Epigraph Vol. 24 Issue 1, Winter 2022
Discovering new drugs for epilepsy: Dr. Karen Wilcox
Listen below or download the episode.
Patricia Grandizoli Saletti, PhD: So we have today Dr. Karen Wilcox from the University of Utah. It’s a pleasure to have you here. Welcome.
Karen Wilcox, PhD: Thank you very much Patricia for having me today, it’s my pleasure to speak to you. My name is Karen Wilcox, I’m the Richard L Stimson professor and chair of the dept of pharmacology and toxicology, also an adjunct position in the department of biomedical engineering here at the University of Utah. I’m also the director of the Anticonvulsant Drug Development Program, or the ADD program, here at the university. The ADD Program has served for the last 47 years as a contract site for the Epilepsy Therapy Screening Program at the National Institute of Neurological Diseases and Stroke (NINDS). We’re really excited about our interactions with that very successful program over the years.
Saletti: Thank you. It’s our pleasure to have your participating with us here. So about this program – epilepsy therapy screening. You have been working for many years in this program trying to find new drugs that could treat and prevent epilepsy. Can you tell us a little bit about this program?
Wilcox: It would be my pleasure. We’re very proud of this program and as I mentioned we serve as the contract site for the Epilepsy Therapy Screening Program (ETSP), which is based out of NINDS at the National Institutes of Health (NIH). It’s been a longstanding public private consortium to help identify novel anti-seizure drugs. Over the last 35 or so years, all of the anti-seizure drugs that have come on the market, the vast majority of them have come through our program.
We’re proud of the fact that the preclinical data that was acquired at the screening program has been used by different companies and suppliers, such as medicinal chemists or small biotech companies, has been used to submit Investigational New Drug (IND) applications to the US Food and Drug Administration (FDA). We’ve really had an active participation in the development of those new antiseizure medications. We’re really proud of that record of success.
The way it works is that drug companies or medicinal chemists, academia, or academic labs that might have novel compounds that they think might be effective as antiseizure medications can submit their compounds to the NIH, where Brian Klein serves as director of the ETSP. They can work with NIH to get their drug into the program. When they do that, they send those compounds to us in a blinded fashion – we don’t know what the compound is, who supplied it. And then all of our experiments are done at the University of Utah in a blinded fashion. The tech support team does not know what they are screening. This allows an exceptional amount of rigor and reproducibility in the data we collect, and hopefully helps us not to be biased in our assessment.
The data all belong to the suppliers, and so we submit the data back to NINDS, to the ETSP, and they provide the supplier with the data set. We have a battery of in vivo and in vitro assays that are used in preclinical evaluation of compounds, and they go from more simple assays in mouse and rat models all the way up to animal models where spontaneous seizures are observed.
We also have two subcontractors – Synapsa in Grenoble, France, helps out by looking at compounds in their intrahippocampal kainite model in mouse, and looking at the ability of antiseizure drugs to stop paroxysmal discharges in the hippocampus, and at the University of Washington, Dr. Steve White and Melissa Barker-Haliski’s group work with us to look at antiepileptogenesis studies as well.
We offer an interesting preclinical package, I believe, to investigators because we have two species, mouse and rat, we have different strains of mice that we use, we have different locations, so that helps to improve the rigor and reproducibility of our assays. It’s been a great pleasure and honor for my career since I’ve been at the University of Utah, which has been since 1998, to be involved in this program.
I started in the program as a staff scientist and worked my way up through the ranks to become a to coinvestigator in 2004, and then in 2016, when Steve White left the University of Utah, I became the principal investigator of the contract site.
We don’t do any clinical trials; we’re not involved in the clinical trials that happen as a result of our preclinical work. That’s usually individual drug companies that work on that, or the NIH has some projects and grant mechanisms to help academic scientists work their way up to Phase I clinical trials, but we’re not involved in that.
Saletti: How do you see this challenge of testing a drug in a preclinical trial, usually with rodents, how is the challenge of translating that research from animal models to humans?
Wilcox: I think one of the nice things about a lot of the rodent models is that many of the anti-seizure drugs on the market today and clinically available for a patient population were discovered using the models. So they have a rich history in epilepsy research and the ability to help identify compounds that might be efficacious in patients.
Certainly we’ve had situations where we’ve had a compound that looks really great at the preclinical level, like it could stop all sorts of different kinds of seizures that might even be refractory to other drugs, and it might go on to fail in the clinic – there’s a lot of reasons why drugs are not successful in the clinic. That’s beyond our control, but it’s an approach that has been validated by history, certainly even as early as the 1930s when Merritt and Putnam used the first electroshock test and discovered phenytoin, and that was discovered for patients a year later. Those models have been very predictive of efficacy in patients.
We’re not going to find all of the drugs that might be successful in patients, and maybe we’ll find some that are successful in rodents and not in patients, but I think the rigor and reproducibility aspects of the program give suppliers confidence that if we see something that’s working in rodents that it’s getting into the brain, it has access to the circuits that need to be brought under control by anti-seizure medications, and that there’s a good chance that those will go on to be successful in patients.
There are a lot of reasons why drugs might fail. We don’t do a lot of sub-chronic dosing in animals, so we don’t look at things like cardiac toxicity, is there concern about metabolism or metabolites – we don’t do those kinds of experiments. Those are all reasons why drugs might fail in the clinic.
Saletti: If we have now over 20 anti-seizure medications available, why is it important to have a program like this one trying to find new drugs?
Wilcox: That is a great question. One of the concerns is that nearly 35% of patients with epilepsy don’t have their seizures adequately controlled with existing medications. We also don’t have a cure for epilepsy. So all of the medications that people with epilepsy take are symptomatic treatments, so if they stop taking them, their seizures are very likely to return. So it’s a lifelong regimen of medications that they must take. We really would like to have a cure for epilepsy, and we would like to have drugs that address the refractory population of patients with epilepsy, and as you know from your work, one of the things we can’t do very effectively is prevent epilepsy in people who are at great risk of developing it, for example related to your work, following traumatic brain injury. We don’t know how to prevent the development of epilepsy in those patients; we don’t know even necessarily who is at risk for developing epilepsy later on.
Preventive medicine is always better than trying to fix something that’s gone awry. So if we know that our blood pressure is going up, we can exercise more maybe, eat better, change our diet or maybe take blood pressure medications to prevent a stroke or a heart attack. We can use preventive medicine. But we don’t really have a way to prevent the development of epilepsy in people at risk, and that’s another huge challenge.
Saletti: Yes, definitely. We still have a long way to go to find drugs that can prevent epilepsy, and also biomarkers that can show us how the disease is going to develop in each patient. Is this something you’ve been working with also?
Wilcox: So, we think about biomarkers a lot and one of the things we rely on is, we’re just a small lab, and we really depend upon the advances of other labs in the field of epilepsy. We keep our eye on the literature, we go to meetings to stay up on this, biomarkers are critical. We recently had a workshop on NIH, NINDs, that I was a cochair of, and one of the focuses was to try to think about ways to identify good biomarkers for antiepileptogenesis. So that’s something we think about a lot, but we depend on the field and the experts and our colleagues who are working on a wide array of different biomarkers.
And as we see different biomarkers emerge, as we see different animal models that might be more predictive of efficacy in humans for things like antiepileptogenesis, we can pivot fairly rapidly. One of our strong areas of expertise is the development of new animal models for epilepsy. So when people come up with new ideas, new models, we can pivot and implement those into our screening program.
It takes more than a village – it takes a worldwide effort to identify new biomarkers in epilepsy that might be efficacious. We welcome partnering with our colleagues in the epilepsy research community.
Saletti: So you’ve published a paper in Epilepsia in 2020 showing a new screening approach at the ETSP. How is the protocol different from the other approaches, and why is it important to have a new approach as part of this program?
Wilcox: Thank you Patricia for asking that question. So the paper you’re referring to used the classic, systemic, low-dose, repeated application of kainic acid in rats to induce temporal lobe epilepsy. This model has been around since the 1980s, so we weren’t the first to use this model but for the first time in our program, we introduced an assay where spontaneous seizures was the dependent measure that we were looking at when we treated with drugs, and that we also can start doing sub chronic administration of drugs.
So essentially what we started doing, which we’d never done before in the program, was to set up miniature clinical trials, if you will, for the rodents. All of the animals get vehicle and all of them get the investigational compound, and then we can see how each animal performs when they are given an investigational compound to stop their seizures. It’s a sub chronic dosing experiment and this paper laid out an experimental paradigm to determine the proper number of animals to use in the study.
One of the drawbacks of this particular animal model, like many animal models of epilepsy, is that some animals have a high seizure frequency, and some have a low seizure frequency. That requires you to increase your power by increasing the “n”, the number of animals you’re using. But we don’t want to use too many animals; we want to limit it as much as humanly possible. So that study allowed us to test a battery of antiseizure medications so that in the same lab, using the same conditions, we could compare head-to-head different classes of anti-seizure medications and how they performed in this particular rat model of temporal lobe epilepsy.
It helped us establish a screening paradigm or platform for screening in a spontaneous seizing animal. This is the first time this has been implemented in our program. We’ve had many acute models of induced seizures in the program. We ‘ve had kindled animals, which will have a seizure when you administer a stimulation, so you know when they’re going to have a seizure, but they didn’t have spontaneous seizures. And the hallmark of epilepsy is spontaneous seizures that occur randomly and are unprovoked. So this allows us to, for the first time in the program, take a look at how novel compounds might perform under these conditions. It helped us realize a lot of the challenges of doing these sub chronic dosing experiments.
The other thing we found, which was quite interesting, was that animals that have epilepsy often respond differently to drugs than naïve rats do. So doses that a naïve animal might tolerate well could be toxic in an animal with epilepsy. Or conversely, a compound that is not well tolerated by naïve animals might be well tolerated by those with epilepsy. We were really surprised to find that, so part of our procedure now is to do a little pre-experiment, in which we administer drugs for three days before we start an experiment to see how animals will respond and whether the dosing regimen we’ve chosen, based on the pharmacokinetics of the drugs and the dose itself, are well tolerated. It doesn’t help to stop seizures if the animals are sedated or are ataxic or have other side effects. We want to make sure the drugs are administered in a tolerated dose.
This protocol was great because it helps us introduce spontaneous seizures into the screening program for the very first time. That was a long-running critique of our program in the past, was that we didn’t have any animal models of spontaneous seizures.
Saletti: That’s amazing, to think that you can mimic better the response that we have in patients. Congratulations on this work. What are some of the program’s accomplishments that you’re most proud of?
Wilcox: I’ve been with the program now for 23 years and I’ve had the honor of working with some very talented scientists including Dr. Steve White, now at the University of Washington, and we now also have an external consultant board that we work with to guide us. I think one of the things I’m most proud of with my 23-year association with the screening program is that many of the compounds that we’ve evaluated are actually now in use by patients. And not just for patients with epilepsy – sometimes the anti-seizure drugs we’ve identified work well for other indications. For example, topiramate works well as an anti-migraine medication, and lamotrigine is a good anti-seizure medication, but it’s also prescribed a lot for patients with bipolar disorder. I’m proud that I’ve had the honor of working with dedicated scientists and dedicated technical support staff over the past 23 years that have benefited patients directly.
Saletti: What do you believe is the barrier to success in finding the correct drugs for refractory epilepsy?
Wilcox: That’s a big question! We could spend a lot of time on this question, but one of the things we’ve done in the screening program is to adopt a lot of models that have characteristics of refractory seizures. So even in some of our acute models, we use the 6 Hertz psychomotor seizure, where we can induce a seizure using a stimulation frequency of 6 Hz, and those seizures are very refractory, very hard to stop with antiseizure medications. And if we look at the back end of our screening program, we work with a lot of spontaneous seizing animals with temporal lobe epilepsy that also are refractory to a number of anti-seizure mediations.
So our hypothesis is that if we create a flow chart of ever increasingly more complex and difficult assays, but that are all refractory in some way, shape or form to some class of anti-seizure medications, maybe we can identify some novel anti-seizure medications with novel mechanisms of action that might address the refractory population a little bit better.
From a big picture perspective, with the field, we now know that there’s over 700 different genes that can be mutated that confer pathogenic disease to patients, so there’s a wide array of etiologies. We also know that with the acquired epilepsies, there’s a lot of ways to acquire it, whether it’s traumatic brain injury, brain tumor, infection, so some of the things we’ve tried to do is develop better animal models. We’ve also developed a model of infection-induced epilepsy into our program, as infection is a major cause of epilepsy – central nervous system infection.
It’s our hope that by having better animal models we might be able to identify better drugs for select patient populations. In the clinical trial realm, we might have to start stratifying patient populations a bit better. We see that now, where drug companies are looking to target their therapies at Dravet Syndrome, or children with Lennox Gastaut Syndrome, for example. By stratifying the patient population and not just giving drugs to a wide array of patients with different kinds of epilepsy, we might be able to have better outcomes in clinical trials as well.
Basic research is key – we have to continue our basic science to understand all the different ways a patient might develop epilepsy or come to have epilepsy, because that might really change the drug that they need. Precision medicine going into the future is going to be really important. That does pose a lot of challenges for therapy development for sure. Some people have addressed that by using model organisms – for example, Scott Baraban’s group and others have begun to use zebrafish, which have mutations delivered to them that are pathogenic in humans and then they can do drug screens on FDA-approved drugs and might identify an already-approved drug that might be very efficacious in a subset of patients with a specific mutation that results in epilepsy. So those precision medicine approaches might hold a lot of promise for refractory patients.
Saletti: So what do you say that are your hopes for, let’s say, short term – the next 5 years in the drug screening research? What are you hoping to see in about five years of research?
Wilcox: One of the things I’m seeing at recent epilepsy meetings – different ILAE congresses, the American Epilepsy Society meeting—there’s a lot of innovation happening in the basic sciences that will contribute to different kinds of medications. For example, antisense oligonucleotides used as therapy might hold a lot of promise for treating different types of genetic epilepsies, or even just acquired epilepsies. What I see in the next five years is that we’re going to have a lot of opportunities beyond small molecules that can help to treat the person with epilepsy. We need to get more information about those strategies – five years is not a long time in trying got develop new therapies. It takes often up to 10 years to have new therapies come through programs, preclinical evaluation, from bench to bedside all the way to the clinic often takes many more yeas than five.
In five years, I hope we’ll continue to make additional contributions to the armamentarium of drugs available for patients and their families, and for clinicians to prescribe for them. I hope that happens. There are several compounds in the pipeline now being tested in clinical trials that hopefully will become available, and hopefully our program will continue to provide useful information to those who provide newer therapies and are open to testing biologics or antisense oligonucleotides, or even stimulation therapies, devices—there are all sorts of approaches that in the future might hold a lot of promise for patients.
Saletti: Do you have anything else you want to add that we didn’t talk about?
Wilcox: I just want to say thank you, but I also want to say I’m very encouraged by the young epilepsy organizations that are popping up, and I think the future is bright for epilepsy research, with individuals such as yourself, and trying to make a difference in patients’ lives by doing basic research that’s going to be really meaningful. I’m optimistic that we can continue to attract the brightest minds to epilepsy research to home in on some of the problems we’ve talked about, like the person who’s refractory or the person who’s at risk for developing epilepsy. We’re trying to find a cure for those who already have it. The future is bright, and I’m really excited about that.
Saletti: Thank you so much for participating in our podcast – it was such a pleasure to have you here. Congratulations on your findings and amazing work you have been doing.
Wilcox: Thank you very much Patricia, and good luck to you too.
Saletti: Thank you.
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