Episode Transcript
[00:00:03] Speaker A: Hello, and welcome to cook children's doc talk. Today, we're talking about muscular dystrophy and gene therapy with Doctor Brittany Rim. Doctor Rim completed her Doctor of Medicine degree at the University of Texas Health Science center in Houston and completed her pediatric neurology residency and neuromuscular fellowship training at University of Texas Southwestern Medical center in Dallas. Darthur REM specialized in pediatric neurology and neuromuscular medicine with clinical interests, including the management of spinal muscular atrophy, muscular dystrophies in myasthenia gravis, along with performing electromyography and nerve conduction studies, and, of course, gene therapy. Worldwide, about 20,000 boys are diagnosed with DMD each year. Their bodies don't produce a protein called dystrophin, which is needed to form and maintain healthy muscles. The disease causes children as young as age two to begin having trouble walking or running. Eventually, their heart, muscles and breathing break down. Treatments can slow the symptoms, but getting medications to market takes time, time that these patients do not really have. That's why research and clinical studies are so important. This is especially true for children with muscular dystrophy. Welcome, Doctor Rem.
[00:01:21] Speaker B: Thank you. Thanks for having me.
[00:01:23] Speaker A: There are currently five neuromuscular treatments underway at Cook children's. One of the more advanced treatments is an FDA approved gene therapy for Duchenne. How did this treatment come about? And can you explain the process?
[00:01:38] Speaker B: Yeah. So gene therapy became a subject of interest in the 1960s and 1970s, when researchers were theorizing that they could potentially replace a defective copy of a gene with a working copy. But at that time, we really didn't have the technology to actually implement this, and we really didn't understand enough about genetics. So in the coming decades, lots of research went into getting us to where we are now. So in the eighties, researchers in Boston were first able to package genetic material in a virus to deliver it to the body. And in the following years, the human genome project was able to complete mapping the genome of the human body, which gave us a lot of useful information. And it was only very recently that we were able to safely deliver genetic material to replace defective copies of genes for patients. And only very recently that that's been FDA approved treatment instead of experimental. The process was very tricky, especially for Duchenne, because the dystrophin gene is the largest gene in the human body. It has 79 exonse and makes up a huge proportion of genetic material. And unfortunately, that meant it was hard to package in a viral vector to bring into the body. So they had to create what they call microdystrophin, which is a smaller copy of the dystrophin gene that has all the critical portions of the gene in order to fit it into a virus, to be delivered into cells and create the functional protein. So that took extra time with getting the gene therapy for Duchenne just because of those limitations with the size of the gene.
[00:03:04] Speaker A: My understanding is that your team began doing gene therapy to treat spinal muscular atrophy in 2019, which led the way for Duchenne gene therapy. Can you talk a little about the things that are at the forefront of what's happening in neuromuscular care for kids?
[00:03:20] Speaker B: Yeah, it's a really exciting time to be a neuromuscular doctor, and I feel very lucky because I came into neuromuscular in a time when there were multiple treatment options for the conditions we treated. And it's been a privilege to be able to offer something to families. Gene therapy right now is at the forefront of most conditions. It's part of sort of precision medicine and treating the root cause of illnesses instead of just symptom management. And spinal muscular atrophy was the first commercially available, readily accessible gene therapy for a recognized condition. And that has been amazing, to be able to offer that to families at a very young age to help prevent the progression of that illness. Duchenne, again, like I was saying, is a much more difficult condition to address genetically because of the size of the gene involved and the fact that patients with Duchenne have diverse genetic changes that cause the same disease. And so it's not as much of a one size fits all as some conditions, and it makes it a lot trickier for them to have created gene therapy. So it was a lot of work from a lot of researchers to get to where we are, and we're very excited that we can offer this to patients.
[00:04:25] Speaker A: Now, how many patients have received gene therapy for Dashenne so far?
[00:04:29] Speaker B: So right now, we've treated two patients, partially due to the restrictions of who is able to receive therapy right now. So we're excited for that number to grow. It also is a treatment that requires really careful administration and making sure the right patients are receiving it at the right time, and that it's safely done. And so it's made it a little bit slower of a process. But those two families have been so grateful to receive this treatment here.
[00:04:53] Speaker A: So is this treatment curative? And if not, what is the hope, then, of this particular therapy? Is it to extend the lives of patients with this diagnosis in hopes that there is a cure down the line or just to improve quality of life? And how improved is that?
[00:05:09] Speaker B: That's a great question and one that a lot of families ask us and that we have to really clarify. It's not curative. Unfortunately, we don't have any cures in neuromuscular medicine right now, but the hope is that it will extend their quality of life. And an important marker for boys with douchebag is how long they're able to walk independently, and that plays into a lot of their secondary health complications. Once patients are wheelchair bound, they have much more progression of their restrictive lung disease. They have worsened cardiac outcomes, they're more at risk for decreased bone density fractures, many more complications that just worsen their quality of life and eventually lead to end of life. So the most important marker in research, reduchenne, is how long can we keep boys walking safely? And that is one major aim with gene therapy, is to extend their ambulation time. And then we know that anytime we're helping produce more dystrophin, it leads to improved cardiac outcomes. We don't understand that quite as well as we understand skeletal muscle outcomes, but we know that there's a benefit to cardiac health, which ultimately is what tends to cause end of life for these boys when they reach adulthood. So we do always hope that they will be alive long enough for a cure. And we have really extended the lifespan of patients with Duchenne in recent years. So that's one of the benefits. And the quality of life improvement, we hope is significant. We want them to be able to be kids and run and play and participate in things that other kids are able to do. And so the longer we can allow that, I think the better for the families and for the kids.
[00:06:44] Speaker A: Is there kind of a length of time that we know that we've extended to, like, a life expectation?
[00:06:50] Speaker B: Yeah, that has been a major part of the research. We just don't have enough data yet to know that. And that is one of the tricky things when we're working with a brand new treatment, is that it just hasn't been around long enough to know how long it works or how long it extends benefit for patients. And so it's something we're all very curious to see, is how long will the benefit of gene therapy continue to show for these boys that are treated when they're four or five? Will it continue to strengthen their muscles their whole life, or will it reach a point where it is less effective over time?
[00:07:21] Speaker A: So understanding research in clinical studies requires tremendous coordination, teamwork, and collaboration with different pharmaceutical groups and other departments. From a research perspective, how does that collaboration advance care?
[00:07:34] Speaker B: So I think at Cook Children's, we're in a really unique and awesome place in that we have a great research department that is very well supported. I think we're easy to work with, and we have a great patient population, and so a lot of pharmaceutical groups are very happy to work with us and extend trial spots for us. So we work with patients that are our own patients. We also recruit patients from outside the institution to be part of our research studies, and it allows us to offer cutting edge treatment, like gene therapy and like other new medications that would be hard to get otherwise. And so I think we have just a great system for supporting research, and it really allows kids to have hope when they really might not have had any other treatment options.
[00:08:17] Speaker A: So what are the issues or challenges that have occurred during this treatment?
[00:08:21] Speaker B: Gene therapy is very unique in terms of treatments for any condition, because it's usually a single time iv infusion of the treatment, which sounds pretty simple, but it comes with a whole host of possible complications that we have to work very hard to make sure we're managing and anticipating. And so the way that gene therapy is delivered is that you can't just insert genetic material into the bloodstream because your body does not take it up into cells. So it's inserted via a virus that carries the genetic material, and it's packaged in the virus, and the virus inserts it into the cell to allow the cell to start producing the protein from the genetic instructions. Because of that, it means we're giving a pretty large load of a virus to the patients. It's always chosen very carefully to be a virus that doesn't cause disease in humans. So for Duchenne gene therapy, it's a rhesus virus, meaning it causes disease in monkeys, but not in humans. And we are able to use that to not cause any illness, but to allow it to deliver into the cells. But the body still reacts to the virus to some degree with an inflammatory response, because it needs to clear that viral material then, and it's such a big load of viral material that there's some inflammation in the liver that occurs afterwards. There can be some inflammation in heart muscle and in other areas of the body. So we have to do very careful lab monitoring for some time after the treatment. And boys with Duchenne are always on a baseline steroid to help prevent muscle breakdown and to extend their ambulation time. But for boys receiving gene therapy, we have to add an additional steroid dose for a brief time. So we do have to add additional medication to mitigate the inflammatory effect of receiving the viral vector. The goal is that we wean off of that extra steroid back to their baseline after a few weeks to a few months, depending on how their lab work looks. But it does require some pretty intensive lab monitoring for a while afterwards. And that's where the potential complications can arise, is just how the body responds to that.
[00:10:15] Speaker A: Do they stay in hospital during that time, or how does that work?
[00:10:20] Speaker B: So we give the infusion in our infusion center. The patients don't need to come into the hospital for it because it's a relatively quick infusion within a few hours and within one day. The lab work is periodically after that. So we just have families usually arranged to stay close by if they traveled a far distance, so that they're nearby if any complication arises. So many will stay at Ronald McDonald House or in hotels nearby if they live several hours away, and then they're usually able to return home and get the rest of their lab work locally. And we just keep an eye on it from here and let them know if we need to change anything with their medications.
[00:10:55] Speaker A: Are there any risks involved with this treatment, and if so, what are they and how are they addressed?
[00:11:01] Speaker B: The risks are primarily in how the body responds to the virus itself. Because of that inflammatory response. It can cause an elevation in liver enzymes, cardiac enzymes, and that we have to manage with changing steroid doses to manage the inflammation. We also know that there's a risk and side effect of nausea and vomiting. And so that's something we have to make sure we manage for the patients, is if they're vomiting and not able to tolerate their steroid, that can be dangerous. So we keep a careful eye on those side effects. There were some risks that occurred during the research phase of gene therapy related to an immune response to the actual protein being created. And because of that, the FDA actually restricted which patients could receive the treatment. So that, we hope is much safer now and much less of a risk, because they kind of narrowed down which patients were just not safe candidates to receive the treatment.
[00:11:52] Speaker A: So what are the criteria for gene therapy and what are the benefits for these patients?
[00:11:57] Speaker B: So the criteria right now are for a patient to have a diagnosis of Duchenne muscular dystrophy that's confirmed by a genetic change in the dystrophin gene. It's restricted to being in the later part of the gene, because the mutations at the very beginning of the gene were the ones that were associated with a potentially dangerous immune response. And initially, when gene therapy was approved in June of 2023, it was only approved for patients age four and five. So very narrow age criteria. In the last month, they approved for patients four and older. So really expanded the population that may be eligible to receive treatment. So now it's approved for all Duchenne patients four and older, whether ambulatory or non ambulatory. So we have a lot more patients that may be able to benefit. Now, once we identify a patient that's interested and in the right age group and the right genetic change, we do have to check whether they have antibodies already to the virus that delivers the genetic material, because if they already have antibodies and have been exposed to that virus before, their body would neutralize it, and it wouldn't be effective, and it could be dangerous. So that's unfortunately something we don't know until we test, because it's not a virus that would have ever caused any symptoms. And so it's something that we have to check to see if patients are able to receive it or not. And it's a pretty clear yes or no from that.
[00:13:13] Speaker A: So how long do you follow a patient, and is there a point where they age out of cooked children's? And if so, do you still follow them?
[00:13:20] Speaker B: We have patients of a really wide age range in neuromuscular because we have patients with SMA that are identified on the newborn screen at four or five days of life, and then we have patients that, you know, come to a diagnosis in their teen years. For patients with Duchenne especially, we tend to identify most of them around four to five years old, some earlier, if we have a heads up about a family history or if they have concerning symptoms earlier, and we typically follow them until at least 18 and often a little bit longer, we try to get them transitioned to an adult provider at around 18. But because it can be so hard to find an adult provider with experience in neuromuscular medicine and with their diseases, we often keep them a little longer. We usually can get by until about 21, and then we really do need to send them to an adult provider. It's very difficult because these are used to be considered really pediatric diseases because they were not survivable into adulthood. And now we have so many surviving that the adult neuromuscular doctors are having to really learn a lot about these, what they consider pediatric diseases.
[00:14:24] Speaker A: So do you have an opportunity to work closely with those doctors sometimes as the patient transitions?
[00:14:29] Speaker B: Yes, and I have the benefit of that. I trained nearby, and we do a significant portion of our training for both pediatric neurology and neuromuscular on the adult side, just because of the way neurology works, we have to learn a lot about adults. And so I know personally a lot of the providers that are experienced in muscular dystrophy, and so it's a really helpful thing to be able to talk to them and let them know about a patient and really facilitate that transition and know who's a good provider for them.
[00:14:56] Speaker A: So what are the most promising results you and your team have seen so far?
[00:15:01] Speaker B: So the most exciting things that we've seen, especially from the research trials with gene therapy, is, again, really increasing that time of ambulation. It makes such a huge difference to a kid how long they can stay out of a wheelchair and play and run with other kids. And so extending that time makes a huge difference to their quality of life and their families and how easily they can get around and live. And so that's been the most exciting thing, and it's also very concrete, so it's easy to see that. And so that's just an exciting progress that we've made.
[00:15:33] Speaker A: So Duchenne is only one type of muscular dystrophy. What exactly makes it different from other types of muscular dystrophy, and why is that important? How does that inform treatment for the broader range of dystrophies?
[00:15:46] Speaker B: So Duchenne is specifically the type of muscular dystrophy that's secondary to the change in dystrophin protein. Other types of muscular dystrophy are due to other genetic changes. The thing that muscular dystrophies have in common is they all are genetically inherited changes in the muscle that cause it to be structurally unstable and break down too easily, which leads to weakness. Duchenne is particularly unique in that it only affects boys. Women can be carriers for the condition, but since they have two x chromosomes, if they have one with a functional copy of the dystrophin, then they're able to produce enough that they don't have any symptoms. Boys only have one x chromosome, and so if they inherit a dysfunctional copy of the dystrophin gene, they have symptoms. And so it's very unique in that way. Treatment for the other dystrophies, I think, will still follow in similar footsteps, because with genetic changes, we hope that a genetic replacement will be available. Duchenne is just the most common, and so I think it got a lot of focus of research before some of the other less common dystrophies have gotten that specific type of research attention.
[00:16:52] Speaker A: So you and your team are clearly at the forefront with treatments and also research which is major for this population that doesn't have treatments for a lot of these conditions. What are some of the more rare or challenging conditions you see?
[00:17:05] Speaker B: So we have a lot of variety in the conditions we see in our muscular medicine because we see any conditions that affect the muscles, the nerves, or the way the muscles and nerves communicate. So I think some of the more challenging ones for me are the patients with the very rare conditions, like the congenital myasthenic syndromes, where they have an inherited change in the way the muscle and nerve communicate that causes some fatigable weakness, some trouble swallowing, breathing, drooping of eyes. And those are really hard because they are so unique. And some of them are one of only a handful of cases in the world. So we just don't have as much knowledge about them. We don't know what to expect as much. We don't know what medicines will help them or hurt them the same way that we do with the more common rare disorders like duchenne or SMA. And so those can be really hard because you're looking at papers to try to find out what will be helpful. And there's only a handful ever reported. And so it's hard to guide the families and know how to help them. And then we have some immune mediated conditions like Guillain Barre and like the long acting form of Guillain Barre, that are really hard because they're more commonly in adults. And so, so much of the treatments and the immune modulating treatments are approved in adults and tested in adults. So trying to get those medicines covered by insurance companies for pediatric patients is really challenging. And it just causes us to have to really fight for them to try to get these things approved.
[00:18:31] Speaker A: So you see patients from across Texas and even the US, coming from the point of view of a pediatrician or a family doctor. How does a patient qualify for this? And is there an age or timeline that is critical for care? How does a patient get referred?
[00:18:46] Speaker B: And how is insurance coverage for pediatricians and family doctors? I think just keeping an eye out for signs of weakness, especially at a younger age. For boys with douche, it often starts with sort of clumsiness, tripping and falling too easily, maybe walking on their toes excessively. And so those are signs to do some screening lab work, like checking a muscle enzyme or referring to neurology, just to evaluate and make sure we're not missing something. So we really want people to feel free to refer early if you're worried so that we can at least evaluate, it's very easy to refer. Any neurology referral that comes through with a concern for a muscle problem comes to our neuromuscular team, and we get them in pretty quickly if there's an urgent concern, and we take most insurances. So I'm very excited about how easy it is to get things covered and done here.
[00:19:34] Speaker A: The idea of gene therapy brings hope to families affected by neuromuscular conditions. As gene therapy continues to evolve, how prominent do you envision this form of treatment to be in the future care of neuromuscular conditions?
[00:19:48] Speaker B: I think it's going to continue to be a really prominent treatment for many things in medicine, especially in pediatrics, and definitely in neuromuscular medicine. The vast majority of our conditions, if they're not immune mediated, they're due to a genetic change and quite often due to a single gene. Genetic change, which is really the target for all gene therapy, is anytime we can replace a single gene or correct a single gene, that really changes the landscape for that condition. And so I think as this progresses, it will become easier and easier to develop gene therapy. A lot of that initial legwork has been done by the early researchers, and they did a lot of work to pave the way. So I think as that goes along, it will be easier to target gene therapy for very specific conditions and even less common conditions in terms of neuromuscular.
[00:20:38] Speaker A: Dystrophy and other neuromuscular conditions. What's on the horizon for research and treatments? What does the future look like for kids and for finding a cure, not only for Duchenne, but for all the dystrophies?
[00:20:49] Speaker B: So I think the most exciting thing on the horizon, which has been sort of out of sight for a little while, but hopefully moving closer, is gene editing treatments, which is CRISPR technology. It involves, instead of trying to replace a dysfunctional gene, it involves going in and actually editing the gene. And so this would be very specific precision medicine for each patient, because it'd be editing their specific genetic change. And I think that has the possibility of really being helpful. It has been sort of in research phase for quite some time, and I hope they're moving towards that, becoming a reality, hopefully during my career at some point. But I think that is the future for gene treatments for many conditions, is going in and actually editing the genes to be the correct order and produce the correct protein.
[00:21:36] Speaker A: If you had to take a guess, how far off would you say we are?
[00:21:39] Speaker B: I would like to be optimistic in, say, ten years. But I will also say I don't think five years ago we thought Duchenne gene therapy was coming this soon. So we have been very pleasantly surprised before and hopefully again.
[00:21:50] Speaker A: So is there anything else you'd like to add before we close?
[00:21:53] Speaker B: I just like to thank all of our families that trust us with their kids and trust us for their care, both research and just their maintenance of care and their routine care with neuromuscular conditions. They come to us from very far away and trust us to take care of their kids, and we really appreciate how much faith they have in us to make the right choices with them.
[00:22:10] Speaker A: Fantastic. Thank you so much for joining us today.
[00:22:13] Speaker B: Thank you for having me.
[00:22:15] Speaker A: If you'd like to learn more about this program or any program at Coke children, please visit cookchildrens.org dot. Want more doc Talk? Get our latest episodes delivered directly to your inbox when you subscribe to our cookchildrens doc talk podcast from your favorite podcast provider. And thank you for listening.
