Michael Smith, MD (Host): This is Pediatric Insights, Advances and Innovations with Children's Health, where we explore the latest in pediatric care and research. I'm your host, Dr. Mike, and today we'll be discussing transformative research in gene therapy for Lafora disease. And with us today is Dr. Berge Minassian. He is the Division Director of Neurology at Children's Health and Professor at UT Southwestern.

Dr. Minassian, welcome to the show.

Berge Minassian, MD: Thank you, Mike.

Host: You're the expert here, Lafora Disease. You're the expert. I know you've been studying this for decades. Can you share with us what it is and what drew you to study it?

Berge Minassian, MD: Yes, absolutely. So I started working on this during my residency almost 30 years ago. This is a disease you can think about Alzheimer's disease. But this one, instead of starting in older people, starts in young teenagers and is very rapidly progressing. These kids start seizing when they are about age 14 years.

Then these seizures just never stop. So they go on seizing every waking moment until they die 10 years after the disease starts. So it's a very aggressive form of neurodegenerative disease. In fact, it was described by the same folks who described the first cases of Alzheimer's disease in the United States.

These were students of Alzheimer's, and they came and worked here in the United States and described this horrendous condition. And so you can see why I was drawn to it, because it is really bad, and we really want to make it go away.

Host: So just to review real quick, if I remember right, the Lafora gene is connected to glycogen metabolism, and there's several different mutations that can happen in that gene. And when that does, these patients start to develop like clumps of glycogen, right, in their brains, nerve tissue, muscles. Is that correct?

Berge Minassian, MD: Yes, exactly. And those clumps, we call them Lafora bodies, they drive a neuroinflammatory neurodegenerative process. It takes about 14 years for the clumps to be big enough to activate this neurodegeneration, but once it starts, it just doesn't stop and results in what I described.

Host: Are there early signs of this? To me, it sounds like if you're dealing with glycogen, which is the storage of sugar, are there fatigue issues, muscle fatigue issues before you even begin to realize this is Lafora Disease?

Berge Minassian, MD: Not really, because there's nothing wrong with most of the glycogen in these patients. It has to do with the way the glycogen is formed. So normally it has to be like a sphere, this molecule of glycogen. In this disease, there's occasional molecules that kind of have like a bad hair day and they precipitate, meaning they come out of solution and accumulate over time.

So, they metabolize glycogen fine. It's the accumulations of these bad forms of glycogen in these patients. The gene Lafora and its colleague there, called Malin, they're involved in ensuring glycogen has a proper structure so it doesn't fall out of solution, and it falls out of solution in this disease and accumulates into these Lafora bodies.

Host: What age are we talking about here, when you start seeing the seizures from this?

Berge Minassian, MD: So around age 14, between 10 and 14. Initially they look like any other epileptic patient. They have a few seizures, but then quickly the neurologist, you know, once they do the EEG, electroencephalogram, they notice that something is wrong and they send the genetic test and we get the diagnosis of this basically fatal disease.

Host: Wow. Now, your team recently delivered the world's first gene-based therapy for Lafora Disease. How was that therapy delivered and what measures were taken to ensure safety in this first human application?

Berge Minassian, MD: Yeah, so this was 30 years of work on my part and lots of other people to lead us to this point. The original discovery of the disease was in 1911, so 110 some years ago. So, anyway, in our case, we gradually, we first identified the gene and then gradually understood exactly what these proteins are doing and found an entryway where we can deliver this treatment. The treatment is a tiny piece of DNA called antisense oligonucleotide, and we deliver it in by lumbar puncture into the fluid that surrounds the brain. So it's put in the back of the patient, by injection and it flows in the fluid that surrounds the brain and controls the production of these abnormal forms of glycogen. In the mouse models of this disease, this treatment basically completely halts the disease progression and the mice no longer have Lafora disease. So we are very hopeful the same will happen here. Lots of studies were done in mice, in monkeys and so on to prove safety.

And, uh, now we are in the middle of a clinical trial. It's a safety study, this clinical trial we are in, but we are collecting efficacy data as well, hopefully to show that the drug works.

Host: When was the Lafora gene discovered?

Berge Minassian, MD: So I discovered that during my residency, again, almost 30 years ago. That's when we started working on it. So 1998 is the publication.

Host: Wow, that's amazing. So I was at UT Southwestern at that time, I wasn't discovering genes. Congratulations. That's awesome. So at that point, that's when it became the name Lafora Disease, I guess.

Berge Minassian, MD: The disease name existed before. We called the protein product or the gene Laforin in honor of Lafora, who was the pathologist, student of Alzheimer who described the condition in 1911.

Host: Very interesting. So can you talk a little bit, about what significance this has on the field of pediatric neurology and what it means to you. I mean, it, it sounds like a big advancement, right?

Berge Minassian, MD: So there's multiple levels to answer this question. Firstly, again, this is probably the most horrible disease anyone can get. So if this works, in that regard, it's going to save a lot of people from a lot of pain. These families, you know, often have multiple children. And you can imagine that the younger children see what's happening to their sibling and know that they're at risk for the same.

That alone is devastating. So there is that aspect. The second larger aspect, is that all these gene therapies are critical for child neurology. Let me take just a few minutes and explain some things. A child is not like an adult. Adults have lived longer periods and are exposed to the environment and have all sorts of environmentally induced diseases, but a child has not had that exposure.

So the diseases in children, especially in child neurology, most of them are inherent diseases, meaning genetic diseases. And because we have 30,000 genes in the genome and the brain being this complex organ uses most of these genes for its development and functioning; we have about 30,000 different sorts of individual diseases each connected to one of these root causes, to one of these genes.

So now that we know what child neurology is, basically a very large group of monogenetic diseases, we really need to develop these treatments at the root, at the gene level. And so here at Children's and UT Southwestern, we've built a big gene therapy program, to do just that. So, Lafora Disease is just one of many diseases that we're working on developing treatments that act at the root cause of the problem.

Host: Yeah, it's exciting, you're literally introducing a gene that can now function the way it's supposed to function. Correct?

Berge Minassian, MD: Yes, exactly.

Host: That's amazing. Are there any case studies or early clinical responses you can share?

Berge Minassian, MD: This clinical trial started only recently and it's a safety study. These are always the first step, and so far everything is safe. The patients are doing like amazingly well, and so we are adding efficacy elements now to show that the disease is no longer progressing as it normally progresses.

So, right this moment, I cannot tell you that we've proven that because we're gathering the data now. Maybe next time you and I talk, we can see what the results show. There's no reason for this to behave differently in humans than it did in mice, and because in mice it completely aborted the disease, it should work. We're very optimistic.

Host: In terms of efficacy, what are the outcomes you're specifically measuring?

Berge Minassian, MD: These patients initially are perfectly healthy and then their first seizures happen, and then kind of all hell breaks loose. So we are diagnosing these patients now very early within weeks or short months of first seizures. So they're still very, very healthy. And so we are hoping that we just stop the disease at that stage and it does not progress. So they remain healthy maybe with the occasional seizure, which we can treat with regular anti-seizure medications.

Host: And what's the average age of a patient in the study right now?

Berge Minassian, MD: Most of the patients are between 16 and 18 years old in the study. But again, these patients, normally the onset is about 10 to 14 years. Because this particular phase is a phase one safety study, we tended to favor the slightly older patients, but as the efficacy arm opens up, we will be recruiting young patients.

Host: Now I know this has been your life passion. This has been your focus, research focus, clinical focus for decades, really 30 plus years. And I'm so thankful for you. This is fascinating work that you're doing and it's bearing fruit. And that's fantastic. But are there other rare epilepsies that you want to start looking at in terms of gene therapy, these monogenetic disorders causing epilepsies?

Berge Minassian, MD: Yes, absolutely. So, because each gene is its own kind of root cause, in most cases, we need to develop individualized treatments for each of these many diseases. And that's what we are doing on a regular basis. My colleague is Dr. Steven Gray, who works on the lab side of things, and I work on the clinical side and we bring it all together.

Now, sometimes, like in this particular case, we can bunch diseases. You can think of the brain like a giant oak tree with its rounded foliage, it has a trunk and it has roots. It has multiple roots. So sometimes just like the oak tree, the roots come together, join, bunch up in the trunk, and then go up and then shoot the branches.

So, in this particular case, actually our intervention is a few steps removed from the original gene. That's why I call it gene-based in this particular case. And so it's at the trunk level. And so, we can treat with this treatment quite a few other glycogen storage diseases, not just this one.

And interestingly, there's recent evidence that this may be a treatment also for ALS. In mouse models of ALS, using a treatment like this one, colleagues of ours got very strong effect, similar to the best known treatments for ALS right now. So that's still at the mouse phase and hasn't entered clinical trial, but there are opportunities with this treatment beyond just Lafora Disease.

Host: That's amazing. I can almost see someday we will have a library of these genetic disorders, these rare disorders, the gene involved and the gene therapy to fix it. And it's going to be almost like you just type in what you need and boom, there it is because of the research people like you are doing.

Berge Minassian, MD: Yes, Mike. That's exactly right. Basically what will happen in the future, and this is not too far in the future, I estimate in the next five to 10 years, every child who is born is going to have a whole genome sequence, and we're going to be able to tell the parents if they happen to have a ticking bomb in there that needs to be addressed early because, you know, in most cases, the brain needs all these genes to develop properly. And if it doesn't have this or that gene, then the development will go wrong. And so time is of the essence. And, you're absolutely right. There's going to be a library of therapies and you pick the right one for each patient, and treat them. That's where we are going. That's what's at the horizon.

Host: It is fantastic. So right now, where your research currently is with Lafora disease, you're at that safety collecting area or phase, you're gathering some efficacy. I'm assuming you're already planning the next phases of clinical trials. Right?

Berge Minassian, MD: Yes, exactly.

Host: And do you have a timeframe? I know it's hard, right? There's a lot of data collected you have to do and review, and it's not as simple as people think, but what's your timeframe that you think you'll start seeing some of the efficacy answers?

Berge Minassian, MD: Oh, within six months to a year, we will start seeing signals. And we hope around that time to start the next phases of the study.

Host: Yeah, that's fantastic. Before we wrap up here, is there anything else you'd like to share?

Berge Minassian, MD: I just want to reemphasize what I said before. We're entering an absolutely new age in the treatment of pediatric neurological conditions now that we appreciate that we are dealing with several thousand individual diseases that manifest in similar ways. You know, the brain does a few things. It siezes, it has autistic features, it has movement disorder and so on.

So it used to be thought that all these diseases are common diseases. But in fact, there's no really such thing as a common disease in child neurology. There's lots of individual rare diseases that look like each other. So we really need to develop these treatments and prepare for the future that's just around the bend.

Host: Dr. Minassian, this was fantastic information. Thank you so much for your time today.

Berge Minassian, MD: Thank you, Dr. Mike. It was a pleasure.

Host: You can find more information at children's.com/neurology. If you found this podcast helpful, please rate and review or share the episode and follow Children's Health on your social channels. This is Pediatric Insights. I'm Dr. Mike. Thanks for listening.