have difficult cases, you're certainly someone that I talk to about it, so always appreciate your help. So when we trained, we always used to use the term anti-epileptic drugs or AEDs, and somewhere in the recent future, I don't see that term anymore. Now it's anti-seizure medication, which is really probably the correct term. But tell me a bit about the transition from AED to ASM.

Imad Najm, MD: Yeah, I think it did happen almost six, seven years ago now that we changed from AED, anti-epileptic drug to ASM, anti-seizure medication. The main reason for that, which is I think very much justifiable by science, the fact that the anti-seizure medications or the pharmacological treatment for epilepsy, it does focus on shutting down the seizures or decreasing their frequency and improvement in their severity. But it does not prevent epilepsy from getting worse or it does not prevent development of epilepsy, what we call now epileptogenesis. So it is a much more appropriate word, hoping that in the future we can resuscitate the term anti-epileptic medication, but this will be in a context of treatment that will stop the development of epilepsy or even reverse it.

Glen Stevens, DO, PhD: It always surprises me when I see that 30% of epilepsy is intractable, that we may decrease the severity and the frequency, but patients up to 30% or even more for different types will still have epilepsy. So that's what we're going to be discussing today, really drug-resistant epilepsy. But I guess we're going to concentrate mostly on temporal lobe epilepsy. So what makes temporal lobe epilepsy different from other epilepsies?

Imad Najm, MD: Yes. If we look at over the last 150 years and try to find out about which epilepsies were the most difficult to treat, and you find as number one, temporal lobe epilepsy, in particular mesial temporal lobe epilepsy due to the pathology of hippocampal sclerosis, which is known since the early 1900s. Then this was the first target or one of the first targets of surgical treatment for epilepsies, in particular the group at the Montreal Neurological Institute that basically revived the concept of modern epilepsy surgery. And their main focus in the beginning, at least, was those patients with mesial temporal lobe epilepsy due to hippocampal sclerosis.

So now why is it still there if it was a focus in the beginning? It was there and it will remain there, actually, because of the fact that although we think that mesial temporal lobe epilepsy, it is unilateral. Studies shown, in particular recent studies from 2011 from autopsies on patients who were diagnosed with one unilateral, one epilepsy that is coming from one single hemisphere that the other hippocampus is almost uniformly sclerotic and show cell death. So this pathology is very difficult to guess, except because the moment we start to think that, "Oh, this epilepsy is very focal, very lateralized," seizures come back from the other side, not always, thankfully. But we know that even under the best hands and best conditions, the success of treating patients even with a resective surgery is around 60%, 65%. So what happened to 35% to 40%? Other hippocampus is picking up and we cannot do surgery on both sides.

Glen Stevens, DO, PhD: Yeah, that was really my naivete when I first started looking at the literature and looking after patients, I thought, "Well, this is very focal. Patients have surgery. You can do a wide excision on them. Why is it 60%?" But, of course, you've answered that question and it's always more complicated than we think it is. But surgery still has a very good role with these types of patients. How many seizure medication should we use, and maybe sometimes it's just one, but how many should we use before we should send somebody for a surgical referral with temporal lobe epilepsy? And are we not sending enough patients?

Imad Najm, MD: Yes, the International League Against Epilepsy back in 2011 made our job a little bit easier by defining what we may call pharmacoresistant or medically intractable epilepsy, which is the failure of two or more anti-seizure medications that are appropriately chosen and dosed to control the seizures. So now two strikes and out. So if we fail two anti-seizure medications and we have a diagnosis of epilepsy because we have to remember some patients with seizures, they don't have epilepsy, they have non-epileptic seizures, and they have focal epilepsy, this is the indication to move the surgical queue and to make sure we do an appropriate evaluation to determine if the patient is surgical or not.

Glen Stevens, DO, PhD: So this is what should be done, but when you look at patients that come in from the outside, are they really just two drug trial or have they been on seven different drugs? What are you seeing with the patients coming in? Are we waiting too long?

Imad Najm, MD: We are waiting too long. Even in a place like Cleveland, Ohio where we really have a big concentration of epilepsy treatment power, we are not seeing patients early enough. I'll give you an example. Back in the 1900s, it used to take around 20 years between the onset of the disease and a referral for higher level care. In the United States, eight years ago, it was 17.5 or 17.8 years. In India from three, four years ago, it is 18 years or 17.8 years. We did not make a huge-

Glen Stevens, DO, PhD: We're not moving that compass very much.

Imad Najm, MD: That's correct. And we are not moving it not only in one area or one geography or one culture across the world, still there is a significant and very harmful delay.

Glen Stevens, DO, PhD: And why is that?

Imad Najm, MD: It's multiple factors. The first one is acceptance of epilepsy surgery and still, there is a significant percentage of colleagues of ours who do not believe that every patient is candidate for epilepsy surgery. And second, there is a belief that if we can control the grand mal seizures or generalized convulsive seizures and we have one to two seizures per night or during the day or minor seizures, what they may call them, it's enough as a decent control of epilepsy. And therefore, there is no push for the patients to understand that even one seizure is one too many. And we do not explain clearly enough the concept of sudden unexplained death in epilepsy. We know the only way we can eliminate the risk of sudden unexplained death in epilepsy is through complete seizure control.

Glen Stevens, DO, PhD: Well, that would be enough for me, right?

Imad Najm, MD: That's what we hoped. But unfortunately, we do not have buy-in, or at least the urgency of our colleagues. They don't see the urgency of treating epilepsy as a potentially lethal disease.

Glen Stevens, DO, PhD: Well, that's a good point. The other thing if I rack my memory is that I seem to recall the theory of kindling, and I don't know if you're a kindling theorist or not, but my recollection of that, just like you're starting a fire when you're in the Cub Scouts and you start with the small pieces and then you build the bigger one, that the more seizures you allow today, the more likely you'll have seizures down the road. So if that theory still is in existence, and you can tell me if it's still thought to be, it'd be reason to try and stop seizures sooner, less likely of having a seizure five years from now, true, false or still a debate?

Imad Najm, MD: Absolutely. Back in the day when I did my postdoctoral training in Los Angeles, I did work on the kainic acid model of temporal lobe epilepsy. And we know you inject one hippocampus, the other hippocampus will become epileptic too and develop cell loss. And this is very true for human epilepsy. And probably, this is one of the strongest hypothesis behind the explanation of why hippocampus sclerosis is in such a large number of patients bilateral. And the only time that we can avoid the kindling effect, which the kindling is just one seizure after another and creating some changes that become permanent in the hippocampus, which is the main structure that is susceptible to kindling. So if we intervene early or we stop these seizures early after they start in one hippocampus, there is a very high chance that the other hippocampus will not kindle and therefore, the success of surgery will be much higher than what we are witnessing now.

Glen Stevens, DO, PhD: Well, I like what you're telling me because I'm learning stuff.

Imad Najm, MD: Thank you.

Glen Stevens, DO, PhD: And that's always good. So I'm curious with what you've said if you've changed your practice in terms of weaning anti-seizure medications post-resection, or has it unchanged now that you understand better the risk to the other hemisphere?

Imad Najm, MD: Still, it is a topic of debate, believe it or not. We don't have very clear guidelines about when, even after complete seizure control following epilepsy surgery, when and if we should stop anti-seizure medications. We know that in the majority of patients whose seizures become controlled after surgery, we can decrease from four to three to two to one medication. And in even with one medication, we can decrease the dose enough to just eliminate or control most of the potential side effects of these medication with some "protection." Now the problem we have, none of the anti-seizure medications, as I mentioned earlier, approved in the United States, are approved as an anti-epileptogenesis medication. And kindling is an epileptogenesis mechanism here. So therefore, we really do not know, even if we keep patients on anti-seizure medication, are we protected or not?

Glen Stevens, DO, PhD: Right, may stop the seizures, but don't prevent the risk of seizures down the road. Good point. So with all the imaging that we have, are you able to look at the contralateral mesial temporal lobe and determine fairly well if people are at higher risk of having seizures post resection of the other hemisphere?

Imad Najm, MD: Yeah, we do have significant improvement in imaging over the last 30 years. MRI is our biggest difference maker in the diagnosis of hippocampus sclerosis outside the pathology lab. Now, we know there is certain percentage of patients whose MRI remains normal and they don't show any significant changes that could be consistent with hippocampus sclerosis. And if we end up implanting electrodes and determine that that one hippocampus is abnormal and we study that hippocampus under the microscope, there is a certain percentage of these patients, they show hippocampus sclerosis. So it means MRI may be showing changes in the majority of patient hippocampus sclerosis, but not all of them. So there may be a group of patients who may have one side clearly hippocampus sclerosis, but the other side is not.

Glen Stevens, DO, PhD: And can you tell from the pathologic specimen the degree of change pathologically what you would expect to see on the other side, or it doesn't correlate?

Imad Najm, MD: No studies were done to find out if there should be a correlation. Let's say we determine, in general, in CA3 and CA1 subfields of the hippocampus should be 30% decrease in cells, neuronal cells, to determine if it is hippocampus sclerosis or not. Now if it is 50%, 60% does it mean the other side is now at 20% or 15%? We don't know.

Glen Stevens, DO, PhD: Well, I've given you some more research opportunities.

Imad Najm, MD: I'm looking for any opportunity I can get.

Glen Stevens, DO, PhD: So we will get to gene therapy here, but continuing with this, so let's say that somebody has a resective surgery and they're having seizures, same side. We won't necessarily go to the other side or I suppose we can. What other non-drug options do we have other than gene therapy for patients?

Imad Najm, MD: Yeah, I think the approved modalities now outside resective surgical technique, actually there is something that is ablative technique with laser therapy. And laser is a much more, some people would say, elegant way of ablating the tissue that is epileptic. The multi-center studies from four or five years ago showed that they lead to a significant control of seizures in a large number of patients, maybe around 55% versus 65% at 20 year after resective surgery. So laser therapy, it is a viable option for these patients. Now, if laser therapy or resective surgery is not an option or failed, and the seizures may be coming from same area, there may be additional resective opportunities outside the hippocampus. But if it's not there or these opportunities or these possibilities are not there, now we go into what we call neuromodulation field.

A neuromodulation field is the first one in 1996, vagus nerve stimulator. Then we have, in 2013, the responsive neurostimulator and in the United States in 2018, the deep brain stimulator for the anterior nucleus of the thalamus. So these, as a group, would put them under neuromodulation because they're dependent on small electrical impulses, the vagus nerve peripherally, responsive neurostimulator mainly in the area where the seizure is supposed to be, and deep brain stimulator in the anterior nucleus of the thalamus. Now, there are additional nuclei used based on the potential connection between these structures and where the epilepsy may be coming from. The success of those, overall, is around 10% to 15% of patients who will achieve complete seizure control. But there is an interesting effect that shows, in particular, for DBS and RNS that this percent of patients who have meaningful seizure decrease, percentage of seizure decrease in these patients is increasing every year, up to nine years of follow-up they're showing. So there is potentially this neuromodulatory effect of the properties of neurons or local or large networks in the brain that we still don't understand why.

Glen Stevens, DO, PhD: Interesting, starting to sound a little anti-epileptic.

Imad Najm, MD: It does. It does sound, actually, there may be some changes. And that was one of the hypotheses in the past of neuromodulation. Now, if you go back to kindling, which you mentioned, the kindling is creating a seizure. But if you look at the responsive neurostimulator, RNS, it is a burst, a high-frequency burst of stimulation, but for a split second. So it's probably same mechanism, plasticity, excitotoxicity and potential neuromodulation, probably same continuum. It depends on the structure and the frequency and the current intensity that is used.

Glen Stevens, DO, PhD: Interesting. I'm curious nationwide how the adoption has been of these neuromodulatory techniques because people generally vote with their feet and they either walk towards it or they walk away from it. What's your general impression in the country with neuromodulation?

Imad Najm, MD: Neuromodulation has been, overall, accepted as an option. Now, the indications of it, they vary considerably, from one place or the one center to another and even from one geographical area to another. So you see some places doing quite a bit of RNS, responsive neurostimulators, some places doing more VNS, vagus nerve stimulator, and others doing deep brain stimulator. At this point, there are no clear guidelines of the indication to each one of these technologies.

Glen Stevens, DO, PhD: So for the last 10 minutes, let's get into gene therapy. Fascinating area, of course, and you could tell better than I can tell you, but my understanding from my recollection was there's not a lot of general gene deletion types of things. You have a specific gene mutation and you can fix that mutation and solve the epilepsy. There's a few of them, but it's not very common. So this would be more affecting the microenvironment with gene therapy, maybe the NMDA receptor to affect glutamate, affecting GABA, the inhibitory or affecting neuropeptides. So talk to me about gene therapy, where it sits, what it is. Educate me.

Imad Najm, MD: Gene therapy, it's something that is potentially very exciting. In your field, in cancer, you guys are maybe 20 years ahead of us because you find mutations in some cancers and that mutation is very focal and very particular for the pathologies that you're treating. In epilepsy, the majority of patients, they do not have a single gene mutation or a pathological single gene mutation. More studies showing something that we call polygenic changes, multiple genes showing multiple mutations, none of them on their own, they are pathological, but altogether, it seemed like they increase the risk of a development of epilepsy. Some of them, they increase the risk of coronary artery disease and other diseases.

So because of that, the field of gene therapy in the context of focal epilepsies and even generalized epilepsies has not caught up ‘til recently. Now what happened? So in over the last 10 years, 15 years, we started to see in some focal pathologies in the brain, such as focal malformation of cortical development, cortical dysplasia, what we call somatic mutation, somatic gene mutations that are very much focal or restricted to the pathology. And these genes, they are part of pathways that are essential for the axonogenesis, neurogenesis, synaptogenesis and as we mentioned earlier, plasticity, long-term potentiation, memory, leading to exitotoxicity. In between, there is the kindling and these pathways seem to be significantly activated in these focal cortical dysplasia, leading potentially, we cannot verify 100% yet, although there are some pre-clinical models showing this, leading to the transformation of a particular pathology from a non-epileptic, but pro-epileptic pathology into an active epilepsy focus. So this gives us some hope that, "Oh, maybe if we can target these genes, there could be multiple genes at multiple level of pathway, we may be able to get something to control these issues."

Now, are there any trials about this? No, not yet for this. Now, the other thing here is, like you mentioned, could we, even if there are that single gene mutation, but target a particular promoter of a gene of a particular protein, like an MDA receptor, like kainic acid receptor? And that is something that is speaking up steam currently, leading to trials happening now or very soon.

Glen Stevens, DO, PhD: And what would the vehicle be that you would use to get these genes or affecting the promoter in the brain?

Imad Najm, MD: There are a couple ways to do it. We all know in your field, in brain tumors, the problem we have is the blood-brain barrier. We have this blood-brain barrier. It's our protection, but at the same time, for these focal deliveries, it is a potential problem for us. There are two ways. First way is direct viral transfection, adenovirus-linked gene therapy to basically deliver in a specific focus in the brain. And that's where treating, for example, pathology like hippocampus sclerosis, which, by the way, did not show any somatic gene mutation. When we studied our big series of almost 1,000 cases, every type of pathology, we did not find a single gene mutation in hippocampus. We found it in focal cortical dysplasia. So hippocampal epilepsy, if we target potentially certain proteins in that hippocampus, we may be able to affect the seizure or the epilepsy as a phenotype and shut it down. And that's something that is potentially happening soon.

Glen Stevens, DO, PhD: Yeah. Well, as you mentioned in brain tumor, we've been using viral vectors for a long time and we've run quite a few trials with it. And of course, the concern was always we're going to cause a problem in the brain. We're going to cause an inflammatory response. And I think that there's been enough trials that these things are pretty safe in terms of getting them into the brain and we've convected them into the brain. We've used different things to get them into the brain, but it's really just a matter of what's the target and what's the input of once you affect that target is the bigger question. So do you have a trial in mind? Do you have one going on?

Imad Najm, MD: Well, there is a trial going on, which is a trial on using a vector, a viral vector linked to a blocker of the kainic acid receptor, which is one of the glutamate receptors, in particular, is very linked to the AMPA receptor, the sodium channel receptor.

Glen Stevens, DO, PhD: Going back to your work from 35 years ago.

Imad Najm, MD: 35 years ago, exactly. Going back to where we started, going back to kainic acid receptor and that kainic acid receptor, it is hyper-expressed in hippocampus sclerosis. The idea here, if we can shut it down, shunt the promoter for that receptor, we may be able to decrease the excitability in the hippocampus and therefore, we control the seizures. Pre-clinical models were encouraging and there is a trial using the adenovirus as a vector to shut down the kainic acid receptor in patients with mesial temporal lobe epilepsy due to hippocampus sclerosis.

Glen Stevens, DO, PhD: And you know how far along that trial is? Is just starting or it's been...

Imad Najm, MD: It is starting.

Glen Stevens, DO, PhD: Okay, excellent.

Imad Najm, MD: Yes.

Glen Stevens, DO, PhD: So Imad, it's been fascinating. Anything that we haven't discussed that you think is important that we need to discuss?

Imad Najm, MD: I think it's very important to know that in epilepsy we should never discount a single seizure. We should treat as promptly as possible. We should aim for zero seizure. And the bright side, the future, next 5, 10, 15 years, I think there are going to be major development in the field of epilepsy, moving away from medications that are very good in controlling some of the seizures, but a lot of side effects to what we always dreamed about the precision medicine field, the field of identifying a target and shutting down that target that is very specific to the particular pathology and the pathology of that patient. So that is where, I think, the hope is and the excitement is in the field of epilepsy, learning from fields, in particular, field of cancer, to apply some of this knowledge and the expertise that in brain tumor and other parts of cancer in these focal lesions in the brains of patients with epilepsy.

Glen Stevens, DO, PhD: Well, very, very exciting. In brain tumor, we used to be very phenotypically oriented for nomenclature, but in the current WHO classifications, everything is going molecular. We're really diagnosing tumors molecularly as it moves forward. And this will only provide better treatments for us as it moves forward, as it's going to for you. But fascinating conversation, I loved our time together. I love what you guys are doing and really look forward to your continued work. And we'll have you come back when you can tell us a little bit more about your vector trial and see where things are going. But I appreciate everything you're doing and I've enjoyed working with you for 30-plus years. Appreciate it.

Imad Najm, MD: Thank you, Glen. It was a pleasure.

Closing: This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast, or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. And don't forget, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website. That's @CleClinicMD, all one word. And thank you for listening.