Transcription:
COA's Neurology Division and the NIH Study for Duchenne Muscular Dystrophy

Dr. Cori Cross: Welcome to PedsCast, a podcast brought to you by Children's of Alabama at Birmingham. I'm pediatrician Dr. Cori Cross. Today we'll be speaking with Dr. Michael Lopez. He's a pediatric neuromuscular physician scientist and is an assistant professor at the Department of Pediatrics at UAB and Children's of Alabama. Dr. Lopez has recently received a nearly $1 million grant from the National Institute of Health's National Institute. Of neurologic disorders and stroke.

He received this career development award to expand the understanding of the role of TGF beta transcription factor in the dysregulation of micro RNA and Duchenne muscular dystrophy. In this episode of Children's of Alabama Peds Cast, Dr. Lopez will discuss with us how he hopes to use this research to identify a barren pathways that can be modulated to mitigate Duchenne muscular dystrophies pathophysiology. Dr. Lopez, thank you for joining us.

Dr. Michael Lopez: Thank you for having me. It's my pleasure.

Dr. Cori Cross: So tell us about your role at UAB?

Dr. Michael Lopez: Well, I'm an assistant professor in Department of Pediatrics and I'm dedicating most of my time to 75% effort to research and 25% to clinical work in the area of neuromuscular disorders. So, and my research focus is on as you mentioned, Duchenne muscular dystrophy. And that's closely tied into what my clinical effort is as well, where I'm taking care of patients with Duchenne muscular dystrophy in particular, but then the broader group of kids who have nerve and muscle problems. And so this makes it for a highly, focused, comprehensive clinical and research program.

Dr. Cori Cross: Tell me what Duchenne muscular dystrophy is and how is it normally diagnosed?

Dr. Michael Lopez: So it's a muscular dystrophy. It's an X link recessive disorder that's caused by a mutation in the gene that encodes for a protein called dystrophin. In absence of this protein in skeletal muscle leads to degradation of the muscle over time, and it ends with a severe, paralyzing disease that compromises breathing and causes cardiomyopathy and eventual death in the early twenties to thirties of defected boys.

Dr. Cori Cross: So you mentioned that it's X linked, besides that, is there a demographic that it is most common to, or an age group where you see the diagnosis? Are we able to make it early?

Dr. Michael Lopez: The earliest presentation is typically between three to five years of age when boys who are affected with the mutation have difficulty with walking for example, toe walking or trouble getting up off the floor. And this is the time when they usually present to the clinic and it's noticed that they have enlarged calves. And labs are checked and eventually you can find that the muscle enzymes are very high, the CK, the creatine kinase, and that typically leads to the genetic testing, which confirms the diagnosis.

Dr. Cori Cross: Got it. And then what is the current treatment for Duchenne?

Dr. Michael Lopez: The current standard of care is a comprehensive, multidisciplinary approach that really makes a difference in the longevity of the patients by providing timely supportive care, appropriate to the developmental stage and to the disease course of the patient. So, for example, that would include good cardiac care, good pulmonary care, rehabilitation. And, overall being directed under, the training of a trained neuromuscular specialist.

Dr. Cori Cross: So can you tell me now a little bit about the grant you received from the NIH, the Career Development grant and how it really applies to studying Duchenne muscular dystrophy?

Dr. Michael Lopez: Yes. So this particular grant is focused on understanding one of the pathways that drives the disease progression. And we know that the immune system is important for, Duchenne muscular dystrophy because if you intervene on the immune system by Tamping the inflammation, you actually improve the care of the patients. For example, with daily corticosteroids. And in that regard, one of the components of the immune system that is overactive is the tumor growth factor beta pathway.

And we have found that the major drivers of signaling within the cell are apparently upregulated and in particular there are two kind of classic pathways that are mediating this signaling, and one has been very studied. But the second pathway is one that we're calling attention to. Which is this BMP4, SMA 1 58 Pathways. So these are the intercellular transcription factors that are driving some abarent cell signaling within very severely affected muscle disease. And we found a very interesting upregulation of this in the human skeletal muscles and have reproduced those findings in animal models at the bench.

And have also now started to uncover a direct, sort of molecular pathway towards how these upregulated signaling molecules are causing downstream impairments in critical muscle function. Basic things like differentiating a muscle cell from its early myo blast form to its differentiated my tube form. So this is an example of how these pathways, when they're upregulated can impair basic properties of muscle function. And so the premise here is that, we can intervene on this pathway and sort of reverse these impairments, and that's what the goal of the grant is focused on.

Dr. Cori Cross: That makes sense. So are you thinking that the pathways are upregulated basically in utero as well. And it starts all the way back then? Or is this something that gets up regulated fairly early in life? You said that the children generally present around three to five years of age. At what point do you think this is starting to have an effect?

Dr. Michael Lopez: That's a really good question. And what we see and what we have been studying is at the end stage of the disease towards the stage where the muscle. Is very, decompensated and, kind of, what we call trophic because it's been replaced by fat and by fibrosis. And so the, healthy fibers are gone. But the immune response is happening for a reason, and that's because it's part of the repair process. And so what we think is going on is early on, it's beneficial, but over time, because it never stops the cycle continues because the muscle is inherently destabilized by the genetic problem.

It never has a chance to fully repair. And this leads to an exhaustion of the regenerative capacity of the muscle in kind over cycling of this pathway that really, in the beginning and in response to injury is appropriate. But is sort become maladaptive and the timing for when that happened is unclear, but certainly that would be of interest to study.

Dr. Cori Cross: Wow, that's really interesting because put it in that way. You understand why the body would do this. We know that our muscles get stronger by having these little micro tears and then we build back up. And it sounds like what you're describing is just too much of good thing not being able to turn that off. How did you become interested in this particular research?

Dr. Michael Lopez: I started in a summer research program as a college student in the lab that was studying respiratory muscle mechanics. And in my mentor in that lab was studying in particular mouse models of Duchenne muscular dystrophy. And it really fascinated me, the skeletal muscle architecture and how absence of this protein dystrophin could cause such a severe disease and pathology under the microscope. And it was so severe in the animal models and that it led me to understand how bad it could be for the humans and sort of inspired me understand this even more.

Dr. Cori Cross: Wow. So you've been working on this for quite a while?

Dr. Michael Lopez: Yes, I started, really, just by chance I was a chemical engineer and they had matched me with a mentor who was a mechanical engineer. And that's how we had that, that's how I had my mentorship match for my very first lab experience. And turns out, the respiratory pump, which is the diaphragm is involved and that's one of the mechanisms of disease progression in Duchenne and, so he was studying sort of the gross macro mechanics of pump failure. And that fascinated me. but then as we pursued those questions, we dove down even deeper to the individual molecular pathways that are compromising the force generating capacity of these, of the respiratory pump. And so I did my PhD with him on, sort of that topic. And this question has fascinated me for a very long time. As you said.

Dr. Cori Cross: Well, I mean, I'm a pediatrician and I can just attest to the fact that what you're doing is extremely impactful to be able to figure out what's going on at a genetic level so that hopefully at some point we can intervene and change the prognosis, change the course of these diseases. It's life changing for these children.

Dr. Michael Lopez: No, I think you're right. I think the landscape for treatment options is bright. You know, as we talked about earlier Multi D care is the standard of care along with daily corticosteroids, but there are newer treatments coming on board that are specific to the patients in terms of individual genetic mutations. Most of those are aimed at restoring the expression of the dystrophin protein, so that the origins of the disease are kind of corrected, but because dystrophin is the largest gene in the body, it's not very easy to do that.

And so looking at some of these other pathways is going to continue to be an important part of the treatment options because, I think we're ever gonna be able to turn it on exactly the way it is in the body like we have done for other diseases. For example, spinal muscular atrophy, where we can just replace the gene because it's not as big.

Dr. Cori Cross: So when you say it's, big, you mean, in sequencing, like it, it's actually a large sequence?

Dr. Michael Lopez: Yes the actual base pair the number of kilo bases, it's just, it's the largest in the human genome. So there's no way it's too big to package that gene information into a viral vector, for example, as in SMA, because it just doesn't fit. It's just too big. And so you. There are three late phase clinical trials going on right now, which are using dystrophin mimics, which are taking the most important, what we think are the most important parts of the dystrophin gene, and truncating them down into something that is packageable into a viral vector.

And then those are being studied now and there's some progress there, and I think we're gonna have good news on that front. But again, they're gonna be, they're not gonna be what the native body would be able to produce, so we'll, have to wait and see how those gene therapy, replacement strategies work out in the long run.

Dr. Cori Cross: That's amazing. So getting back to your grant, so your grant covers five years of research. Can you tell me where you are in your progress right now?

Dr. Michael Lopez: Absolutely. And so this is a career development award and part of the grant is aimed at kind of ensuring that the investigator myself is pursuing career development to help launch an independent research program, and I think we're making a lot of success on that front. And the other part of the grant is the actual research questions themselves, which recently we've published the major findings that describe the barring up regulation of this pathway that I've mentioned. The BMP4 MAT 8 pathway. And this is recently published, and I think this is gonna change a little bit of how we think of the traditional pathology of TGF beta signaling in Duchenne because There were only a handful of papers describing, some components of what we've been able to publish recently.

So I think we have generated a lot of interest and I think this is gonna. Propel the rest of the questions going forward. The other piece of this to really get at the role of the particular molecule that we're interested in, the gene of interest, MAT 8 is using genetic models that knock out Thema eight in mice, and then seeing how absence and presence of the. In the dystrophy mouth s changes the disease. And so we, made good progress on that front. Took about two years to derive all these, specific strains that will allow us to enter the question. If we take it out in the MDX or the mouse model of Duchenne, how does it change the disease process? So that work is ongoing and we're just getting to the point where we're gonna be able to start testing that question this year.

Dr. Cori Cross: So it sounds like you're approaching it from a lot of different angles to see how the genetics is playing out in the body?

Dr. Michael Lopez: And it's a key point because a lot of the successes we've had in the preclinical research have sh have shown that we can make the disease better in the animal models. But then when they go to translation in the clinical realm, they fail to show improvements. And there's a number of reasons why, but that's why we think it's important to tie together early on as you're doing the preclinical research, both the human, tissue the animal models to sort of cross validate what you're seeing is relevant in the disease, across the human and the animal models.

Dr. Cori Cross: So it sounds like there's a lot of potential for advancement.

Dr. Michael Lopez: I think that's a great point. And that's exactly what our hope is, that this will be able to have a high relevance for therapeutic investigation.

Dr. Cori Cross: How far off do you think we are from seeing some of these things in our patients outside of a study?

Dr. Michael Lopez: This is pretty early work. And so, this kind of basic bench work generally takes quite a while. you could feel a career essentially with the hope of getting one of these down the pipeline to the clinical stage. But sometimes it happens faster. It just kind of depends on, how the research pans out and sometimes you have unanticipated discoveries that lead you in a whole new direction. So, but I do think that this particular pathway has a lot of potential for changing our fundamental understanding of the disease process and the role of this particular signaling pathway, and for opening new lines of investigation for clinical intervention.

Dr. Cori Cross: I think we've talked a lot about the research, but I just wanted to ask you, are there any best practices that you would share with colleagues based on this research?

Dr. Michael Lopez: The main ones I would say are to recognize the disease. A young boy who's, learned to walk and is tripping and falling with a high CK and large muscles, for example, in the calves. Think about muscular dystrophies and the current best diagnostic choice is to use genetic testing, in appropriate, patient with symptoms and, treatment should be multidisciplinary and typically includes corticosteroids. And the other reason genetics are important, that because there are several gene specific treatment options available for children with Duchenne.

So, and these are already FDA approved, so-called Exxon skipping drugs. And these help to turn on the expression of the dystrophin that's missing. And I think over the long term, what we have been seeing is that these are making a difference in improving re respiratory function, improving the, duration of ambulation and, slowing the disease down overall in addition to the standard oral daily corticosteroids. So those would be the main things that, I would take away from this. and the other point is that the future is bright. There are newer treatments coming down the line that include gene replacement therapies.

But I don't think they're gonna be as successful as we have seen in for example, in SMA or spinal muscular atrophy. So we're still gonna need to use a comprehensive approach to really slow this disease down and improve the quality of life of Duchenne patients.

Dr. Cori Cross: It's just so impressive what you're doing. I'm sort of blown away by the amount you've been able to discern about this disease, how different it is from what I learned back in medical school. It's just, amazing to see how far we've come and, I'm really grateful for what you're doing for our patients, so thank you.

Dr. Michael Lopez: Well, thank you for inviting me to talk and to share with you a little bit about what we're doing. It's been my pleasure.

Dr. Cori Cross: Is there anything else you'd like to share with our listeners today?

Dr. Michael Lopez: I just end on the message that I think the future is bright, and I'm hopeful that we'll have a number of additional treatment options that will start to make even better, improvements for the patients. And just wanna say thank you to your listeners and to the families and patients for all their volunteering and participation and, research studies and, I'm hopeful for the future.

Dr. Cori Cross: I am as well. For more information or to refer patients to Children's of Alabama, please visit childrensal.org. That concludes this episode of Children's of Alabama Peds Cast. If you found this podcast helpful, please share it on your social channels, and be sure to check out the entire podcast library for other topics that might interest you. Please remember to subscribe rate, and review this podcast. Thanks for listening to this episode of PedsCast. I'm your host, Dr. Cori Cross.