Investigating Therapies for Genetic Epilepsy with Alfred George, Jr., MD

Erin Spain, MS [00:00:10] This is Breakthroughs. A podcast from Northwestern University Feinberg School of Medicine. I'm Erin Spain, host of the show. Epilepsy is one of the most common neurological disorders in the world, known for causing unpredictable and repeated seizures that can cause injury and impact quality of life. Here at Northwestern Medicine, research is underway to advance the genetic understanding of epilepsy and discover new targets for drug development. Dr. Alfred George Jr, chair of the Department of Pharmacology here at Feinberg, is leading much of this work and joins me today to talk about the exciting advances in his lab in the field of genetic epilepsy. Welcome to the show, Dr. George. 

Alfred George, Jr., MD [00:00:56] Thank you very much, Erin. I'm pleased to be here. 

Erin Spain, MS [00:00:58] Tell me more about genetic epilepsy. Explain it to me. How it's different from other types of epilepsy. 

Alfred George, Jr., MD [00:01:05] So epilepsy is, as you said in the beginning, a very common neurological disease. It affects approximately 1% of the world's population. And there are estimates that for all of us individually, there's a 1 in 26 chance that we may develop a seizure disorder sometime in our life. Now, there are many, many, many causes of epilepsy. Some of them can be easily understood, and infection of the brain can disrupt brain function and lead to seizures. Trauma to the head can damage the brain. Some structural abnormality in the brain that you're born with or acquire a tumor in the brain. So there are many, many causes of epilepsy, but probably about two thirds of all cases of epilepsy have no certain cause. And over the years, evidence has piled up, suggesting that the causes are rooted in the genetics of brain development. So each of us carries innumerable numbers of genetic variation that makes us unique. In some cases, that genetic variation can be predisposed to disease. We think that a large fraction of epilepsy is genetically driven, and it's probably the result of multiple genetic variations in multiple genes. The type of epilepsy we study is a fraction of that larger picture. We are mainly interested in forms of epilepsy that can be related to a single gene defect, what one might call monogenic epilepsies. Reason for studying those is that there's a great opportunity to learn more about molecular mechanisms if you only have to focus on one gene. And so what we've studied primarily are monogenic epilepsies that can occur in families or can develop spontaneously in someone at birth. That's the spectrum of disease we're talking about. 

Erin Spain, MS [00:02:55] So tell me about this gene KCNQ2 and when you first began studying it and what's happening right now with that gene? 

Alfred George, Jr., MD [00:03:03] Well, KCNQ2 encodes a brain potassium channel that's necessary to control electrical activity in sets of neurons in the brain. In 1998, a group of geneticists discovered KCNQ2 as the gene responsible for a rare familial form of epilepsy called benign familial neonatal convulsions. It's a condition in which babies born healthy immediately began to have seizures. Fortunately, over time, within the first year of life, the seizures stop and the child can develop normally and go on to have children of their own who may themselves be affected with the condition. So there were large families that were available to map the gene responsible for that. And KCNQ2 was identified. It turns out that this gene provided a link between years of neurophysiological investigation, understanding how neurons work. And so it it fit a role and completed a picture that this was the gene responsible for a physiological activity in neurons called the M current. And M in this case stands for muscarinic. There's a long, complicated explanation for why it's called M current. But years later, genetic testing was becoming more routine for this gene. And not only were mutations found in family forms of this condition, but they were starting to find cases in which there was no family history. So what we would call a de novo mutation, where the child appears to have seizures on a sporadic basis. That was a breakthrough in the field because now people began to look at everybody, and now an infant or a neonate with epilepsy should get genetically tested. And of those infants in neonates who get genetically tested. KCNQ2 is one of the most commonly discovered genes with mutations. Another important reason why it's an important gene to identify is there is a drug that was approved but then subsequently removed from the market that was directed at this gene and could repair its functional activity. We may talk more about that later on when we get into our specific paper. 

Erin Spain, MS [00:05:18] Tell me about this study, what you discovered and how it may be another stepping stone to precision epilepsy treatment for some patients in the future.  

Alfred George, Jr., MD [00:05:26] So the study that we published in March of 2022 was a large-scale evaluation of cases in KCNQ2, genetic variants that were associated with epilepsy. Up until that point, many laboratories around the world had been able to study a function of a small number of variants, and typically an individual lab might study two or three or four at a time and publish a nice paper. We studied 80 variants using a high throughput, electrophysiological system that is unique to our work, and that gave us a better appreciation for the breadth of and diversity of functional effects. All studied in one system, in one laboratory. The other thing we did in that study is we coupled determining the functional consequences of individual variants with how those individual variants responded to a drug that is known to act directly on KCNQ2 to that drug known variably as either retigabine or ezogabine . And it was marketed in the U.S. for many years, but then removed from the market because the drug company didn't feel like it was making enough money for them. And I think there were some side effects that they were worried about. But there is a new effort now with a newer pharmaceutical companies to bring that back to life for children who have case in KCNQ2 related epilepsy. So we were able to profile the effect of that drug on all of these variants that we studied. And what we learned was that not all variants respond the same way, and that wasn't really appreciated before because the assumption was this drug would correct everybody's case in KCNQ2 mutation. But that's not true at all. We found a lot of variability in how individual genetic variants of KCNQ2 responded to retigabine, and that may have implications in terms of who should get the drug. And if the drug isn't working, is it because they have a genetic variant that is resistant or for some other reason doesn't work? We are continuing to do that work and ultimately we would like to test newer drugs too that are targeted to case in KCNQ2. 

Erin Spain, MS [00:07:39] You mentioned that this was a large study. Explain that to me. How many samples were involved? 

Alfred George, Jr., MD [00:07:45] Well, we studied 81 different genetic variants. And again, from the perspective of other people in the field, that was easily ten times more than any individual lab had ever done before. And I think the total number of of variants that had been studied to date and we're talking over 20 years, was about 50, and we did 80 in our study. And by the way, we have about another 40 that have been studied and are haven't been published yet. Some more to come.   

Erin Spain, MS [00:08:12] More to come. Much of your work involves working closely with patients, specifically these pediatric patients with epilepsy. Just tell me about some of your collaborations with the Ann and  Robert H. Lurie Children's Hospital of Chicago and how that's really a win win relationship for furthering research and helping the patients who are in need. 

Alfred George, Jr., MD [00:08:29] Absolutely. When I came to Northwestern University, Feinberg School of Medicine in 2014, I didn't have a full appreciation for the extensive expertise in childhood epilepsy that were sitting right down the block from us at the Lurie Children's Hospital. I was familiar with a few of their faculty, but over the first several months to a year, I made a point to meet many of their leaders and the child neurologists there, and we really started an important collaboration with them. One of those collaborations was to identify patients that had ion channel mutations and epilepsy, and those patients became subjects of our research for doing functional and pharmacological studies. A separate endeavor which involved an investigator in neurology, Dr. Evangelos Kiskinis, began to bank blood samples to develop induced pluripotent stem cells, which is a way to model human neurons in the laboratory. And so to date, we've collected well over 80 samples from children seen at Lurie or who had some connection to Lurie Children's Hospital that have epilepsy and known ion channel mutations. And this has become really a great opportunity to investigate genetic epilepsy using human neurons. There is also an academic component to this endeavor. We felt it was really important to understand the breadth of research interest in epilepsy at Northwestern and Lurie Children's Hospital. And so. In partnership with their child neurology division we began a twice monthly seminar series that we called Seizure Focus, and this was an event that we designed around the idea of pairing up basic researchers from Northwestern with clinicians and clinical researchers from Lurie Children's Hospital, to basically put together a joint seminar a couple of times a month exploring our shared interests. And that really helped catalyze new collaborations, important new grant initiatives in several papers. And so and that's ongoing.   

Erin Spain, MS [00:10:35] Speaking of these grant initiatives, and you're in the midst of a $12 million five year grant from the NIH. Can you tell me about that work? 

Alfred George, Jr., MD [00:10:44] In 2018, w e were very fortunate to receive this large multi investigator grant from the National Institutes of Neurological Diseases and Stroke. It was a program grant that they referred to as a center without walls. And the intent of these centers is to fund research that is not restricted to investigators at one institution. In fact, our Center Without Walls includes 20 investigators spread across several academic groups, two companies and a couple of research intensive children's hospitals. So we really put together a great team. An entire focus of the center is to investigate ion channel genetic forms of epilepsy. We call the research center the Channelopathy-associated Epilepsy Research Center Without Walls. People at Lurie Children's Hospital have been involved from the very beginning. 

Erin Spain, MS [00:11:32] You are also very interested in studying other rare genetic diseases that impact children. Tell me about that work. 

Alfred George, Jr., MD [00:11:39] I think that the one thing that really impressed me over the last few years is that rare genetic diseases do not get enough attention. A rare genetic disease in a child may seem like such an imperceptible public health problem that it's ignored. And these diseases are largely underrepresented in the larger NIH funding portfolio. So what has happened is families who have children with these disorders, who are desperate for cures and research to understand their child's condition, that they live with 24/7. They have formed foundations and have raised money and have funded research to move the ball forward where and they have helped to fill the gap. I must say that one of the unforeseen scientific aspects of this field that we've been working in that I really cherish now is the opportunity to work with families and these foundations. They're extraordinarily driven. They have a mission and we try to do whatever we can to help them accomplish that goal. And that's been very inspiring. And I often think that if it wasn't for those families and their drive to help their kids, the fields wouldn't be moving along as as fast as they are. 

Erin Spain, MS [00:12:54] Can you tell me about one of those diseases and the foundation? 

Alfred George, Jr., MD [00:12:57] There are a lot of them. I think for almost every individual gene that's been identified, there's at least a foundation or two that has emerged. And the stories are all very similar. Somebody gets a diagnosis from their physician based on a genetic test and the physician says, I've never heard of this, you should go Google it. And literally they go on the Internet and they learn what they can. They get on Facebook. They look for other people that have shared experiences, and the Internet has brings people together. It's a story that has repeated itself over and over and over again. It's not specific to one gene or another, but we've had a very long standing relationship with foundations that study a disease called alternating hemiplegia of childhood and going on ten years now. And it's an extraordinarily committed group of families that we want to help in every way we can. And they've been very prolific at raising money and helping to fund research. 

Erin Spain, MS [00:13:52] Explain alternating hemiplegia of childhood. How does it affect children? 

Alfred George, Jr., MD [00:13:56] The name of the disease was coined to describe a major initial symptom that the children have. Alternating hemiplegia, meaning hemiplegia is weakness on one side of the body, and alternating means some attacks of weakness may occur on the left side, another may on the right side, and they may flip flop or they may occur on both sides at the same time. That is just one of many neurological symptoms these children have, is sometimes they have unusual eye movements. They can also have seizures. About 50% of the children have seizures, and they all have some level of neurodevelopmental delay with cognitive impairment and motor and movement impairment. So it's a devastating disease. And I have great sympathy and empathy for the families that are going through this. And, you know, it really is something we've been motivated to try to work on. 

Erin Spain, MS [00:14:50] Tell me about that long term goal and the hope that you're going to be able to have some sort of precision medicine that you can use. And what would that mean for these patients? How do you hope it could change their lives? 

Alfred George, Jr., MD [00:15:00] Well, I think there's hope that we can by understanding mechanisms of the disease and we have the molecular target, that we can come up with some treatment that's better than what they have now, which is nothing or symptomatic treatment which doesn't modify the disease. We really want to figure out disease modifying treatments. That's the buzzword disease modifying. You know, you can treat seizures with drugs that stop seizures, but it turns out seizures are just one of many ways the brain says, I'm sick. Autism is another one. Movement disorders is another one. Not being able to develop thoughts, not being able to speak. Those are other manifestations. So there's a lot of non seizure manifestations of these disorders. I can treat the seizures or somebody can treat the seizures, but that's like putting a Band-Aid. It's not addressing the fundamental. So disease modifying treatment is better than symptomatic treatment. And so we're all hoping we can find disease modifying treatments. We think it's possible. And we look at the example of spinal muscular atrophy, which is a rare infantile neuromuscular disorder and universally fatal disease. Now, there is a cure. There is a cure. It's comes from an RNA therapeutics perspective. And now children get this disease modifying treatment. Life saving treatment. So we're hoping that that is that's in store for the future of some of these rare genetic diseases. And I hope before I retire, I can say that we helped move the ball a little bit along and maybe have a role in moving something forward like that. 

Erin Spain, MS [00:16:29] I did want to ask you about some of the other big projects taking place in your department right now that you're really excited about? 

Alfred George, Jr., MD [00:16:36] Well, I'm excited about the whole department. It's grown considerably since 2014. When I came, the department was our head had been split from its original roots as the Department of Molecular Pharmacology and Biological Chemistry, and that spawned two independent departments led by myself on the pharmacology side, and Dr. Ali Shalati on the biochemistry molecular genetics side. So our department has grown from about seven in the beginning to now we have 21 faculty and we're very excited. Our department is made up really of three camps of researchers. The largest camp is individuals who work at the interface between neuroscience and pharmacology, who are interested in studying diseases such as epilepsy, autism, Parkinson's disease, Alzheimer's disease and pain. And then another third of our faculty are invested in studying cancer pharmacology, investigating the mechanisms responsible for cancer, but then taking it one step further and looking for opportunities to attack cancer in some way. And then the remaining third or so of our faculty are using genetics and working at the interface between genetics and pharmacology and what an area we call pharmacogenomics. And so one of the things that it's emerging from several of our laboratories is the idea that conventional drugs aren't the only weapons anymore for diseases. So I'm very excited about opportunities in RNA therapeutics for treating especially rare genetic disorders for which we need new strategies to really accomplish therapeutic goals. 

Erin Spain, MS [00:18:08] Well, thank you so much for being on the podcast today. We really appreciate your time. 

Alfred George, Jr., MD [00:18:13] Yeah, a lot of fun. 

Erin Spain, MS [00:18:24] Thanks for listening and be sure to subscribe to this show on Apple Podcasts or wherever you listen to podcasts and rate and reviews. Also for medical professionals, this episode of Breakthroughs is available for CME Credit. Go to our website Feinberg.Northwestern.Dot edu and search CME.