Episode #153 - On the Brink of Breakthrough: How an Arthritis Med Could Stop Seizures featuring Dr. Olivia Hoffman
On the Brink of Breakthrough: How an Arthritis Med Could Stop Seizures
Episode Overview
This month on Seizing Life® we welcome Dr. Olivia Hoffman to the podcast to tell us about one of the most exciting discoveries in epilepsy research in recent years, a repurposed drug that has shown remarkable promise in eliminating seizures and restoring cognition in animal models.
Regular listeners of the Seizing Life® podcast may recall a recent episode in which Dr. Daniel Lowenstein referred to “one of the most spectacular discoveries (he’s) seen in the last couple of years” in the field of epilepsy research. That discovery was made in Dr. Avtar Roopra’s lab at the University of Wisconsin-Madison, and key post-doctoral researcher Dr. Olivia Hoffman joins us to explain the process, promise, and possible impacts of her work. Tofacitinib, a repurposed and FDA-approved drug for arthritis, has shown amazing promise in treating epilepsy in laboratory animal models. In mice, the drug has shown incredible results: it suppresses seizures, even eliminating them in a majority of the animal models; it seems to restore cognitive functions; and it is well-tolerated with few side effects, while also seemingly providing future protection from seizures. Dr. Hoffman details how she and her team built upon previous research to arrive at this surprising and encouraging discovery, shares theories behind how the drug may be working, explains how it could impact the lives of those living with epilepsy, and charts the next steps to get the drug into a human trial – steps which may be hindered, slowed, or even halted by recently threatened cuts to NIH funding.
This is one of the most promising and hopeful epilepsy discoveries in recent years, but it comes at one of the most anxious and challenging times in history for medical researchers, placing this discovery and Dr. Roopra’s lab at the crossroads of science, government, healthcare, and bureaucracy. It’s an important story at a crucial time when our country is reassessing the value of scientific research.
Episode Transcript
Kelly Cervantes:
Hi, I’m Kelly Cervantes, and this is Seizing Life, a monthly podcast produced by CURE Epilepsy.
Today, I’m excited to welcome Dr. Olivia Hoffman to the podcast. Olivia is a postdoctoral epilepsy researcher in Dr. Avtar Roopra’s lab at the University of Wisconsin-Madison. The lab has made headlines for a potential breakthrough discovery, a repurposed drug that has shown amazing promise in suppressing seizures, restoring cognition, and even curing epilepsy in animal models. In fact, if you watched or listened to our previous podcast with Dr. Daniel Lowenstein, he noted this as one of the most spectacular discoveries that he’s seen in recent years. Olivia is here today to share that discovery and explain how proposed cuts to the National Institutes of Health budget may derail this potentially life-changing treatment. Thank you so much for joining us, Dr. Olivia Hoffman. Is it okay if I call you Dr. Hoffman? Olivia?
Dr. Olivia Hoffman:
You can call me Olivia for that.
Kelly Cervantes:
Perfect.
Dr. Olivia Hoffman:
I’m not quite used to the title yet.
Kelly Cervantes:
So to that end, it is a rather new title for you. You’re a postdoctoral researcher. Can you tell us a little bit about your professional life, your background, and what exactly that means, to be a postdoctoral researcher?
Dr. Olivia Hoffman:
Sure, yeah. So in terms of my background, it’s pretty easy because I’m a lifelong Badger. I grew up in Wisconsin and did my undergraduate and graduate training, so my doctoral training at the University of Wisconsin-Madison, I’ve worked at the UW Hospital. And so I’ve been living in Madison for about 11 years now and now I am, yes, a postdoctoral researcher at the University of Wisconsin. And what that means is I’ve completed my formal educational training, I am now Dr. Hoffman, so I’m no longer a student. I’m kind of in this in-between phase of, not a student and not a professor. So, right now I’m doing advanced research and trying to deepen my expertise with the ultimate goal of becoming a professor at some point.
Kelly Cervantes:
Okay, and what is the research that you’re doing?
Dr. Olivia Hoffman:
I am studying epilepsy. That was also what I studied for my doctoral degree, so we’re sticking with it. Right now, I am studying the impact of a drug on epilepsy and looking to repurpose it. It’s already actually approved, in order to treat epileptic animals and hopefully humans at some point.
Kelly Cervantes:
Yeah, I cannot wait for us to dive into your research because it is absolutely fascinating. Can you give us a little bit of background about how you got interested in epilepsy?
Dr. Olivia Hoffman:
Yeah, for sure. So I guess I do have a bit of a personal connection when it comes to epilepsy, but at the same time, it’s a little nerdy and a little personal. Right? So I was interviewing for my doctoral program here at the UW and Avtar Roopra, my PI, my principal investigator, mentor, he was one of my interviewers. And we really hit it off because I mean, if you know him, he’s just this super enthusiastic, passionate scientist and I really connected with that, that resonated with me.
I’ve always been interested in the brain, and it just so happens that when I was a kid, I did have seizures. I think they were focal, sorry, they were partial complex seizures. I was able to take a medication for a time and eventually wean off of it. And so I haven’t had a seizure in almost two decades, but that’s not the case for everybody, which I learned very shortly after chatting with Avtar for the first time. And I’m now just fully on board, want to do this research, epilepsy-specific research for the rest of my career if I can swing it, so.
Kelly Cervantes:
Well, we are thrilled that you chose epilepsy as your focus, and I think it’s so interesting and fascinating that you had epilepsy as a child, but I think we are so secluded by our own experience. So you took a medication, and like two thirds of people with epilepsy, take a medication and their seizures are controlled but there is still that one third of epilepsy patients who remain uncontrolled. And so, I think it’s really remarkable now that you’re fighting for research for that other one third.
Getting to your research, which is so incredibly interesting and exciting, so you mentioned that you’re looking at this drug which has already been approved for treating arthritis, and now you believe that it could help treat people with epilepsy. Tell us more about that and how it works.
Dr. Olivia Hoffman:
Sure. So the drug, its name is tofacitinib. You may have seen it marketed as Xeljanz. And yes, so it’s an antiinflammatory medication that’s approved for rheumatoid arthritis and ulcerative colitis. And I’ll give you the short story here, I’m sure we’ll dive in deeper. But in a nutshell, when we give it to animals over the course of two weeks, their seizures are suppressed a lot. Mice that are getting placebo are having about one seizure per day, mice that are getting this drug are having about one seizure every two weeks. And the remarkable thing, there are a couple remarkable things about this drug. When we take it away, the animals remain protected. So their seizures do appear to be coming back up around the five-month mark. So five months since their last dose, however, from the time of their final dose to three to four months after, they appear to be protected in terms of their seizures. And the other incredible thing that this drug does, sorry, I laugh about this because I’m just like, I can’t believe it.
Kelly Cervantes:
It’s remarkable.
Dr. Olivia Hoffman:
Yeah.
Kelly Cervantes:
It’s absolutely… I mean, I can’t think of another drug that has that kind of a lasting impact. The fear that so many patients feel when they’re going to miss a dose or if they’re going on vacation or they forget their medication or anything, all of the practical real-world situations that happen, and here is a potential drug that at least in mice is showing that you miss a dose, you forget your medication, that you’re still going to be protected. I mean, that is real world, life-changing stuff.
Dr. Olivia Hoffman:
Right. Yeah, and I mean, it’s wild. The drug also appears to not only get around a lot of the adverse effects that many epilepsy drugs have on cognition, the brain fog that a lot of patients report from existing antiepileptics. I mean, we can’t ask the mice, but we can test certain aspects of their cognition. And we found that not only does the drug not exacerbate or worsen those cognitive issues that a lot of patients report with antiepileptic drugs, it actually appears to rescue a lot of the cognitive decline that occurs when there’s tons of electrical activity happening in your brain. The mice appear to be getting a lot of their spatial memory coming back online, and we can talk a little bit about that if you’d like. But also when we take the drug away though, that protection appears to stick around as well, which is crazy.
Kelly Cervantes:
It’s wild. Tell us about the journey that led to this discovery because I mean, this is a drug that you said is used for arthritis, that you don’t automatically think repurposing a drug, that this is the one that’s going to work for epilepsy. How did you get here?
Dr. Olivia Hoffman:
Right. So, it’s quite the story, and actually, it begins well over a decade ago. I think the work that sort of birthed the project that I am currently working on started when I was in high school. So, that was a minute ago.
Kelly Cervantes:
Well, and speaks to how long it can take some of these discoveries to reach a patient. I mean, you’re still not at a human clinical trial at this point, and it’s already been 10 years. I think that’s so important for people to understand, but please go on.
Dr. Olivia Hoffman:
Yeah, no. So at least where it began when I joined the laboratory was, we were actually studying a molecule in the brain that is not the one this drug targets. We were studying this molecule called EZH2, which actually appeared to be protective in epilepsy. So it goes up in the brain after seizures, and when we inhibit it with a drug or we knock it out, the animals were worse off. So we were like, oh, this is so cool, but it’s really hard to increase the activity of a protective protein or a protective molecule. So we were hoping to find what EZH2 is targeting and then target that.
So, we ended up finding this other molecule called STAT3, and we have a lot of fun toys we can play with as scientists these days. So, one of those things that we can do is take every cell in the brain, break it open, and measure the gene levels. And when we did that in mice, we found that STAT3, this molecule that appears to be pathological in epilepsy, was driving the levels of thousands of other genes across not just neurons, which is what we talk about a lot in epilepsy, but also all of the immune cells in the brain. So microglia, the neuron support cells, astrocytes, it was just everywhere. So, that was really interesting.
And then when we looked in the data sets that are available from human patients who have to get temporal lobectomies because they don’t respond to medication, we found a STAT3 there as well. So, that was exciting because we were like, yes, not only is this molecule, does it appear to be relevant across different animal models of epilepsy, it also appears to be doing something in human patients, which is so important when you’re doing research like this to have that translational relevance. Right? It’s all well and good for something to work in animals, but it needs to be in the human patients as well.
Kelly Cervantes:
Right, and this study showed that it could work in humans as well. So, how do you get from knowing about, from making this discovery to realizing that there is a medication that is already FDA approved that is in the market that could potentially affect the very thing you’re studying?
Dr. Olivia Hoffman:
Yeah, absolutely. So, what you try to do when you’re doing this sort of discovery-based work, is you’re trying to find a target because all of these drugs, they bind molecules and do stuff. Right? So our target we were hoping was STAT3, just based on all of the discovery-based research we did to get to that point. So having the target is huge, but then you need to find a drug or develop a drug that actually hits that target. So luckily, there are a lot of inflammatory diseases, STAT3 is part of an inflammatory signaling cascade. And so there were a number of drugs already on the market or being tested in clinical trials that inhibit STAT3. So honestly, what I did was just look at all of them, get a list of all of them, and then I was searching for articles to suggest that any of these drugs would have the ability to penetrate the blood-brain barrier, because that’s the big thing with these drugs is they tend not to.
So, I found tofacitinib literally just I found two papers. One was, oh, when we give this drug to mice for dermatitis, they get aggressive. And I’m like, okay, well, maybe there’s some central nervous system penetrance going on. Obviously, we don’t want to give the drug to animals if they’re going to be aggressive, but I think these animals in particular were just itchy, so.
Kelly Cervantes:
I get angry when I’m itchy too, it’s fair.
Dr. Olivia Hoffman:
Yeah, yeah. So yeah, I found a couple articles to suggest that this drug might get into the brain were also sort of helped. I mean, it’s not great when the blood brain barrier breaks down in epilepsy, but because of that, I was hoping the drug might be able to get in there and target STAT3 because we weren’t ready to inject the drug directly into the brain, we weren’t set up for that. And also, I wanted to mirror the current clinical administration of this drug, which would be oral for patients. Mice don’t appreciate oral administration of drugs, so I just wanted to give them a systemic injection, get it into their bloodstream, and see if it got into the brain, and it did.
However, then we had the problem of timing when to get this drug, right? Because there’s a huge body of work, and this was where we were focused initially, that is looking to identify targets for drugs in epilepsy where we could give the drug before the patient ever begins to develop seizures and prevent epilepsy altogether. I mean, that’s the dream, right? The problem of course is that we don’t have any biomarkers for epilepsy currently. Now, there are a bunch of excellent folks and researchers looking to discover some of those to make it possible to prevent epilepsy altogether. But just for fun, I was like, let’s try and give this drug to mice before they develop epilepsy and see what happens. And it didn’t work. The mice still went down to develop epilepsy.
And so, we were kind of at this impasse where I’m like, okay, we’ve got this target that’s active in mice and it’s active in humans. And the turning point was really that human data because I realized, oh my gosh, these humans, this human data which is showing that this molecule is active, they’re already having seizures, they’re chronically epileptic, so much so that they had to get brain surgery in order to correct it. So, what we see with this molecule is it goes up after initial insult and then comes back down. But I was like, what happens when the mice start having seizures? Does this target become available again? And sure enough, in our mice, just like in these human patients with epilepsy, once they started having seizures, this molecule comes back up. So I was like, okay, obviously every researcher wants to find a drug that just prevents the problem altogether, that’s the holy grail. But I’m like, all right, well, maybe we have a potential treatment for epilepsy.
So, I gave the drug to mice after they’d already been having seizures. Most of them have been epileptic for three months by the time they get the drug, and it worked. That was the crazy part because I was like, well, it didn’t work when we tried to give it preventatively, so whatever effect it’s going to have when the mice are already epileptic, I mean, we’ll see what happens. And we were blown away, we were so blown away. Our collaborator in Boston performed this initial round of experiments for us, and she held off on sending us the data because she was like, okay, I don’t believe this, I need to add some more mice to this experiment.
Kelly Cervantes:
Wow.
Dr. Olivia Hoffman:
And just astounding reductions.
Kelly Cervantes:
And how often were the mice getting the medication? And I think you said that you’d given it to them for two weeks, but how frequently were they getting the medication?
Dr. Olivia Hoffman:
Right. So in our initial pass where our collaborator performed that first experiment, those mice only got the drug for one week. So it was one dose per day for six days. So by day three, the animals were pretty much seizure-free, except for one. And then in our hands, I decided to extend the dosing period a bit, and so I gave 10 doses over a two-week period, one dose per day. One per weekday because I was like, if this drug is going to work, it better work if I don’t give it on the weekends. Just 10 doses, 10 doses over two weeks, and then we stop.
Kelly Cervantes:
Wow.
Dr. Olivia Hoffman:
And the drug, it doesn’t stick around. The interesting thing about this drug is it has a really short half-life. And when we talk about that in science, we’re talking about the time it takes for a drug to go from 100% of the dose you gave in the body, and then come down to 50%, and that’s only two hours for this drug. So by 24 hours after the last dose, this drug is out of the system, essentially, or at least not at a therapeutic dose. And the fact that we only had to give this drug in a series of 10 doses over 14 days suggests that whatever it’s doing, it’s persistent and it’s lasting. So, that was pretty wild.
Kelly Cervantes:
That is so wild that it’s not even in the system anymore and it’s still effective. And then, how did you test for their cognitive ability?
Dr. Olivia Hoffman:
Oh, yeah. So that’s tricky, right? Because you have to come up with these tests that give you a measurable result, but allow the mice to kind of do their thing. So we built in lab this Y maze that it’s basically just three arms that are, it’s like a peace sign. And what we can do is we can just stick the mouse in one of the arms and a normal animal, or sorry, an animal that doesn’t have epilepsy or isn’t impaired in any way, because mice are just naturally curious, they’ll alternate and explore each arm in a relatively circular fashion because they’re always looking for the thing that’s new. And so, that’s an example of working memory. It’s the kind of memory that you and I would use to explore a new house that we’ve never been in before, and just keep track of which rooms we’ve visited. But mice with epilepsy lose this ability, they can’t remember where they’ve been in real time like that and can’t hold onto those spatial memories. But when we give the drug, that ability gets restored.
The other thing we can do is test short-term memory. So the way we do that is we block off one of those arms in the maze and just let the mouse explore the other two for 15 minutes, and then they go back to their cage for half an hour. And when they’re returned to the maze, that new arm is open. And if they remember where they’ve been before, they’ll want to go into that new arm. Again in epilepsy, this ability to remember where they’ve been for any amount of time gets impaired. But when we give the drug, the mice remember again.
Kelly Cervantes:
Wow.
Dr. Olivia Hoffman:
And they spend all that time in the novel arm.
Kelly Cervantes:
Wow.
Dr. Olivia Hoffman:
So at the very least, this drug appears to be restoring some of the most important pieces of memory that not just mice, but people like you and I use to navigate the world and move through it effectively.
Kelly Cervantes:
As with so many things with seizures and epilepsy, I feel like we don’t know why they happen, we don’t know why. Do you know why this drug is working the way that it is?
Dr. Olivia Hoffman:
I don’t have hard conclusions for you unfortunately, but we do have several theories. So, we put the cart before the horse on this one because a lot of times when people are developing drugs for diseases, they have to figure out how it’s working, and then they have to figure out how it’s working because to know how it’s working is to know what adverse effects it might be having outside of what you’re seeing in the animal. The cool thing about this drug is that it’s already FDA approved, so we know that it’s tolerated in humans to some level, right? And the effect was so profound that we just had to document that immediately and catalog all of the effects it was having on these animals. But now, we are trying to understand what it’s doing exactly and why it’s so effective, and also what it’s not doing. Could this drug have synergy with other existing antiepileptic drugs?
So, at least I’ll give you a little pet theory because I feel like I’m just waving my hands here. So, one of the things that we are thinking this drug might do better than other drugs that have come before it or what have you, is inflammation is not just an inflammatory cell thing. It happens in neurons and astrocytes and microglia. The whole brain gets inflamed and it’s kind of this feed forward mechanism, where neurons can release molecules that activate immune cells and then those immune cells make life more difficult for the neurons and so on. And this molecule that the drug targets, STAT3, is present across all of those cells. So what we’re wondering is whether this drug, based on the cells it’s targeting is able to quiet that mechanism across cell types, so that one cell type can’t get excited again and be like, okay, we’re ramping all this thing up again. Right? And that’s kind a broad strokes view of what we’re thinking might be happening, but we are performing several experiments to try and understand that more thoroughly, which I can talk about if you’d like.
Kelly Cervantes:
Well, I’m actually curious, I mean, we know that epilepsy is a spectrum disorder that people can develop epilepsy either from genetics or from injury. Is there a certain type of epilepsy, a certain type of seizure that you think this drug is going to be more effective treating?
Dr. Olivia Hoffman:
Yeah. So what I’m guessing, and we are planning to test… So, hold on, let me back up, I’m getting too excited. So, we have tested this drug mostly in models of acquired epilepsy. So these are animals who had a big initial insult, and then that latent period where they don’t have seizures, and then seizures begin to ramp up. So, there’s a big neuroinflammatory component to those sort of types of epilepsies. Other models or types of epilepsy where I think this drug could be relevant is traumatic brain injury, so post-traumatic epilepsy because there’s a huge inflammatory component there. And that might actually be a situation where preventative intervention works in a way that it doesn’t in our models, where we just give the mice this big round of seizures and then wait for them to have seizures on their own. Because that first insult, especially with TBI, is going to kick off a ton of inflammatory cascades.
In terms of genetic epilepsies, what we know is that when you have a bunch of seizures, it does cause inflammation. What we’re dealing with right now is kind of a chicken or the egg situation, where and at least in our model of epilepsy, we don’t know we inflammation comes up before seizures or comes up in response to seizures. Clearly, at least based on what this drug is doing, we know that inflammation or ongoing inflammation appears to be required for seizures to continue because when we shut it off, the seizures come down and stay down. But because of that whole interplay between neuroinflammation and seizures, I’m wondering if this drug might help treat seizures in cases of genetic epilepsies, but it won’t necessarily have the lasting effect, because if you have a gene mutation, tamping down neuroinflammation isn’t going to fix that gene mutation.
However, it could be another therapeutic option or maybe like an adjunct therapy, which is why we’re looking at how this drug might interact with existing antiepileptics. And so far the data there is pretty promising that’s being performed by a graduate student, Jennifer Kahler in our lab. And they’re looking at treating animals who are epileptic with both valproic acid or Depakote, and this drug tofacitinib. And they appear to be really effective when put together, which is super exciting.
Kelly Cervantes:
That is really exciting and I imagine for so many of our listeners or watchers that they are, so many people are looking, they’ve tried everything and they’ve run out of options. And here is something that sounds so incredibly promising. What are the next steps? How do you get from, oh my goodness, this is wild and it works in these mice, to a doctor being able to prescribe it to a human patient?
Dr. Olivia Hoffman:
Right. So I would say we’ve got a couple scientific hurdles and a lot more bureaucratic hurdles in this process going forward. So, we’ve got a bit of due diligence to do on our end, which is to make sure that this drug is targeting what we think it’s targeting. So for example, we’re going to need to take a molecule that’s not this drug but which targets the molecule we think the drug is targeting, if you follow, and inject it into the brains of these animals and make sure that we’re seeing that same effect.
We’re also going to need to make sure that this drug is actually working in the brain. And by that I mean, we’re wondering whether by giving this drug systemically, so it’s all through the body, not just the brain, whether there’s inflammation that’s being controlled in the rest of the body and having indirect effects on the brain. So we’re trying to tease apart those two things. Because one of the things that happens in epilepsy, which I’m sure is when the blood-brain barrier breaks down, that’s immune cells from the bloodstream getting into the brain and making inflammation worse. So we’re wondering whether this drug is not just working in the brain but also the rest of the body. So, those are some of the scientific things that we need to do on our end.
In terms of getting this drug tested in humans, we’re at an advantage that’s also kind of a disadvantage. So this drug has already been through clinical trials for a different disease, so we know it’s safe and tolerable in humans up to an extent. It does have a black box warning because people with existing cardiac problems may have adverse reactions to it. Also, just by nature of what it targets, there are some immunological cancer, scary stuff that can happen if patients are on it too long, which is why us being able to give it briefly to mice is so promising. So we don’t have to do the work, the same kind of work like looking at lethal doses, that stuff has already been completed. But the problem is this drug has already gone generic, so what that means is pharmaceutical companies who would normally really want to develop this drug and put it through clinical trial, don’t stand to make a ton of money on it, because the doctor can just prescribe the generic. So, that’s where entities that are not necessarily looking to make a profit really come into play, like the NIH.
Kelly Cervantes:
So you need funding to move it forward that is not pharmaceutical funding, and unfortunately, this is not a super awesome time to be looking for NIH funding, as the current administration is proposing a 40% cut on the NIH budget. So, not a super awesome time to be looking for private or for looking government funding. What are the options here and how does that affect you? I’m also just thinking, not even just this drug, I’m also thinking of you as a person. You’re not a student but you’re not yet a professor, you’re in this limbo stage, you’ve been working on this research. What are the ramifications there for the research, for this potential treatment, and also for you?
Dr. Olivia Hoffman:
Right, that is a loaded question. So, I guess right now we’re in a holding pattern in our laboratory. So the scientific hurdles that we need to clear in order to get this drug to some entity to run a clinical trial, because we’re not set up to do that, we are going to struggle to clear until we can get reliable funding back. So I guess I can give you an idea of what that looks like in our lab right now, because I feel like that’s important, so.
Kelly Cervantes:
Yeah, please.
Dr. Olivia Hoffman:
We have a lot of mice or we had a lot of mice. A lot of them had genetic mutations that we were using to study various aspects of this disease. So we have colonies for each of those, and we have had to scale all of them back to essentially a cage of breeding animals that we just recycle. Because every mouse that we have here pays cage rent, and then the mice are also expensive to order in. So, I’ve just finished wrapping up the final arm of this long-term experiment where we’re looking at mice who’ve been without drug for six months, and I’ve just harvested the last of those animals to clear out our space and not have to pay for cage rent. So that hamstrings us.
I mean, but the big thing is also personnel. So it’s not just the mice, it’s also the personnel, the people who are so important for keeping day-to-day functions running in these laboratories, and our department is not alone. There have been layoff notices, and really important people from our lab and others on this floor who are going to be losing key personnel. And it’s not just the day-to-day functions either. What’s important to know about how research, basic science research labs work especially at these universities and research institutions, is you can write everything down, you can write the stuff down that you did and try to keep a good record for the people who come after. But what’s super important is being able to personally train and pass down knowledge to the next generation or the next crop of graduate students so that they can do the same thing.
And for example, behind me is an electrophysiology rig that I don’t know how to use because I came into the lab in 2019 and Avtar had just graduated a graduate student and I was the only grad student in the lab. There was no one here in our lab to train me on how to use this. So, it’s kind of just a fancy piece of furniture right now. And that wasn’t critical and there are people on this floor who could train me if I needed to, but the thing is, it takes time. And when those people aren’t on hand with the knowledge of your particular equipment, you lose time and you lose expertise. And when we lose people, it’s not like it’s easy for them to come back. They’re going to move on to another job and they’re not going to come back.
Kelly Cervantes:
Well, and you’re also going to end up with fewer people wanting to go into that field because there are fewer jobs for them when they get out. This is a systemic issue that you are looking at affecting years if not generations of scientists, of laboratories, of treatments. The research that is often done in a university lab is basic science, basic research. That is what CURE Epilepsy funds, that’s what the NIH funds. And then typically in a typical process, pharmaceuticals would then come in and buy up the molecules, buy up the research, the science, and then take it and scale it. What happens if that basic science isn’t being funded?
Dr. Olivia Hoffman:
Yeah, that’s a great question and a good summary of how that flow works. And I would say, society depends on both entities sticking around and continuing to have funding and to continue functioning. So, what happens is as basic scientists, we’re kind of building up this body of work that industry can then take from and scale, and they’re really good at that. They’re kind of like silos, so they specialize in one thing and they do it really well, but they do need us and eventually, we need new knowledge in order to push new interventions forward.
And the continual advance of society and knowledge and science and medicine depend on this relationship, because what we do at universities is not profitable and it doesn’t work in companies. Because I can go to a different department like the biostats department or the epigenetics department and have a conversation with someone, and all of a sudden we have a collaboration. Or Avtar actually has done breast cancer research and epilepsy research in concert in this same laboratory. And these are things that require a degree of breadth that industry is just not set up for. Universities are already here, we’re already set up for it, having these spaces where people from different fields can intermingle and share their ideas, and that’s what creates innovations that can then be scaled up to medications, clinical trials.
Kelly Cervantes:
Well, and universities, typically NIH government funding is willing and certainly CURE Epilepsy, is willing to fund that riskier science, whereas a commercial prospect like a pharmaceutical company is less likely to fund a riskier research study because they need to turn profits, they have investors that they have to report back to. So, whatever they’re purchasing up already has to be proven to a certain extent by those universities. So, it’s just a whole other layer to our conversation about how if all of the different facets that not funding medical research, the impacts that it will have, and we may not see them today, we may not see them tomorrow. But if that basic innovation that you’re talking about, that these cultural institutions of knowledge are not funded, then we don’t have the pharmaceutical treatments of the future because those initial building blocks just were never created to begin with.
Dr. Olivia Hoffman:
That is so well put and I think that yeah, you got it. Yeah, if we have to depend on industry to not only develop the knowledge but also the intervention, and we have to know it works, if we’re constantly just trying to develop stuff that we’re pretty confident will work, we’re never going to get anywhere new.
And to be clear, I think that a lot of people don’t understand what an NIH grant is. We don’t just get it, right? We do have to provide that body of preliminary evidence and rationale, and these are incredibly competitive grants which are now only getting more competitive with funding being cut. And so, a lot of times it’s the purview of nonprofits like CURE, like Lily’s Fund, to give us that seed funding to try out an idea that might be crazy, that might not pan out, but that we’re really excited about. And then when we have that body of evidence built up, we give it to NIH and say, “Give us the long-term funding. We’ve got all of this evidence to show that we think X, Y, and Z are happening. Let’s look at it further.”
And right now, we’re in a situation where there are a lot of good grants that have completely sound scientific basis that just aren’t getting funded because only the top 8% of grants are getting funded, and that doesn’t mean the other 92% are bad grants. So, it’s really important that we keep building up this reservoir of knowledge so that it can be used down the road to develop interventions. And we’re just in the unique space right now in our lab where we’re sitting at the edge of basic research and translational research. And so we’re so close, we just need that final push to get there.
Kelly Cervantes:
So, we know the challenges that you’re facing with this research. What is your hope? What are the next steps that you can take? Because this drug deserves a human trial. Just because it works in mice doesn’t mean that it’s going to work in a person, we’ve seen that happen before, but we deserve to know. With such incredible results in mice, we deserve to know if it could potentially work in humans. How do you get there in this current environment?
Dr. Olivia Hoffman:
Right. So the NIH does currently have a program for piloting clinical trials on this drug, so that would be ideal. Right? The other option is to go international and connect with collaborators in countries where it’s more common to repurpose generic drugs because the healthcare system isn’t for profit. That’s been made a little difficult because right now, international collaborations, at least one way where NIH grants are shared with collaborators in other countries, that at least to my current events knowledge has been-
Kelly Cervantes:
It’s constantly changing, so that’s fair.
Dr. Olivia Hoffman:
Yeah, but an embargo was put on those. However, maybe our altruistic friends across the pond will still be willing to make use of collaborations in the other direction, which is helping us move along until things settle in the research environment.
I understand that this is not particularly hopeful, but what we are going to do is continue to try and make ends meet, try to do those risky experiments when the budget allows. And the thing that we’re trying to do is really just hold onto as many personnel as we can so that we can keep this knowledge, keep this project together in some fashion, and move it forward when the time is right. I know that that’s not as satisfying as, we’re going to get this drug to clinical trial tomorrow, and it probably wouldn’t work like that.
Kelly Cervantes:
No, I was going to say even in the best of times, nothing happens in medical research tomorrow, but I do think that it is encouraging though to still hear that your lab is not giving up, and especially to the epilepsy community to hear that, that you will still continue to work on this and do everything in your power to make sure that this research doesn’t die. What can the community do to support epilepsy research and researchers?
Dr. Olivia Hoffman:
Yeah, first of all, I’m going to give a little silver lining before anything else because I know I’ve been kind of grim, and it is a serious situation that we’re in right now. But I would say that we in the basic research community studying epilepsy, I think you know from your experiences like interacting with us, that we’re a pretty tight-knit community. And part of that is because we have the privilege of getting to talk to people who deal with the disease that we’re studying and that’s not possible in a lot of different fields like Alzheimer’s disease or cancer. A lot of people know someone with cancer, but I feel like the epilepsy community is super unique, in that when we go to AES annual meetings, we get to chat with y’all and hear your stories and hear the stories of people with epilepsy, and that is hugely motivating. So, I will say that we are trying to stick around and we’re not going anywhere unless we’re pushed out.
And then in terms of what the community can do, I mean, you guys over at CURE already do so much for us. I think that there have been a number of times just in the time that I’ve been here where folks like CURE or Lily’s Fund, which is a local nonprofit funder of epilepsy research here in Madison, have gotten us through and have been willing to fund those risky experiments when there was some promising preliminary evidence but it was a bit too risky for NIH. So, there is that piece of it, which has been so critical and we’re deeply appreciative to you guys for believing in us, and I feel like that’s been huge just for getting this project to where it is now.
And then in terms of what anybody can do, I would say silence is deadly, and not everybody has deep pockets to contribute to funding situations, but most of us have a voice. And if you know somebody with epilepsy or you have epilepsy, you know someone or you yourself stand to directly benefit from the work we’re doing now. And it might not be today, it might not be tomorrow, but with time, it will happen. And I think that’s super important to remind people of, because a lot of times the work we do doesn’t pay off in this lifetime. The guy studying how yeast metabolizes glucose, back in the ’80s probably didn’t anticipate Ozempic in 2024, 2025 being repurposed as a weight loss drug.
So, what I’m doing now and what I’d encourage everyone to do within their power and within a reason is just use every opportunity to be loud and inconvenient. Democracy is kind of just the work of being a nuisance enough so that you create friction and get people to sit down and come up with a solution together. And so, that’s what I’m trying to do. I’m trying to use my voice where I can and if we’re all really loud and annoying, I think we might get some important people to listen.
Kelly Cervantes:
Yeah, medical research is, NIH funding is certainly not where I would choose to see any future funding cuts come from, especially, especially when we know that there are drugs like this on the horizon.
Dr. Olivia Hoffman:
I feel like I’m in an incredibly privileged place despite all of the uncertainty right now. Most scientists work their entire career, live, and pass on without getting to see the fruits of their labor. And just to be doing work that may meaningfully impact the lives of people with epilepsy in my lifetime is a really rare and special privilege. So, it’s tough right now, it’s tough out there, but I’m happy to be here and I’m going to stick around. I’m going to try.
Kelly Cervantes:
I am so unbelievably grateful to you, to Avtar, to your whole lab there at University of Wisconsin. I know I speak on behalf of the CURE Epilepsy team that we are so incredibly honored to have been a small funding part of this journey, and just grateful for the dedication that you have to our epilepsy community and to pushing this possible treatment forward. I know I for one, will be watching very, very closely to see where all of this research ends up. So, thank you from the bottom of my heart, for continuing to push forward.
Dr. Olivia Hoffman:
Thank you, Kelly. It was great talking to you.
Kelly Cervantes:
Thank you, Dr. Hoffman, for sharing your discovery with us today. And thank you for all of the years of work by you and your collaborators that has led us to this potentially life-changing treatment.
As our conversation with Olivia makes clear, research is a marathon, not a sprint. It takes years of work and incremental scientific advances to bring about new discoveries and treatments. CURE Epilepsy is here for the long run. For over 25 years, we have been pushing science forward with your support. Now with the looming cuts to the NIH budget, organizations like CURE Epilepsy are more crucial than ever in assuring that epilepsy research continues to make advances. If you would like to support CURE Epilepsy in its mission to fund breakthrough research, please visit cureepilepsy.org/donate. Thank you.
Legal Disclaimer:
The opinions expressed in this podcast do not necessarily reflect the views of CURE Epilepsy. 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 conditions be made in consultation with the patient’s physician or other qualified healthcare professionals who are familiar with the individuals’ specific health situation.
