Okay, so I think we can get started here. So thank you for joining. So today we'll have Dr. Stratton. I just have a slide up here. We do have an open survey that's really just looking at a needs assessment for our community. So we appreciate any feedback you can provide there about how else we can best serve you. I also have our community leadership listed here so you are always welcome to reach out directly to any of us. Some upcoming community education. So we have our ongoing monthly lecture series every second Tuesday. If you're just joining, there is an error there. The SMA lecture will be in May. And then we also have some trainee series board lectures coming, board review lectures coming up. The date will be advertised shortly. And then just a reminder, we also currently have a call for proposals out for our member May sessions. The theme will be innovations in rehab. Those are due on February 22. And we have further instructions that we have posted to PhysForum. But you can also reach out to us if you need that directly. So moving on to our lecture today. So thank you, Dr. Ann Stratton. I'm very excited for this lecture. Let me stop sharing so you can start. So Dr. Stratton completed medical school at the University of Cincinnati where she was first introduced to pediatric rehab medicine and neuromuscular disease. She completed pediatric and rehabilitation residencies at the University of Colorado School of Medicine and she joined their faculty in 2010. She's currently in attending in their multidisciplinary neuromuscular clinic. And she's been active locally and nationally in patient advocacy, education and clinical care for those with neuromuscular disease. And she's been on the medical advisory committee for Cure SMA since 2015. She also has a recent podcast out that has additional information on this topic through the AANEM that was posted in November 2023 for people who will want to hear more after this. And I will hand it over to you, Dr. Stratton. Thank you so much. I'm really excited to be here. This is a passion of mine. And so I'm excited to hopefully stir up some excitement for this topic and this patient population and all of you as well. So we're going to be talking about current and emerging genetic therapies in Duchenne muscular dystrophy and dystrophinopathy in general. And I have no personal or financial relationships or interest in any of the products or companies discussed or alluded in this presentation. And just another little disclaimer, I gave a version of this talk in Amsterdam in May of last year. So there are some things here that you'll see me allude to things more pertinent in the European Union. And just roll with it. It's kind of interesting as well. Anyway, but a large part of this talk will be forward looking discussing investigational products that do not yet have fully defined risks or benefits and are not yet approved for marketing in the EU or in the U.S. of A. And so therefore, nothing in this presentation should be construed as seeking to promote any specific therapies. This presentation is for educational purposes only and solely intended to provide and discuss scientific information. So, important, important note. So my goals and objectives. I'm going to do a quick review of the genetics and pathology of dystrophinopathies. I think a good base of understanding is important before we move forward. And while we all sort of know this stuff, it's good to re-cement it in our heads. And I'm going to discuss the current and hopefully upcoming genetic-based treatment approaches for dystrophinopathies. We're going to discuss the mechanism of action of antisense oligonucleotide exon skipping treatment approaches and the benefits and limitations of this type of therapy. And then discuss microdystrophin gene transfer therapy approaches and the benefits and limitations of these therapies. And then I want to touch on some other genetic-based therapies in the pipeline to help round things out. And then, of course, a quick plug for why it's good to be in this space as a physical medicine and rehabilitation doc. I think this is a very dynamic place and I want to attract more folks to it. And then understand why we really can't abandon the traditional standards of care yet. So, this space has absolutely exploded in the past 10 years. Muscle disease is just incredibly dynamic. We've gone from being mostly palliative focused to now much more active. It's incredible. So I swiped this graphic from Parent Project Muscular Dystrophy back in 2020. And you can see that I've had to make clumsy attempts at extending five of those bars showing that five additional products have come to market since this graphic was made back in 2020. So it's absolutely incredible. But Duchenne muscular dystrophy is the most common hereditary neuromuscular disease, affecting 1 in 3,500 male births worldwide. And for the longest time we only had steroids as the only disease-modifying treatment option. And you all know that they do have benefits and there's a reason that they are the standard of care. But they have a lot of limitations as well. And for the longest time, the holy grail of treatment for Duchenne was to come up with a genetic-based therapy to increase dystrophin. And incredibly, we are now living in that timeline now. So, quick refresher on what dystrophin does. So again, this is an X-linked condition and the dystrophin protein is huge along with the gene encoding it. It's 79 exons long. The N-terminus binds to the F-actin and then there's that long chain of spectrum-like repeats that we call rods that act as springs and hinges, connecting the actin all the way up to the DAPC, the dystrophin-associated protein complex in the sarcolemma. And that connection and that flexible chain, that structure, helps protect the muscle cell and stabilizes actin, the shock absorber, with repeated muscle contraction and relaxation. But it does even more than that, because that interaction between the dystrophin and the dystrophin-associated protein complex actually activates a lot of cell signaling pathways that are crucial in repair. So, inevitably, damage happens with these repeated cycles, despite the stability that the dystrophin provides. And so, it is active in the cellular repair necessary. It also has an additional association with binding and localization of nitric oxide to the muscle membrane. And so, it also helps improve blood flow and decrease ischemic injury to the muscle. So, it is a really, really important protein. I love this picture. This is a scanning electron microscope picture with added color of the muscle. But, as you can see, the goal of genetic-based therapies is really restoring or replacing dystrophin to try and improve muscle stability, muscle health, contractility, and longevity. I'm having some slight advancing issues on my computer. So, there are five main strategies that we utilize. So, five different strategies or approaches to increase dystrophin out there. The first that we'll talk about is exon skipping to restore the reading frame. And then, I'm also going to touch on nonsense mutation read-through, which is a little more pertinent in Europe right now. They have Adelorin approved there. Then, of course, gene transfer with microdystrophin gene transfer. And then, there's another strategy that's being explored, which is utrophin binding upregulation. And then, for completeness sake, because your patients and colleagues will probably ask at some point, we are going to touch on CRISPR-Cas9 gene editing. All right. So, now I'm going to take a dive into antisense oligonucleotide technology. Now, I'm going to take a dive into antisense oligonucleotide technology. You may also hear this class of medications referred to as PMOs, which is phosphorodiamidate morpholino oligonucleotides. That's the last time I'm going to say that in this lecture, PMOs. And, alternately, another term that you may hear is SSO or splice-switching oligonucleotides. I just want you to be aware that all of those terms refer to essentially the same thing. ASOs are the big umbrella class. PMOs are a subset of that. And then, splice-switching is even more specific. But I think that this group of medications holds a lot of promise across the spectrum of medicine, and you'll be hearing a lot more about it. So, I want to make sure that you have some understanding about this. So, antisense oligonucleotides are synthesized, single-stranded, deoxyribonucleotides anchored to a stabilizing backbone. And they are engineered, they're designed to hybridize with a pre-mRNA or an mRNA target sequence. And this hybridization is engineered to alter the translation of the mRNA. So, you can see right there how powerful this technology is. You can essentially up-regulate or down-regulate or change a protein being translated with this technology. And so, specifically, we are looking at splice-switching oligonucleotides. And the way those can act, I like to akin it to either, they can either act like scissors, if they're engineered, or they can act like duct tape. So, in exon skipping, they are actually designed to attract an exonic splice enhancer. So, they attract the splice enhancer to splice out the problematic exon. So, essentially, you bind the little snippet, the ASO, to the target sequence, and it attracts splicing, and you get that exon spliced out, and you skip that exon. In SMA, which Mary's going to talk about in May, you can, it acts more like duct tape, and the ASO comes in and actually attracts a splicing silencer. And so, it keeps that exon in place, and you get it included. So, amazing stuff, and worth knowing about. So, how does this help our patients with DMD? So, as you, with DMD, remember, the phenotypes are affected by whether the mutation is in-frame or out-of-frame, whether it's frame-shifted. So, in-frame mutations, while they still cause an alteration in protein function, they allow continual translation of the protein with it, so you get at least a partially functional protein product. But with frame-shift mutations, the protein may start to form, and then the translation machinery hits that frame shift, and then the rest of the codons don't make any sense. And so, the rest of the protein falls apart and is meaningless, and you don't get a protein formed. So, the goal of this exon skipping is to restore that reading frame, so that you can get the rest of the read-through, and once again, get a partially functional protein. So, this isn't a perfect correlation in the real world. We have patients who appear like they would have an in-frame mutation, and they still can be pretty affected, but it's a pretty, it's a decent correlate. So, fortunately, people much, much smarter than me have figured out that there are statistically common places, hot spots per se, where frame-shift mutations happen in the dystrophin gene. And they have figured out that there are certain splice sites that they can apply this technology to, take out these exons, and then get the translation back on track to restore the reading frame, so that the rest of the protein, which in theory is at least partially functional now, right, because you've got the remainder translated, so that it can form. So, the different PMOs that have come to market are, have targeted the first three most common exons, where upstream mutations tend to cluster, and those sites are exon 51, which account for about 14% of Duchenne mutations, exon 53, which accounts for about 8%, and exon 45, which accounts for another 8%. So, if you do the math real quick, taken together, that's about 30% of patients with dystrophinopathy have mutations that are amenable to this technology. Now, there are more sites that cluster, and there's current development ongoing for exon 44, skip amenable mutations, and exon 2 duplication skipping mutations, and there are other ones that are possible that I can touch on in the next slide. This, this drug is, these drugs are actually pretty well tolerated. It's an IV delivery, so it's simple IV delivery, well tolerated, good safety profile, and we have seen improved disease trajectory with our patients receiving this. The first drug was approved in around 2016, and that was an exon 51 skipping target, and so it's been around for a while, and, and ongoing data is still being collected. Again, these are small numbers in a rare disease, but, but things look favorable. The things to watch out for is you do have to monitor for renal toxicity, so we get safety labs at baseline, and then about every three months, and it is, I have not seen any problems with this, fortunately. The challenges are getting this construct delivered to the nucleus of the muscle cells is challenging. There is, recognize that there's an endosomal entrapment problem. It's not a super efficient system, and so to overcome that, the patients have to get weekly IV dosing. And the issues that, that we have encountered, the logistical issues that we have encountered in our clinic are, are really access issues. If we have patients that live more remotely in resource poor areas, getting home health nursing to, to come to their, to their homes reliably can be a challenge. Heck, even in the, in the Denver Metro area, getting reliable home health nursing can sometimes be a challenge to get these weekly infusions, but getting them into the lab in a timely manner, getting the labs sent off, even if the home health nurse draws them, can be challenging. And, and it's a weekly infusion. That's, that's a lot for a family to endure. A lot of patients end up opting to get ports placed, which is great, but, but comes with this whole other set of issues. So, so you can see, you can, you can see why we might want to look for, for a more robust delivery. And so currently underway, there are next generation products that are, that are being explored. So ExxonSkipping Next Generation, the, one of the techniques that is being looked at is something called PPMO technology, which is a peptide conjugated PMO. And the peptide is specifically engineered to help penetrate the cell membrane better and maintain better stability of the construct and induce leaking in the endosome actually so that it releases better into the cytosol and the nucleus can uptake it more efficiently. So that's the first strategy that some companies are working on right now and exploring. The next technology is also pretty cool and that's a peptibody, coined that term, and basically it's an antigen fragment, antigen binding fragment, engineered with a link to the PMO or the ASO, and that allows the uptake to be enhanced through a receptor. So it's an antigen fragment and it binds to a receptor on the cell membrane and that receptor mediates intracellular uptake, which is such a cool solution for this problem. And interestingly, this technology is also being looked at for delivery of target molecules and constructs in other neuromuscular diseases as well, not just Duchenne, so keep an eye on this. So stay tuned, this is the current whole list of Duchenne populations potentially amenable to exon skipping. Currently, like I said, we have 51, 53, and 45 that are out there, FDA approved, and there's a bunch more. So currently we're able to treat about 30% of the Duchenne population with these medications. If a PMO construct is created for every one of these, in theory, we could expand our treatment to between 60 and 80% of the mutations out there. And this is great, but obviously not at 100%, which is where we would like to be. And again, we're shifting the phenotype from more of a Duchenne phenotype towards a Becker phenotype, but there's still a lot of gaps to fill. So it's a great technology, but we're not done yet. So next I'm going to touch on nonsense mutation read-through, and this is a different strategy for another subset of the DMD population, have nonsense mutations. And Adalorin is a product that has been going on in clinical trials in the U.S. for a very long time. It was approved by the European Medical Association, their equivalent to the FDA, back in 2014. But some of the endpoints that were set up in the U.S. trials, the FDA hasn't been satisfied yet, and so it has not come to market in the U.S. The way Adalorin works is it interacts with the ribosome and competitively inhibits this RFC, the release factor complex. And so that allows recruiting of near-cognate tRNAs, and so it allows for more flexibility in that reading. So instead of hitting the nonsense mutation, that then stops translation and you can read through that premature stop codon. And there has been some favorable pooled longitudinal data. So standard of care alone, of course, is steroids therapy and the like. And with Adalorin, it has shown that there's a delayed loss of ambulation about three to five years longer than standard of care alone. So we will see whether this ever can wrap up here, whether the clinical trials can ever wrap up here in the U.S., but to be determined. So now moving on to gene transfer therapy, which is the big buzz right now with the approval, the FDA approval, of Sarepta's gene therapy product, Alevitis, back in, I think it was July, or June or July, and this is pretty exciting. So the way these gene, I'm counting in general now, the way these gene transfer therapy products were engineered is based on a notable case report several years ago, like 20-some years ago, of a 61-year-old male. Several years ago, like 20-some years ago, of a 61-year-old male who was found to have Becker muscular dystrophy, and he had a very large, about 46 percent of his gene was deleted internally. Exon 17 to 48, I believe, was internally deleted. So it was a very large deletion, and yet he remained ambulatory through his 60s, so pretty impressive. Many of you might be familiar with the gene transfer therapy for SMA. Well, that's kind of a lucky gene. Fortunately, the SMN gene is very small and is easy to fit into that viral capsid. The gene for Duchenne, the DMD gene, is gigantic, and there is no way that it could fit into a viral capsid, and so the first hurdle that researchers needed to tackle was how to get a smaller construct that retains the essential domains and essential functionality of the dystrophy, but into a much smaller package, and this gentleman with the large internal deletion was a big step forward in being able to identify what exactly the critical domains were to try and maintain function for as long as possible. As you can see from this simple infographic, the recombinant AAV capsid binds to the cell membrane of the targeted cell. It goes in, and then the…that doesn't release the capsid, it goes in, and then the…that doesn't release the capsid into the cytoplasm. It delivers its single-stranded DNA vector. It has a self-promoter, and you get transcription of the epizootal DNA into RNA, and then get translation of the RNA into protein, and again, this is not going to be the full-length dystrophin. This is just the engineered shortened product. So, consideration of gene therapy products. They needed to be engineered to retain that essential function, but still fit into the packaging. They are the…the proprietary components of them that make each product a little bit different are the capsid that they use, the specific transgene that the company has engineered, and then a specific muscle-specific promoter to try and get the protein product into the correct type of cells, right? So, there are a lot of safety considerations. This is a very exciting product, but the patient…you're infusing a large amount of virus, and so inevitably, a high…very high proportion of patients end up with nausea, vomiting. They can have fevers. They feel gross the first two days after this. There also is a high risk of liver inflammation, complement-mediated thrombocytopenia, a hemolytic anemia picture, so TMA, which is thrombotic microangiopathic…microangiopathy, thrombotic microangiopathy, and those are our risks after this gene therapy treatment, and then there is a risk of myocarditis and myositis after this. So, there is a lot of monitoring that has to go on for our patients that are being considered for this therapy and that we discuss the risks and benefits. We stress with them that the monitoring seems excessive, the blood draws seem excessive, the visits seem excessive after receiving this treatment, but it is crucial to the health and safety of your child that we do this monitoring because if we miss that their liver enzymes are starting to shoot through their wound or that their platelets are dropping or that they're going into renal failure, this is life-threatening, and so we have to…we stress this very, very strongly with our patients and families that they cannot take this lightly. This is not something where we infuse them and they're cured and they get to dance off into the sunset. We have to monitor them very closely for at least the first two months post-treatment and sometimes extending longer. So, it is also important to know that the constructs may have increased risk to certain mutation genotypes and thus excluding their eligibility. This is…you're essentially introducing a protein product that this patient has never…their body has never seen before, their immune system has never seen before, and depending on where that gene mutation is in their own DMD, they may start to produce some of the protein, and that helps their immune system be more accepting, but if their mutation is in a different place and, for instance, a patient with a mutation at the very early part of the gene, their body has really never seen any of this dystrophin protein and they are at a much higher risk of an immune reaction. So, you can look it up and see exactly which…your team should be familiar with which patients are eligible for this and which are not, and it may be construct-specific. So, highly, highly recommend that you have a full team assembled of genetics, immunology, nephrology, cardiology, hepatology on board with you and looking at these patients with you and looking at their lab values with you as you treat these patients. Again, it's not a cure. We're introducing a truncated Becker-based transgene and we're not… there is not going to be perfect transduction of all the cells, right? So, the response is to be determined. We're still looking at this and seeing how our patients respond and seeing if there are any tricks that we may have to increase response, but this is a one-chance therapy. You can't get repeat dosing later in life at this point due to immunogenicity. Your immune system will create antibodies against the AAV vector and will inactivate it. And so, you also have to consider this is a genetic disease. I'm sure in your clinics as well, we certainly do have family members where there's two or more family members with Duchenne. And so, the vector shedding might sensitize a family member and make them ineligible for gene therapy in the future. So, something else to consider of making sure you really take care of that. And to this point, the durability is also still unclear. We hope that we have a nice robust response and that it lasts the child's lifetime, but we just don't have that data yet. So, there's a lot to be determined. The current gene therapy product that is FDA available is D-landistrogen moxiparbebec. And that is the clinical, the name of the product while it was still in clinical trials was SRP9001. And this is an infographic of their design. And they utilize the AAV-RH74 viral vector. They have a muscle-specific, a specific diskeletal and cardiac muscle promoter. And they engineered it to make sure that it does help assemble and maintain that different associated protein complex. And they engineered it to include the spectrum like repeats two and three, which they feel help maintain that contractile force of their distroferin product. So, interesting their approach for this product. So, differences in the gene transfer therapies. Here are four products. The first one is the D-landistrogen moxiparbebec that is currently FDA approved and clinically available. Again, FDA approved only for patients aged four years to five years of age. And for this particular product, there are exclusions for patients with mutations involving exons eight and or nine. And there's a caveat. So, patients with mutations in exons one through 17 and 59 through 71 may be at risk for immune-mediated myositis reaction. So, there's not a complete contraindication in patients with those span of mutations, but something to consider. There is a definite contraindication in patients with exons eight and or nine. So, considerations for that particular product. SGT001 transgene product is another microdistroferin product and it uses a different vector. So, AV9 vector in this one. And it is designed to include that specific and NOS binding region, again, to help that decrease muscle ischemic injury. So, the RGX202 transgene product uses an AAV8 vector and it is designed to include the C terminal portion for goal of full recruitment of that dystrophin-associated protein complex and NOS. So, that's the difference with that particular product. It's still in clinical trials. And then Fortidisrogine moxiparmavec also uses an AV9 vector and that specifically has exclusions for patients with any mutations involving exons nine through 13 or deletions of 29 and 30 due to a myocarditis risk that can result in death. So, again, this is exciting stuff, but not to be taken lightly. So, does it work? Well, like I said, it's fairly fresh. We don't have a lot of data. The initial study that induced FDA approval, you may have read, didn't meet its primary endpoints, but it was a very small N, only four patients. So, meeting those primary endpoints was very difficult. They also used a low-dose and high-dose. So, there are lots of logistics as to why it didn't meet its primary endpoint, but it does induce protein expression. So, you can see here, hopefully this shows up for you, you can see the nice red outlines on the normal control and you can see the pre-treatment muscle biopsy versus the post-treatment in all four patients there do seem to have a nice robust expression of the protein. And then the functional outcome measures, so four-year timed function tests are also trending in the right direction. So, instead of a decline, which you would expect over four years, you see improvement and maintenance with those timed function tests, which is encouraging. Alright, so now I'm going to switch gears. We're going to talk about a different genetic-based treatment that might be an alternate to inducing dystrophin production, and this is through a surrogate gene transfer. So, GAL-GT2 is a protein that helps preferentially bind something called utrophin, which is another protein that acts a lot like dystrophin, and it's naturally produced, we all produce utrophin. It tends to be clustered more around the ligaments, but it also binds the dystrophin-associated protein complex and functions very similarly to dystrophin, but just isn't around in very high quantities. So, there's some research being done at Ohio State that has found that if you upregulate the production of GAL-GT2, that you can preferentially switch from dystrophin binding to utrophin binding, and then that upregulates production of utrophin. And so maybe you can bypass the need for dystrophin altogether. And the cool thing about this is that because the patients are already producing utrophin, it would not induce an immune reaction, and it can also be used in any mutation. So, very cool technology. Not ready for primetime yet, but I hope that they get there. So, keep watching this space. The way that they would deliver it would be gene transfer, again with a muscle-specific promoter. They're anticipating using an AAV vector as well, and essentially, yeah, this protein also upregulates other proteins that may be protective of muscle architecture and function. So, very, very promising. I'll stop waxing poetic. So now, touching on CRISPR-Cas9. CRISPR-Cas9 has been discussed as genetic scissors. So basically, it is a construct that can be utilized to edit the patient's own genome. So, any exon skipping that could be induced with this technology, this CRISPR-Cas9 technology, would be permanent in the patient's genome. And so, the theory is that you could utilize this technology, go in, edit the patient's genome, and shift that patient from a DMD phenotype permanently to a Becker phenotype. And so, the way that it is is getting these, getting this into the patient's cells. So, the Cas9 enzyme has to be introduced, and that is the guide that does the cutting. And the CRISPR technology acts like that matching sequence to help guide where it's going to do the cutting. And you can alter that to basically customize whatever you're going to be doing. So, you have to create the guide RNA for each target. So, for each exon skipping target, you have to create the guide RNA, and you have to deliver these gene editing components into the cell. And so, viral vectors have been proposed. There was a single case study performed on a patient with advanced DMD using this technology. He was dosed in early fall of 2022, and unfortunately had severe complications and died approximately a month later. So, preliminary findings on autopsy, it's very hard to find information on this, but preliminary findings suggest that maybe it was an immune response to the vector. Again, this was a patient with very advanced DMD, medically fragile, and so perhaps just succumbed to his body's immune response to the vector itself. So, there are some unknowns with this. The immunogenicity of the gene editing components themselves, especially Cas9, it comes from a bacteriophage. The immunogenicity of that protein product, again, you are inducing the cells to create a protein that they have never seen before endogenously, and then there's always the risk of off-target double-stranded DNA breaks. So, there is really only preclinical work going on with this currently. It is very interesting, very compelling, but not ready for prime time, clearly. So, now back to the basics. As hopefully you can see from everything that I've presented, we have a lot of gaps to fill, and we do not have a cure for Duchenne muscular dystrophy yet, and it's unlikely, I feel, even if we get to the point where we're doing CRISPR-Cas9 editing, that we'll ever get to a full fix of the Duchenne gene. I think that at this point, the best that we can do is shift our patients' phenotypes from Duchenne to Becker, and that would be a huge leap forward and very worthwhile and very exciting, but there's still a big role for our specialty in this patient population, and I really hope that this presentation excites interest and enthusiasm amongst all of you to consider working in this space. And get your adult colleagues, those folks that are like, I'm terrified of kids, get your adult colleagues on board with this also, because essentially, we are creating a patient population for them that is going to need long-term care. I think our specialty is particularly well-suited to understanding and looking at outcome measures. We're good at thinking long-term and big pictures. This is brand-new territory to be charted. We're mapping brand-new trajectories for these patients, and so there's a lot of exciting work to be done. These patients still need musculoskeletal monitoring. They still need monitoring for scoliosis. They still are going to end up with joint range of motion issues, I suspect, in those Achilles, especially, and are going to need recommendations for therapies and monitoring for bone health and interventions. They're going to need DME recommendations, and I think we're particularly good at patient advocacy also, so big plug for our specialty to continue looking at this, being involved in the standard of care recommendations, and helping put it all together for our patients and our colleagues moving forward. Here are my references, and I hope you enjoyed that. Here's our muscle team. Actually, I need an updated picture because Michelle Yang is not in this picture, but we have a great group here at Children's Colorado. We have five minutes or so for any questions. I was wondering if there's any new light on what role dystrophin plays in the brain? Excellent question. Oh, my goodness. Unfortunately, not yet, and none of the treatments that we have now are really targeting dystrophin in the brain. They're all geared towards muscle uptake, but great question. I was at World Muscle in November, and that was a very hot topic. It is being studied, but I don't have anything to really present on that, but super important. I think that as we get better treatments and look at treating younger patients, I hope that we can make some progress in dystrophin effects in the brain as well. Thanks for that question. That was so great. Thank you so much. While we wait for any more questions, Dr. Apgon did post in the chat for anyone who didn't see, just working on getting our rehab community together for those who care for patients with neuromuscular conditions. She's asking to please send her a note, and she posted her email here. She said that she can send some links on brain behavior correlation. I have a question. I don't know if this exists in Colorado, but when I was in my training in Boston, they have a really cool program that's primarily their hormonology team that actually goes and does home visits for the ventilator patients. I haven't seen something similar where I am now, but as a fellow, I went with them, and this is amazing. I wish Peds Rehab was a part of this because you see them in their environment and can really see how you can improve their function. I was just wondering, do you know of any other programs in the country like that that Peds Rehab is involved in? That does sound fantastic. We utilize telehealth now a little bit like that so we can see how their house is set up and make recommendations that way. Logistically, I don't know how we would pull off home visits just at our institution, but I love the idea. It is hard for families to get in sometimes with all of their stuff, so I think a home visit would be pretty powerful. Anyone else know of any mechanisms for that? I know that we work with a lot of community therapists that will work in the home and communicate with us in that regard. Do you find that from a neuromuscular standpoint, are you, you know, sometimes when I am seeing these kids as their landscape is changing, I'm kind of thinking almost from a CP standpoint, like doing the hip surveillance, doing all of, you know, that kind of checklist. Do you find that you're doing that and are you, you know, recommending standing and weight bearing and all of those kind of typical checkmark things for best care of CP? Yeah, because we are, we're thinking more long, you know, longitudinally, we're thinking, you know, what, how can we keep these patients with good, good bone health, good joint range of motion, no, you know, decreased pain, and all of that through their lifespan, which we anticipate to be a lot longer, it already, our life expectancy for these, these boys and young men with, with Duchenne has, has really expanded significantly with the advent of, you know, non-invasive ventilation and, and enteral nutrition. So we've already made great strides, but I expect even more. And so I do, I do sometimes get hip x-rays in our really low tone boys that I'm worried about and, and of course monitoring for scoliosis and, and the like, so. And I think, you know, continuing to educate the therapy community, I have a, a friend who has a child with SMA type one who was treated a few months in, so has, has a lot of the effects, but is also doing wonderful and certainly not like an SMA type one patient from several, several years ago. And, and it was pretty clear to me that some of the providers and therapists that she was seeing didn't fully get that this was a different prognosis than it would have been many, many years ago. So even just for parents to kind of arm them, feeling confident explaining to other providers that the neuromuscular diseases are, are different now, which is great. Right. It is not, it's not just a palliative approach. It is a much more anticipatory and, and active treatment approach now. Yeah. It's exciting. All right, well, thank you all, I'm tickled I got to do this. Thank you so much again. That was wonderful. All right. Bye.

Duchenne muscular dystrophy

genetic-based therapies

exon skipping

gene transfer therapy

CRISPR-Cas9 gene editing

muscle stability

contractility

longevity

pediatric rehabilitation