Good afternoon and welcome. I'm Susan Apkon. I am a pediatric rehabilitation physician at Children's Hospital Colorado and faculty at University of Colorado School of Medicine. Welcome to all of you that are here in person and also welcome to all of you who are here virtually. We appreciate your participation. I have a few housekeeping items. One, we are going to be, I'm going to ask that you turn off your cell phones and we will be recording this so there is no need to record this session on your own. I'm going to encourage you to fill out an evaluation form at the conclusion of this. This will allow you also to get CME credit. And finally, a gentle reminder to support our sponsors down in the PM&R pavilion down on that lower level and check out the swag that they have with them today. It is really a pleasure to have an opportunity to share the podium with these three speakers. I'm going to start by introductions and then we're going to just move right into the session. All the way at the far end of the table is Dr. Tom Crawford. He is a professor of neurology at Johns Hopkins University, so a local guy. Dr. Crawford is nationally and internationally known for the clinical care he provides to children and adults with spinal muscular atrophy as well as his contributions to research. As you hear today, him describe some of the clinical trials that led to the FDA approval of these three novel treatments. It was Dr. Crawford and others that were instrumental in moving this forward. Next is Anne Stratton. Dr. Stratton is an associate professor at University of Colorado School of Medicine. She is one of my colleagues also at Children's Hospital Colorado. And finally, Dr. Kathy Mosher, who is also an associate professor at Northeast Ohio Medical University and she works at Akron Children's Hospital. The last two presenters, Dr. Stratton and Dr. Mosher, I just want to point out are two of the few pediatric rehabilitation physicians that are providing care to children with spinal muscular atrophy. So it's exciting that there are actually three pediatric rehab physicians, including myself, up here today. So welcome and thank you. I will move past my disclosures. As you're reading the course objectives, what I'd like to do is just share an anecdote. You know, I had a number of people ask me how my job is going in Colorado. I've been there now four years, back there for four years, and it's given me a time to reflect. I certainly had a lot of time reflecting as I put this talk together. And I think it has been an incredible experience over the last now just over 20 years that I've been in practice. I reflect back on when I was transitioning from being a resident in our combined pediatrics and rehab program and transitioning into being a young faculty member. And during that time, it must have been probably May and June and into the fall, we had the privilege of admitting three infants with spinal muscular atrophy. All were the most fragile of types, we used to refer to them as type one infants. For various reasons, their three families, Cheyenne, Serena, and Allie, I will never forget their names. For various reasons, their families were unable to provide care for them at home. And so we electively admitted them to our inpatient rehabilitation unit. And we provided them supportive care, palliative care, it wasn't a term really 20 plus years ago we used. We didn't have cough assist machines, we didn't have BiPAP. We did some chest physiotherapy, we provided them oxygen, suction, and nutrition. And we supported them and their families until ultimately they died, each within weeks apart by about a year of age. I fast forward now to where we are today and we have not one, not two, but we have three treatments, they're FDA approved, that have completely changed the way that we experience, or these kids experience, their families experience their lives. They are truly life changing and they're life saving. And so with that, I'm gonna invite Dr. Crawford up to share a little bit about some background of SMA and then talk more specifically about the new treatments. That's great. Welcome. Yeah. There we go. So I get a chance to talk a little bit about the disease and a little bit about the therapies that are... Oh, hey. In front of here. That's cool. Okay. Forward. Disclosures. Whatever. Okay. So this is something that I hope not to be able to... So in addition to being a researcher on motor neuron biology, I also was in the practice of flying around the country doing autopsies on babies that died from this thing and we would go anywhere where I could get an autopsy within a small amount of time. This is an example of a spinal muscular atrophy as it was defined by Wernig and Huffman in 1891 and 1893. And what the feature they described was the smallness of the ventral root. This is a spinal cord ventral side up and you can see there's atrophy of the ventral root. This was before they knew that the ventral root was the motor root and the dorsal was the big one. But they saw that there was these little tiny ventral roots and the dorsal roots were the normal size. And so they said, there's something wrong with these kids. They have atrophy on a spinal cos. And so that was the beginning of that name later and they've sort of used that to figure out that the ventral root was the motor. And the classic muscle biopsy is important here. You have normal muscle fibers intermixed with a sea of denervated muscle fibers. And so this is a funny disease where they're like little Schwarzeneggers but they don't have very much Schwarzenegger. They've got these massive muscle fibers in a sea of denervated muscle fibers that don't contribute anything at all. So it's kind of different than other muscular dystrophy, things where the muscle themselves are degenerating. It's just denervation atrophy and proportion is responsible for that. So there's something else that's weird about SMA and it's troubled me for the longest time. I think we might have the answer to this, which is that for some reason this disease, the kids look normal at birth and then they sort of hit their ceiling and they might decline a little bit. We were just talking about the kids, their worst off decline for a bit. But then they sort of settle into a plateau phase where they stay that way for a long time with just the slightest downhill course. What's weird is that the copy number, we'll talk about it in a second, but the different genetic genotypes are responsible for varying severities, severe or mild, but they have a different threshold at which they reach. So that's the quantity that we were having for a long time. Now I'm at a rehab place though. And so what we realized is that actually when I got to watching people for a long time, I'm realizing that actually they do decline. But how much of that decline is related to the underlying disease and how much of that decline is related to all the other stuff that you guys have to deal with, which is the contracture, the increased weight, the fact that they have nutritional problems, the fact that they have pulmonary stuff, they have all kinds of other things that are elapsed onto them. I mean, it takes a lot more power to stand from this position than it does to stand from this position. And in fact, that difference, just the tiniest little bit of a knee flexion contracture could be the difference between whether you walk or not. In fact, a lot of the ambulatory people lose amputation because they've got a four, a five or 10 degree knee flexion contracture. So there's a big role for rehab, even before we ever got to Neusonursin and Spinarosa and all the other things. So I've been measuring muscle power in kids ever since. So I've now measured about, I forget, 1,300 patient visits and my ICC on dynamometer is now 0.91, so it's pretty good. And with that, I was able to develop these curves. What you see here is traditional type one, type two, don't worry about type two, type three, don't worry about that. But on the top curve, you see the biceps power of everybody I ever measured at 1,300 visits. And you'll see this, it's a bit smoothed. But what you see is that there's a peak around age 11, whether or not you're a type three or type two. And after that peak, everybody declines at a rate of about 5% per year. That's interesting. Now the up part is because normal development, actually I think they're probably declining from the very start, but this is plotted in absolute powers rather than a percentage of normal. And so what you're seeing is normal development and then the decline when normal development sort of is washed out. Get that inflection point. Oop. No, there we go. Okay. So there's a little bit about the SMA genetics. I did want to talk about it. It's a unique gene. It's a digenic disease, meaning there's two conditions that have to be met. One is you have to have absence of this SMN1 gene, but you have to have at least one and usually two, three, four, or five copies of this SMN2 gene, which is partially functioning. I'll talk a little bit about how it is, but basically this is really fascinating. SMN1 and SMN2 broke apart in human evolution and the second copy got broken down a little bit, but it makes a little bit of protein. Not for that we wouldn't have SMA. But then when you lose the type 1 because the 2 got messed up in all sorts of unequal crossing over events, when you lose the 1 you have to have some of a 2 to keep you alive. Otherwise you would be an embryonic lethal. So here's the thing that works, and I did this in a stage when it was kind of weird. Exons come out, I like to call it a loosely strung strand of pearls. So you've got pearl 1, exon 1, pearl 2, 3, 4, 5. Exon SMN2, SMN protein has got 8 pearls, and the difference between the SMN1 and the SMN2 gene is the difference here. So when you have the spliceosome come through it, it cuts at the end of one and connects it to the next. Take that loosely strung strand of pearls and put it into a single tightly strung. And so that's the spliceosome, which by the way, curiously enough, SMN is responsible for forming the spliceosome, a unique reflexive thing that is like beyond irony. And so what is happening, the normal kind of splicing event would be that it's spliced from 6 to 7 and 7 to 8. But in the case of SMN2 there's a single letter right at the second base pair in exon 7 and that makes that splice site rather unfavorable. And so in exon 7, in the second copy, SMN2, you skip the exon 7. And so that makes a non-functional protein. But about 15% is spliced the right way, and that's why they're alive. So it's a broken down gene that sort of works. That was like hanging fresh meat in front of pharma when they discovered that thing. Oh my God, we don't have to cure the disease, we just have to make SMN2 work better. And so right away, all these companies were trying out their different ways to try to make it better. And they happened upon these various established therapies, three different pathways. Very, very cool. First pathway was a brand new technology that was emerging at the time called antisense oligonucleotide, ASO. It actually should be called synthetic antisense oligonucleotide, but be that as it may. The therapy is called nusinersen, and it's a whole class of drugs. You're going to be seeing a lot more of them, just like we have non-monoclonal antibodies. They end in the suffix S-E-N, sen. And this is a remarkable thing. When we saw the trial, the babies went from, they died beforehand, and now I'm not doing autopsies anymore because we do this therapy. It's just absolutely frigging amazing. And so we'll talk about the trials. The next one that came along a couple of years later was a brand new technology. We can package this tiny little gene into a sniveling little sort of half a virus that doesn't really, it isn't competent to reproduce by itself, but it only reproduces when it happens to be in a cell that adenovirus comes into. And when it does, when the adenovirus comes in, it says, hey, we'll use the adenovirus machine to make more copies of ourselves. So it's a gene that only has enough space to contain two genes, and in fact, it only has enough to space the SMN gene. So you've got the AAV, enters out, and you put in a sequence of SMN, put it in there, and the gene is, the cell is transfected. It does not reproduce. It doesn't do anything, but just sits there and makes protein, waiting for something. And it turns out, in the case of our engineered construct, you can have it make SMN and essentially repair the cell at the cellular level. And then the third thing that came along, Ristoplam, was actually the first one out, but we had some problems with the development and side effects, is an oral drug that does exactly what the Spinarazzo one does. It changes the splicing efficiency so that SMN7, I'm sorry, that exon 7 is now included into the transcript. This was done by a screening process. So just to go through the, you know, the amazing, impressive things. In the ENDEAR trial, which was the first trial of already symptomatic infants, we see that there was a massive difference between the way the nusinersen folks got it and their controls. The same sort of thing... Oh, and this was the older ones, the kids. They also were substantially better, a huge salutary effect. And then this is the one that was the knock your socks off one. This is Nurture. This is the 25 babies that were asymptomatic at the time of treatment. And what this curve, which should look like if you weren't treated, you wouldn't see anything after about 180 days. They're dead. And so instead of being dead, they're, like, getting better. And I have three Nurture babies in my practice, it's just awesome. Anyway, so... This is Abaparvavac is the words we're going to be using for gene transfers, so get used to it. This is Onasemnagine Abaparvavac. It took me forever to learn to be able to say that like this. But it's Zolgensma, one gene for SMA, if you want to hear for that. I don't know where Spenroza came from, but anyway, Zolgensma. And that's the gene transfer technology that, and again, I could talk for a couple hours about how this thing works, but it works pretty cool. The curves look exactly the same. And then you have the Ristoplam, the trade name for that is called Evristi. Everyone should get Ristoplam. That's where that came from, Evristi. But the Ristoplam had a budget, a development program, two of which were important. They liked fishes for some reason, so the Firefish and Sunfish protocols. The Sunfish was exactly the same as that first one I showed you with Endear, and you can see that the curve looks almost exactly the same. When you take it, you do well, if you don't take it, you don't do so well. And the other one is the baby one, which is this one at the bottom, and you can see that the babies were doing almost exactly the same. So small differences in occlusion criteria and how it was measured and all that kind of stuff, so we really can't compare efficacy. As a matter of fact, as near as I can tell, efficacy for these three drugs is identical. So how do we choose? What's the difference between them? Well, so Nusinersen, Spinaraza, it can be used in infants. In pre-symptomatics, we know the effect in all ages is clear and substantial, except for adults. So there's a special issue with adults here. Onasemnidine, Abaparvavac, I almost did it, can only be used in infants, and licensed up to age 24, but it turns out the enabling trial was only up to five months. But anyway, so we know that it works in infants and probably very young toddlers. And for risk deployment, it was approved for everybody up to 25. The data on it improving people at older ages is a little bit less clear, though. Now here's where they differ. The ASO Spinaraza has to be given by spinal tap. That's not trivial. So these hands and those of my colleague, I do this Spinaraza thing, have delivered $62.5 million of drug into 100 patients now, and so it's incredibly expensive. It has to be given by spinal tap every four months. That is an incredible burden. Spinal tap headaches, all that kind of stuff go along. On the other hand, it works, and it's a lot better than not having anything. So I'm wildly enthusiastic about it, but with an awareness that it's an issue. Zoologensma is associated with liver damage in almost, I think it's something like 60, 70% of people will have liver transaminase elevations, and rarely it can go really badly. We recently had two deaths. And there's also rare thrombotic microangiopathy, TMA, but there are other concerns. Is it going to wear... Is it going to last for a lifetime? We don't know. Is it going to... The way it's engineered, it has persistent overexpression, which may not be a good thing. SMN levels are regulated, and this is an unregulated overexpression profile. And then Ristoplan, we know that they can have problems with fever, diarrhea, and GI upset. There was a little bit of concern, because one of the preclinical animal models had testicular pathology, so there may be problems with male fertility. So how do you decide? I would say that the issue for that is, how do you decide between these things? Oh, one last thing, is that the labels don't always match the studies. Interestingly enough, I used to think of the FBDA as being horribly regimented and very Cartesian in their thinking. But actually, when we saw the result in the babies and the kids with Spina Raza, I was stunned when the FDA gave us the label for all ages on the awareness that SMA adults do decline. They just declined really slowly. But the FDA... But Biogen said, we want to use the same drug level. So FDA said, that's fine. It's safe. You've proved it was safe in kids. It's going to be safe in adults. So they gave us the label for everybody. That's not the same thing as saying that we have the indication that we can get approvals for it. So now it's on the insurance companies and us docs to have to try to plead the case, which is a tough thing to do. The cases decline so slowly that it's hard to prove that you have stabilization or benefit, because it takes years and years. No one will ever pay for that. On the 7th gene was only studied in kids less than five months, but it was given a label up to 23 months. Go figure. Ristoplam was studied in kids up to 24, although frankly, it was mostly younger ones. And they were also given the label for all ages. So there's some problems there in terms of... It means that the onus has shifted to us docs to have to try to get approvals and argue with insurance companies and things of that nature. Okay. So here's something that I thought a lot about. I don't think we've ever made anybody better with these therapies, even though it's... I'm up here saying, oh my God, oh my God, this is amazing. But frankly, we've not made anybody better at all. What we have done is stop the generation of time when kids naturally get better. So if you take a baby and they're like cute little things that don't do anything, and then pretty soon they're out of mom's hands and running, we allow that to happen. And so that is absolutely spectacular. So what we're doing is allowing things to happen. But that means... That tells you something about the nature of what we can do. If you start the therapy really, really early, the kids do well. If you start a little bit later, they've already lost half of their motor neurons, or 90% of their motor neurons. So the outcomes you can get as a result is related to how much they're... And by the time they're adults, well, we can slow the rate of further degeneration, but probably not improve anything if they're after development. And I think that was my last slide. Oh, no. How do we function in the real world? So the choice of therapy is, to me, is dominated by availability. Some states have one thing. Some countries have others, obviously. Insurance companies have a rate, ungodly costs. On Ascendagine, Apoparvac costs $2.1 million. Nusinersen, $125,000 per dose, four doses initially and three doses per year thereafter. Evristi is just a tad bit cheaper for the little ones and the same cost for the old ones. So who can afford that? Well, I don't know that we as a society can, and I have to say I'm queasy about the fact that I went from being a hospice doc to being the doc that prescribes the most expensive drugs in the American pharmacopoeia. It's like that's not right. And furthermore, as things go further and further and we start developing similar ASOs and gene transfers and other specific small molecules, this is unsustainable. And so I think we as a community, as a physician base, have to be advocates for some right sizing of therapy. You can't just say, what do you want? You want to live or not and we'll price it based upon that. There has to be some other metrics by which drugs are priced. The newborn screening obviously is extraordinary. We now have it in all 49 to 50 states, but not yet Washington, D.C. We will get those two last ones, the recalcitrant ones soon. All patients decline over time. We'll be talking about some cases. I'm going to tell you about a couple adults that I have, and I want to say stability is an important role. So where choice is possible, where you have one, I think the issue is that there's a perception of burden. What do you want? Do you want a gene transfer that we can't pull back that may have toxicity late? Do you want to do spinal taps over and over and over and over and over and over again? You want to do a newer oral molecule that may have off-target effects that we haven't found yet? Which one do you want to choose? And frankly we don't have data to fill out any of those things. All we have is the perception of the burden of those things. Well, it's about the spinal types are real. Yours. That's great. Thanks, Tom. What I'm going to do is I'm going to continue along this thread of how do we make decisions when there are three novel treatments available. And as Dr. Crawford said, sort of as far as we know, be equally effective. So I'm going to provide just a few general principles to think about as you are the provider facing a conversation with a family or a patient. How should you or how could you think about supporting the decision that the family is making? The first thing to keep in mind is complex. You heard everything from the genetics with Dr. Crawford's talk to some of the side effects from each of the individual treatments. And so understanding that the decision is going to be complicated, giving families time to make that decision, balancing that with the sense of urgency in treating a newborn, especially one with two copies, so the most fragile type. It's a shared decision between the child, the parent, and you as the provider. We are diagnosing... Obviously, we're continuing to diagnose in adults, and so it is a one-on-one conversation you have with an adult. In the setting with child, obviously, it is the parent surrogate. We know that earlier diagnosis will lead to better outcomes, so that sense of urgency is important. Dr. Crawford mentioned the copy numbers. So the more copy numbers a child has of the SMN2 gene will predict a better outcome. We talked about the age, and then the one thing that I want to emphasize, the children and the adults who are treated with one of these three novel treatments will still have spinal muscular atrophy. They will still need to be followed closely. They will still need adherence to the clinical care guidelines that were established several years ago. And so that's some point to emphasize with families and with patients as we're discussing this treatment. So who are the decision makers? Obviously, the parent in the setting of pediatric care is a decision maker. I am a provider. As a provider, I am a decision maker. The hospital, believe it or not, is a decision maker in this. The hospital is at risk for losing a significant amount of money because the cost of the drug to the hospital is higher than the reimbursement that the insurance will pay. There's a significant financial impact to the point of, in one case, $500,000 for treatment of one child. The FDA, the EMA, other national regulatory agencies are gonna be decision makers. You heard Dr. Crawford say that, you know, RISDA plan and NUSA Nurse Center approved for all ages and on a seven gene for just under age two. That was an FDA decision and we then are adhering to that. And finally, the insurer. Not surprising, they are a decision maker in all this. So I'm gonna talk a little bit about each of those. So what does a patient or a family bring to the decision? What do you as a provider need to know as you're sitting down and talking to maybe parents of a two-day-old or a four-day-old, a mom who just delivered, a mom who had a cesarean section, a mom who might have had some complications? Their family values, their backgrounds may help inform if they've had another child or a sibling with this condition. That will help inform them of a decision. The scientific data that we bring to the table. When I meet with a family of a newborn, I bring with me a packet that explains what SMA is and all the treatment options and the logistics involved with the decision-making process. But I have to be up-to-date with that scientific data. So the night before or the morning of that first visit, I'm online making sure that I'm presenting them with the most up-to-date data that's available. The delivery method, LP versus oral agent versus a one-time IV infusion. The safety is gonna play into that decision-making from a family's perspective. We have to be honest with what safety risks there are. We talk about the deaths associated with liver failure now. And finally, social media. It's amazing what families learn on social media. And you as a provider need to be aware of that. Oftentimes, it's the most outspoken people who are on social media sharing their experiences and pointing families, new families, families with high emotions around this new diagnosis. And they're being pointed in one direction or another by other families. As a provider, I'm obviously looking at the scientific data also. I'm thinking about the safety. I lose sleep depending on what decision a family makes. The delivery method. If we have a child who's diagnosed at a later age or a child now who comes into our practice who's not yet received nusinersen as an example, they have a complex spinal deformity. Maybe they've had a spine fusion. That has to play into the decision-making. Kids transitioning from one agent to another because of the challenges with lumbar punctures, especially, again, in the setting of someone who's had a spinal fusion. Access to care and follow-up is an important point. The follow-up after gene therapy, the frequent lab draws, the every four-month lumbar punctures, it requires a family to have reliable transportation. It requires a parent to be able to take time off from work. And so understanding where that family is coming from, what they're bringing to this decision-making is important for me to provide them that support and the resources that are necessary to be able to complete that treatment. This is a diagram that my good friend, Julie Parson, shared with me. She's a child neurologist that I get to work with at Children's Colorado. And this is just a different way of thinking about the decision-making process. Again, breaking it into the age. At what age will a child be eligible for what treatment? What is their SMN2 copy number? That comes into the sense of urgency, the speed at which we want to make a decision. If they have four copies or five copies, I feel a whole lot more relaxed when a newborn presents to my office about making the decisions. If there's a delay in insurance approval, I'm a lot more relaxed knowing that the progression of their condition is going to be slower than that of an infant with two copies or that most fragile of types. Access to health care I talked about. If you live in an urban area versus a rural area. If you have transportation versus no transportation. And the economic burden. Whether insurance is going to pay for it. If you have a co-pay that you're going to have to deal with. If you aren't going to be paid to go to work that day that you take off to take your child in for a lumbar puncture. And then finally, the insurance status. We navigate insurances every day. We're advocating for all of our patients, whether they have public insurance, private insurance, or they have no insurance. So I'm going to actually just very quickly jump over this because Dr. Crawford talked about the different considerations in terms of the logistics around lumbar punctures versus male fertility considerations for RISDA plan and on a semi-gene, the antibody status. So at the time of diagnosis, if a family is interested in gene therapy, we want to make sure that they don't have antibodies against the AAV9 vector. And so we're checking antibody status. And that's going to play into the consideration of what treatment might be available. And yes, the insurers have a say. They're going to think about the cost and value. So cost over outcome. There's policy coverage issues that we have to navigate. And they're going to look at the available data. We've seen it in other novel treatments. We see it in the exon skipping for boys with Duchenne dystrophy. The approval process is oftentimes for insurance companies very narrow. So if boys who are X age to Y age in this ambulatory status, then they will approve it because that's where the studies were done. Frankly, I was surprised when Nusinersen and RISDA plan got approved for all ages because the trials were not done on all ages. We were very lucky in that setting. We haven't been lucky in some of the other diagnoses. So again, I would refer you to these two papers that were recommendations that came out of a work group. I think, Dr. Crawford, you were part of this. Published in 2018, 2019. And this is a proposed algorithm. Again, looking at the age and the SMN copy numbers and then the treatments. In 2020, this working group updated the recommendations. The original recommendation for someone with four copies to sort of wait and watch if they had symptoms, consider treatment, but otherwise to wait and watch. There's a paper that came out of Spain several years ago looking at a very large cohort, Spanish patients and then worldwide. It was almost 3,000 patients. And what they found was that about 5% of people with four copies of the SMN2 gene. So we would think it would be more of an ambulatory person. What they found was about 5% of four copy patients actually were non-ambulatory. They looked much more like a classic type two. And that's the paper that I use when I'm advocating to an insurance company to pay for coverage in a newborn with four copies. That wait and watch approach, there's no other biomarkers that we know of that can really help us right now tell us whether this is gonna be an ambulatory, non-ambulatory. So the current recommendation when you have four copies is to treat. And then finally, an infrastructure that you need to have in place. If you were to consider initiating a treatment program for kids or adults with spinal muscular atrophy, having an infrastructure in place, including the medical providers, nurses. I didn't add physical therapists. As a rehab physician, I am just incredibly embarrassed. The physiotherapists in our center are the ones who are doing our outcome measures. When we ask for reapproval for something like NUSA Nursing or RISDA plan, we have to be able to provide data that they're stable or improving. And so our physiotherapists are critically important in that. Having a social worker help us navigate some of the challenges that families might experience. And finally, the organizational support. We have a hotline to our CFO who has been incredibly supportive. He sometimes before I know of a newborn in the state of Colorado or the state of Wyoming who has tested positive for SMA, and they are already behind the scenes working on insurance approval. And finally, our governmental affairs team members at the hospital. They are the ones who are helping us work directly with commercial insurers, public insurers, to help them understand the urgency in which we feel to get these approvals, to get treatment going. So with that, I am going to hand it over to Dr. Moser to start presenting some cases. Dr. Stratton will follow, Dr. Crawford, and then we will open it up to questions for those of you here in person, and then for those of you online, please submit through the chat, and we will be able to address them when we are finished. Great, thank you. So I'm gonna start, can you start at slide one? There we go. So I'm gonna present to you what happens with the two copy babies. These are the most severely affected infants. I have no disclosures related to this disease state. And just as a reminder for you, the type one patients are typically expected to present with weakness prior to the age of six months, and they do not achieve sitting. Oftentimes, they have severe respiratory weakness. They may require a trach vent, and they typically also require G-tube for nutritional support. So currently, in 2022, as Dr. Crawford alluded to, we have 48 states that participate in the newborn screen with two holdouts that I'm sure feel a lot of pressure from the SMA community. And so I just wanted to walk you through, kind of put together what actually happens when a newborn screen comes back positive. And this will vary a little bit state to state and environment to environment. But in Akron, Ohio, what happens is our genetics department is notified of the positive results, and they immediately notify our neuromuscular team. And our neuromuscular team is very wide, but includes physiatry, neurology, and social work are really the core people who are alerted to that positive result. Once we know that a baby has a positive result, that's when the clock starts, right? Time equals neurons. You cannot regenerate anterior horn cells, so once they're gone, they're gone. So there is a deep sense of urgency. The other important thing to note about the newborn screen is that it does not include copy number of SMN2. So when you get a positive newborn screen, you actually really do not know what you're looking at. And that is a source of frustration that I hope someday will be resolved. I feel like it wouldn't be that bad or that difficult to reflux to an SMN2 copy number. So we try to get the patient in within 24 to 48 hours. As you can imagine, these people are overwhelmed. A lot of families had absolutely no idea this was headed their way. Some families do because thankfully, more and more OBs are offering carrier testing to pregnant women. So we do have some families who were aware it was a possibility, but we have quite a number of families who had no idea. And as soon as they come in, we have about a 60 to 90-minute visit. Typically, it includes at least two of our three core team members, neurology, physiatry, and genetics. Sometimes we all three are able to clear our schedules to be available. And we really focus on, first of all, you have to explain. What is SMA? That's a huge thing. And you're really kind of walking families through a genetics class, to be honest with you, because you have to explain the role of the SMN1 gene and the SMN2 gene, and what those protein products do for your body, and what different outcomes you might expect. And then on top of that, you have to give them a crash course in three FDA-approved therapies that work through your genes, right? So it's a very, very complex process as you're trying to counsel families. And then at that test, we send confirmatory testing, including the SMN2 copy number. And we also send that AAV9 antibody screen to see if patients will be a candidate for gene transfer therapy. So it's like sending out the bat signal, right? There's a lot of mobilization that has to happen in a very short period of time in order to really best serve these patients. As Sue also alluded to, we actually have a hospital policy regarding orphan drugs. Because these medications are so overwhelmingly expensive, they literally could bankrupt institutions if they were not reimbursed. So unfortunately, we have to tell you, your child has SMA, here's the therapy options. And by the way, here's our disclaimer. You know, if you choose one of these medications. At the same visit, the family is asked to sign permission for us to seek insurance authorization for therapy. Typically, they will have an idea which therapy they want to select. And in the case of SMN2, that is typically going to be gene transfer therapy. And then we notify all the other relevant parties within our institution, hey, we've got a patient who may need this therapy and be prepared to mobilize quickly. So I want to walk you through a couple of cases. And what I really like about these cases is that they demonstrate the difference between pre-newborn screen and post-newborn screen and one FDA approved therapy and three. So the first patient was born prior to the FDA approval of gene transfer therapy. And also prior to RISDIPLAM. So we did have nusinersen available to us. The newborn screen was not available at the time of this child's birth. So, you know, we were not aware, although the mom knew that she was a carrier. So she recognized at about two months of life that something was wrong. And she notified her pediatrician that she had concerns that her child might be affected. So she came to our clinic at about two and a half months of life. And we agreed she had significant weakness. She had some anti-gravity strength of her upper extremities, but very minimal on her lower extremities. We also were very concerned that she looked like she may have some bulbar involvement. And so we sent confirmatory testing. We did send her home with plans for a pulmonary and pulmonary consult and swallow study the next day. And within a week she was already admitted to our institution with poor feeding and a URI. Her diagnosis was confirmed at three months of life. And we were waiting for approval for Spinraza when she was admitted to our PICU at four months of life with acute on chronic respiratory failure. And because of her fragility, we were able to actually advocate with the company that was working on this gene transfer therapy to allow us to do compassionate use, which is something you can do even when a drug is still in clinical trials. Sometimes they will donate a dose in a dire situation. And so that's what this happened here. And she really responded very well. She did go on to get Trach, Vent, and G-tube. And she took some time to stabilize. But we were actually admitted her to our acute inpatient rehab unit at seven months of life where we were able to give her all three therapies every day and do some further education and training for the family. We then started her on RizdaPlan at two years of life, which was really shortly after RizdaPlan became available. But we had also noticed that she was starting to kind of have a decline in her trajectory. So the CHOP-Intend is a standardized measure that is commonly used in this population to track disease progression. It consists of 60, you have a total potential score of 64 and you grade one side and the other side of the body separately. At three months of life, she had a grade of 22 on both sides. When repeated her CHOP-Intend at four years, CHOP-Intend at four years, she's now on dual therapy. Remember, she was at 40 over 64. And if you look at the natural history data from different groups that have collected long-term data on these patients, they all declined. So this is clearly a deviation from the natural history. Unfortunately, even with all this intervention, she has been admitted to our hospital 14 times in her four years of life. She's had six admissions to our intensive care unit, almost all of them related to respiratory issues. She is now four years of age. She uses a power wheelchair for mobility and she is able to use her arms for functional play. I should also have put in here, she can sit independently but she cannot crawl or walk. She's still G-tube dependent, which is somewhat common in this patient population because when you're an infant and you have a lot of vulvar weakness and you're not allowed to eat, a lot of times patients develop an oral aversion. It can be challenging to transition them to oral feeds. Although she does do some oral feeds and her CHOP-Intend scores remain stable. So case two, this is now post-newborn screen, okay? So this infant, we knew within 48 hours of her existence, we were able to get her SMN2 copy number within a week and we got approval for Zolgensma by the third week of life. She also is on dual therapy. We started her on Rizdiplam at 11 months of age because again, sort of felt like maybe she was not improving as quickly as we would like and her CHOP-Intend at 15 months was near normal. So now she's hitting almost the ceiling of this measure. So this is her. This was supposed to start immediately. Oh, this isn't the right copy of this talk. Oops. This isn't the right copy of this talk. Do you have another copy? Oh. Wing it. Well, because there's videos. Oh, this is really disappointing. Okay. I have these beautiful videos that are worth more than me speaking. Enable content. There you go. Maybe that'll help. Still not. There we go. Can you hit play for me? So this is her at 23 months of life. So this is a child who should never sit, right? I'm Anne Stratton, I'm from University of Colorado, and I'm going to talk about a series of patients that are pretty interesting siblings that have four copies of the SMN2 gene. And then the considerations that that has set up, we follow them in our clinic. So sibling set number one, this sibling set has a four year age gap. So obviously the infant was identified on newborn screen, and then subsequent to that we identified the older sibling that had been born obviously prior to Colorado having newborn screening available. So sibling set number one, GF was the infant identified on newborn screen, diagnosed on day of life four, we were notified about this infant, and then around day of life ten we confirmed that they had zero copies of SMN1 and four copies of SMN2. PF is the toddler sibling identified at four and a half years of age, confirmed again zero copies of SMN1 and four copies of SMN2 about two weeks after the infant sibling diagnosis came. So background on each of these children, the healthy newborn was completely asymptomatic, born at term, vaginal delivery, mother had gestational diabetes but was well controlled, and there were no delivery complications. On day of life ten we brought them in for a CMAP, which we standardly do, and was within a normal range, 5.6 millivolts, and we had a PT assessment done at that time, and the CHOP and TEND score was within normal limits for age, 56 out of 64, and the HINE was also within normal limits for age. So we discussed, we had extensive discussion. Our clinic is set up very similar to the one at Akron Children's, where we'll have the genetic counselor, myself a neurologist, and our care coordinator come in and meet with the family, and it usually is about a two hour visit to talk about the diagnosis, do all the education and everything, and broach the idea that there are these three treatment options. So nusonursin, onosimnogene, apoparvivec, and ristoplam. So we discussed that with the infant, and we said, oh, by the way, your older child may also have this, and would you like us to screen them as well? They said yes, and sure enough, the older child was diagnosed, as I said. History on that child, that child had been born at 37 weeks, so again, term, walked at 18 months of age, no significant past medical history, had had, we'd had records from their four year old well child visit that their ASQ scored within normal limits. In reviewing gross motor skills, parents said, well, they did toe walk at around three years of age, but that self-resolved, and maybe not as fast as the peers, but really family had no concerns. C-MAP was performed, and that was normal at 6.3. Again, on physical exam, did a thorough physical exam, there were no evidence of any trebor fasciculations. The PT performed a revised Hammersmith, and the child scored 61 out of 69 points, which was also within normal limits for age. Just so you have a clear picture, the points that the child got off were for lifting the head and supine, hopping on one leg on each side, and then the quality of how they ascended and descended stairs. So, sibling set number two has a two year age gap, and I don't know how much that played into when we get to the family's decision making, but it's worth pointing out. So, AL is the infant that was identified on newborn screen, diagnosed at day of life six, and then confirmed on day of life 14 to have zero copies of SMN1 and four copies of SMN2. My genetic counselor and our clinic coordinator wanted to point out this is an outlier. There was a long holiday weekend involved that had a little bit of a delay. We're normally much faster. We've gotten even faster since then at the turnover for identifying these infants. And again, same situation. There was an older sibling that clearly had been born before newborn screening was available in our state, and when we broached this subject with the parents, they agreed to have the older sibling tested as well. Also confirmed to have zero copies of SMN1 and four copies of SMN2, again, about two weeks after the sibling was diagnosed. So, AL found healthy newborn, completely asymptomatic, again born at term, vaginal delivery, no complications. CMAP was tested... This a little later, but anyway, day of life 37, but was normal at 5.4 millivolts. PT assessment at that day of life 14, Trapin 10 was 50 out of 64. The HIND was five with the normal limits for age. So same discussion with the parents about the treatment options. The older sibling, the two and a half year old, again, careful review of their symptoms, past medical history and the like, all within normal limits. No concerns about their development either, and their CMAP was also normal at 5.6. Again, on physical exam, no tremor, no fasciculations. PT assessment on the revised Hammersmith was 66 out of 69 points, again, within normal limits for age at two and a half. This child had points off for ability to hop and descending stairs, but at age two and a half you wouldn't expect them to be able to do those things. So again, completely normal. So treatment decisions. So the first sibling set with the four-year age gap, interestingly, ultimately decided on watchful waiting. So the infant, we discussed, they were eligible for nusonursin, onosomnagene, apoprovavec, I've been practicing that one, and risoplam, and preliminary lab work was drawn and they were determined to be eligible without any concerns. This family took some time in making their decision and they initially decided on the gene transfer therapy. And the dosing was scheduled for three months of age, however, they, again, they were thinking a lot about this. Again, they had a four-and-a-half-year-old that they had lived with and loved and cared for for the past four-and-a-half years that they had no idea had this condition. And so I think that maybe that weighed a lot on them. They canceled about a week or so before the dosing was scheduled due to concerns that they had... We had initially discussed that there's this theoretical risk of overexpression of SMN. We didn't have, you know, couldn't give them much more information about, but they decided that that was a big concern for them and that they decided to wait on pursuing treatment. And ultimately, we agreed upon bringing them back to monitor every three to six months in neuromuscular clinic their child's condition. So, to date, the child actually ambulated at 14 months of age. Remember the older sibling ambulated at 18 months of age. So this child ambulated a little younger and thus far seems to be hitting milestones without any signs or symptoms. Most recent CMAP was 6.6, again, within normal limits for age, and the revised Hammersmith at about 15 months of age was 34 out of 69, which is, again, normal. The four-year-old child we discussed was eligible. Remember outside of... You have to be younger than age two to qualify for the gene transfer therapy. So that... So the four-year-old was not eligible for that. So we discussed that Neuson-Nursen and Risterplan were the options available and they ultimately decided that the risk benefit profile for them and their family was not worth treating at this time and, again, decided for that watchful waiting. So every three to six month clinic follow-up and they have been good about that. Thank goodness. Outcome to date on the most recent visit, actually revised Hammersmith done at now five and a half years of age was 68 out of 69, and the child presents as really stable and technically within normal limits, but really this child is more at a four-year-old developmental level. And remember at this age you should be hitting a really sharp increase in your trajectory and your gross motor skills and strength, and this child really is not doing that. So we had some preliminary discussion that this may actually be signs presenting with SMA and the family is taking that into heavy consideration and we're going to have another in-depth discussion of the treatment options and their decision on pursuing them at our follow-up visit, which is coming up pretty soon. For the next sibling set, the infant sibling, again, in theory was eligible for Nusinursen gene transfer and a RISTA plan, and the family decided on the gene transfer therapy for their lifestyle and just their family unit. They were hoping that a one-and-done treatment would work well for them. The preliminary lab work, however, for this infant did show some baseline elevated LFTs and actually the kiddo also had some elevated AV9 titers, and so we could not pursue gene transfer therapy. It was not safe. Because of the four copy, the fact that the child was four copies, the fact that we had a control sibling that did not have symptoms yet, we felt comfortable and the family felt comfortable waiting instead of pursuing one of the other therapy options. So we waited and watched and obtained approximately every two months follow-up labs, and over about a six-month period, the titers did normalize. Thank goodness. We also had an appointment with the liver team in there just to make sure that there wasn't some other congenital liver condition. There was not. The liver function tests also normalized, and the child was cleared to receive gene transfer therapy, which the child received at about seven months of age, fortunately still pre-symptomatic. So we had a PT assessment at the time of treatment. CHOP and TEND, sorry, he's sealing out at 64 out of 64, and the HINE, I think I mistyped that, but anyway, the HINE was age-appropriate as well. Outcome to date, LFTs did bump actually as we were beginning the prednisone taper at about six weeks. Those lab... At about week six, lab values did come back with a bump in LFT, so we reversed our prednisone taper and took them back up to treatment doses, and then instead of spacing out to Q2 weeks of monitoring, we kept it at one week Q1 week monitoring. Fortunately, the LFTs then did normalize. We were ultimately able to resume and complete the prednisone taper. And at 11-month assessment, the child's maxing out on all their scores, pulling to stand and cruising, which is just awesome. The two-and-a-half-year-old sibling, we discussed, again, two-and-a-half, so not eligible for the gene transfer therapy, too old, but we discussed nusinersen and ristoplam, and the family decided that there was no earthly way that they were going to get their two-and-a-half-year-old to take a medication every day by mouth, and so they opted to move forward with nusinersen treatment. So that was initiated at two years, seven months of age, again, still completely pre-symptomatic, and the treatment assessment of the PT assessment showed a revised Hammersmith of 66 out of 69 at the time of treatment, again, age appropriate. So she received all the loading doses and is doing well on maintenance now, and developmental screen at three years of age was actually advanced. She looked more like a four-year-old with gross motor skills. Revised Hammersmith was a 68 out of 69, so really encouraging. So a lot to think about with these cases, and we'll pass it on to Tom again. We have about 10 minutes, so Dr. Trappert is going to briefly share a case of a... Two. Two. Two cases, briefly. Yeah. Yeah. So I'm a PEDS guy, but I also see adults SBA, and so I've had the opportunity to see quite a few now and follow them. I thought it would be poignant to do this because of the PM&R interest, and so I selected two people for whom there's rather substantial PM&R interest. They're the bookends, the severe and the mildest. The mildest one is a young lady. I diagnosed her when she was 10. I followed her for now 16 years. She is able to walk. I have watched her decline in that ability, but she continues to be able to walk, but she has to struggle to get up from the chair, and we started therapy. So she went to school, went to college, and I learned so much from her about how to live with weakness. So she's cute. She's very social. She's interested in the social world, but she also is aware of the fact that having a disease is off-putting. So the number of ways she learned to hide the disease was interesting, because she would not do things because she didn't want to do it. She wouldn't go to a party. She would go to the house ahead of time and see if there were steps. If there were steps, she would decline to go. If there were no steps, she would go, because she knew that if there were steps, people would watch her struggle, and they'd say, what's wrong with you? She's a little bit diminutive of size. She's very cute. Everybody wants to hug her. She's aware that that's danger, so when somebody comes up to hug her, the first thing she does is reach over and grab something, because it's not the hug. It's the release, because she's propped up on those legs. The moment you let go, she's going to go down, because she doesn't have the ability to control for that. So the first thing she does, whenever she's in a party, she'll stand next to the table where she could always lean against something, so when somebody hugs her, she's not going to go. Another guy that I know always used to carry a book, so when he went down, he would open the book and say, I meant to be here. I'm reading Pride and Prejudice or something, in the middle of the street, and said he could wait until this coast was clear, and then he would struggle to get up. It's amazing the world of self-censorship that happens at the mildest end, and I had no insight into that world until this young lady taught me. She's now pregnant. Delighted to say she's a lawyer. She is, like a lot of these people, extraordinarily accomplished in her awareness, and the world is just fantastic. So the other case is exactly the opposite in terms of severity. It's a young lady who was diagnosed with SMA when she was two, one of a rather large family. The mother basically said, you may need a wheelchair, but that's your problem, and kicked her out of the house when she was in school, so she wouldn't be a shut-in. She and her friends would wheelchair her around everywhere, and she tells a story about how her mom would let her do everything, except one time when her friends tried to hoist her in the wheelchair up to the treehouse. She said, you can't do that, but otherwise, she did everything. That led to high school, college. She is a teacher. She became a teacher of the most profoundly behaviorally challenged people in Baltimore, and so she has a locked classroom of eight guys who are there for delinquency. They have attacked teachers before, and she does it by herself with supposedly an alarm bell, but I find out that the alarm bell doesn't work, and how does she do it? First off, she's profoundly weak. Her fingers, she can move her fingers. She's got a voice. That's it, and I say, how do you do that? She says, well, how could they possibly threaten me? It's like, yeah, you kind of have a point, because she's in this big wheelchair, and she's pretty intimidating, even though she can't move anything. She's learned to manipulate the world by the force of her personality. This is not unusual amongst this range. She then came in to see, and she controls the classroom. She never has more than four new ones per year, so she graduates four and takes four on, and the old ones school the new ones in how to behave there and not mess up too bad. She has a feather. She puts a big feather between her fingers, and she can wave the feather. That's all she's got, these two fingers. The guys know, it's all boys, know that when the feather moves, they have to shut up and come back and learn what they're supposed to be doing. She's ruled it that way. She came in to see me, and she said, Dr. Crawford, I'm disabled now. It's like, now? What are you talking about? You must be kidding. She says, well, my fingers don't move. I can't move the feather. If I can't move the feather, I can't control the classroom. If I can't control the classroom, I can't have a job, so I went on disability. It's like, oh my God. For one motor neuron, because that's what it was, it was the difference between a gainful employment and self-respect and having to be on the dole for other people. She's actually found a job now. This is amazing. So whenever I'm asked about what the meaningfulness of a little bit is, I have to say, what is it like to be in that body? Because if you've got just a littlest bit more, it can be everything. And far be it from me to be able to value the meaningfulness of something that is below measurability. So this is my two poignant cases that I want to bring up. We've done that. Okay. Thank you very much. And that last case really resonated with me, and I think as a rehab physician, we appreciate that the littlest of movements can sometimes be so profound and so impactful in terms of the difference between being independent or not, or having a job and not. And so sometimes we lack that measurement tool, whether it's the Chobham 10, the Hammersmith, or any other outcome measure, and it's important for us as rehab physicians, neurologists, to advocate on behalf of our patients, that that little tiny movement can make all of the difference in the world. So I'm going to open it up to questions from the audience, either about the cases or in general the management or the decision-making around these three novel treatments. Okay, so I'll answer from my perspective, but I think we should have Dr. Crawford weigh in on this as well. So at our institution, you know, I think there's no clear answer to that. There's some ongoing trials currently looking at infants who receive Zolgensma and adding an SMN2-enhancing medication, but we don't have a lot of long-term data available. And so for us, it was sort of like, you know, if it might help, it's probably worth trying. In the first case, you know, it wasn't even approved until the child was two. And so when it became approved, then we sort of had a discussion amongst ourselves and with the family as to whether or not we should try to pursue that. And because she is still pretty profoundly weak, we felt like it was definitely worthwhile in that particular case. Then when the second child came along and the first child did seem to have a little bit of a bump, she did seem to do a little bit better, we just decided to try it again. And we're a trial site for the RESPOND study, which is infants that have received the... on a SEMNA gene... I'm going to say that as many times as I can... the gene transfer therapy and then are still weak and would still benefit and they... Nusinersen is the second agent in that trial. So we have two infants now on that. Alright. So here's the interesting thing. I'm an outlier. I'm not super enthusiastic about the second drug. The only place where we have a sort of a head-to-head comparison is on the babies and the outcomes look awfully similar between the three. Is it the case that there is leftover therapy margin to be had or have we saturated the full effect to be condoned with SMN enhancing agents with our first therapy? If we have, then there's going to be no benefit with the second one and all we're doing is adding the potential side effects that is going on with whatever they might be. On the other hand, I don't believe myself ever and so my opinions shouldn't be the determinative factors about whether or not... If a mom is... So by the way, there was one fact that I left out that is... it was on the table and we've been assuming you all know it and I assume that it was obvious, but copy number of the SMN2 is variable. Some people have two, three, or four copies. The two-copy kids are usually the babies that are profoundly impaired and the three and four copies are variably... So if you have a two-copy kid and we treat them early, it looks like they're a lot better, but it seems as though maybe half of them don't fall into the normal range for Baileys when they're two and three years of age and half do, but it looks when I'm doing physiology, they're all doing so with these massive motor units that are the size of old polio victims. So they're probably getting along by virtue of the fact that they have fewer motor neurons, they're doing more work and, you know, there may be post-polio concerns there. Does that mean that we have more to be gained from a second drug? I don't know. So I would love there to be a commitment to the right kind of therapy and to be honest with you, I'm a little bit perturbed at the three companies, because they each are doing what I call marketing kind of studies. This response study is not really a blinded study of yes or no. They're taking the kids where the parents say they don't like what's going on and giving them another drug and if anything good happens thereafter, they say it's the second drug. It's not science. It's just we can do it. It's safe. On the other hand, if I had a kid that was not doing well, wouldn't I want that second drug? You know, you talk about... You know that first slide that talked about disclosures? I would rather talk about conflicts. I'm massively conflicted about this question and I don't know the answer to that one and we need to have the answer. We need to have some... There is the potential for science and I'm not seeing a push on the part of the companies to get it, because they would rather battle it out on the playing field of stories. Excellent point. One final comment about that is, at least in Colorado, when an insurance company approves a drug for a newborn, they are very clear that they will approve one drug and that they want us to reiterate to the family that a second or third drug is not an option in the future. And so that is something that we discuss. I know that we have gone offline now for those live folks. Can we still stay in this room for a few minutes? We have to leave. One final question? You have another... One final question? One final question. Go for it. Thank you very much and I just want to reiterate, this was a great talk. From a prescriptive standpoint in terms of physical therapy, occupational therapy, speech therapy, how would one try to cater a therapy plan in conjunction with the pharmacologic interventions? Because I think that's one thing. Can you maximize benefit by frequency, duration? I just want to get your input on that. Do you want to take it on? No, I'm not doing that. Yes. We definitely prescribe PTOT and speech. Um, for our kids and find it helpful. Um, so are you asking like specifically how many sessions or what? So, you know, for instance, you know, you have CIMT protocols that will intensify therapy. Um, so I'm just curious, is that, you know, an option? And if so, do you all utilize that during your... You have an interesting case. You admitted. Yeah. Yeah. So I'll let you... So, so it's a challenging thing. And I, unfortunately, I feel like rehab is more and more insurance driven. Um, like a lot of our private insurance patients have 20 sessions of PTOT as if PT and OT are the same thing. Right? Um, so unfortunately I feel like our intensity is more ruled by how much can we get. And thankfully in the state of Ohio, we have a supplemental insurance that will add additional benefit that we can draw on. Um, but the infant that we admitted for inpatient rehab really did benefit. And so I do think that increased intensity of therapy can be helpful. Um, the challenge is getting it covered. I think, I think there's a lot of opportunities here. I think that we as a rehab community have a lot of work to do. Um, we don't know the right dose. Um, we don't know the intensity. We don't know the right type of therapy. There are a lot of really smart physical therapists across this country and internationally who are very engaged in this question. Um, there have been some, uh, other folks that have done inpatient intensives, um, outpatient intensives. We don't know at this point, um, again, um, how best to deliver that post, um, novel treatment therapy. Um, and I think it's an imperative that we as a community, uh, really start to answer that question. So stay tuned maybe for next year's, um, uh, symposium and we can add that to our docket because again, uh, so critically important. So I, uh, I'm getting a hand wave... I'm getting a hand wave from the left, um, saying that, uh, we are going to have to end this session. Tom, one final word? Well, just on that point, remember those muscles are like little Schwarzeneggers. They have these massively overcompensated because they're, they're dealing with a massive, a huge load, um, uh, although they're not much power. So the kids with SMA are, uh, extremely amenable, uh, uh, sensitive to disuse atrophy because, uh, you know, use hypertrophy and the flip side of that is rapid decline in the situations of illness or, or, or immobility. So we definitely have that side of things. I want to keep them working. On the other hand, um, how much more can we do? They're already working... they, they work throughout the day. Just the process of living is causing them to have used her, her hypertrophy. And I'm, I'm not joking when I say Schwarzenegger, their muscle fibers are as big as bodybuilders oftentimes. So it's like, interesting, how much am I going to get from that? Some, how much? These are good, good questions. Uh, I also don't want to minimize the effect of playing outside in the dirt. You know, I think kids have to be normal and to me that's, uh, that's really important too. So thank you all for attending. Um, we are, um, happy to, uh, answer any questions afterwards, um, and, uh, enjoy the rest of your meeting.

spinal muscular atrophy

SMA

diagnosis

genetic testing

specialist

treatment options

early intervention

supportive care

treatment plan

insurance coverage

therapy

ongoing research