It's a pleasure to be with you here for part one of a two-part session on advances in neuromuscular medicine. The goal of our sessions is to provide a field update in the latest advances in neuromuscular medicine and neuromuscular rehabilitation, but more importantly, it's also to inspire the next generation of physicians and scientists in neuromuscular medicine and rehabilitation medicine to pursue some of the most important clinical problems out there. The session one today is going to feature a great lineup of speakers, Dr. Lieber will be talking about tendon transfers for spinal cord injury, Dr. Arnold will be talking about gene therapy breakthroughs in neuromuscular medicine, and Dr. Rath will be talking about SMA, a form of motor neuron disease that is quickly becoming an adult disease and she'll explain why that is and without further ado, I'll have them start. Thank you, Dr. Franz. I'm excited to talk to you today about the biomechanical basis of surgical tendon transfer in spinal cord injury. As you probably know, a surgical tendon transfer is the transfer of a distal tendon of a functioning muscle, we refer to it as a motor, on or near the insertion site of a paralyzed muscle. And this is done for peripheral nerve injury, spinal cord injuries, spasticity, contracture, any time where more force or power is needed to move a particular joint in a particular direction or even to restore function that's completely lost. Now the physiological basis for the tendon transfer has to do with the fundamental properties of muscle, which are shown here. On the horizontal axis is the sarcomere length of the muscle, that's the length of these molecular machines that are in muscle, and on the vertical axis is the amount of force generated at the various sarcomere lengths. And you can see in the white curve that in terms of active muscle contraction, that is muscle contraction when the muscle is either being stimulated or voluntarily activated, has an optimal. At sort of moderate lengths, the muscle generates its maximum force, and at longer lengths or shorter lengths, the muscle generates less force than that. Unfortunately, you can't tell that force in the operating room, and all you feel is that blue curve, which is the passive curve. And it turns out, as we've looked at decision making over the years, surgeons make their decision based on that passive curve, even though the functional outcome will be due to the active curve. ...transfers, sort of... ...et cetera, and we found that on average, if you measure the sarcomere length at the time of transfer, so this is now the same kind of curve that I showed you previously, but it's for humans, that red dot represents the average sarcomere length and the vertical dotted lines, the 99% competence interval of the transferred sarcomere length. And you can see here that that sarcomere length is relatively long, resulting in a maximum tension of about 25%. So you may have heard in the literature or in conversations that when you do a tendon transfer, you lose a strength grade. Well, losing the strength grade is probably a result of too long a sarcomere length. And that results from the fact that when muscles are felt, passive tension is not consistent. So here you see that same white curve, and now I just drew three theoretical muscles, one, two, and three. One is a relatively stiff muscle, where if you pulled it to a certain force, it would generate a very high force. Number three is a compliant muscle, where if you pulled it to the same force, it would generate no active force at all. And this is a problem. These data are not very well understood in the surgical literature, so we actually have developed tools to use in the operating room to measure muscle forces. And here you can see a torque motor that's attached to a swing arm that we can use in the operating room attached to a distal tendon to measure the properties of the muscle. Now this happens to be the distal tendon of the brachioradialis muscle, which is often transferred into the flexor pollicis longus to restore a key pinch or create a key pinch. In our case, what we're doing is we're measuring the brachioradialis tension so that we can create a muscle simulator for surgeons to do surgical training. And in this slide, you can now see that we have a surgeon at a meeting. This was a meeting we had with 44 hand surgeons who participated in the trial, where the surgeons who have done this particular procedure are feeling a muscle, which we're creating by this motor. And the tester is telling them to go ahead and test or tension the muscle at the level they think is appropriate. Now just to remind you, the brachioradialis tendon, the distal tendon on the distal radial side of the wrist can be detached and inserted into the flexor pollicis longus tendon to create a key pinch action. So what we did is we told them to go ahead and tension the muscle as they would, and we just gave them a screen that said here, please pull the brachioradialis muscle as you normally would. And they measured the tension. Then we did a complete educational program for the surgeons where we showed them the link tension curve, as I've just showed you, and we had them do this again. And now we gave them the link tension curve so they could see the exact sarcoma length they were going to at the tensioning. And we measured the sarcoma length with visual feedback of the link tension curve and without. And not surprising, as shown in this slide, they got the tension in a better position as shown here. So the red dot, the 23% value, that's the force that the muscle would generate at the position they chose initially. The green dot, the 48% value, that's the force they would generate if they tensioned it at the new length. And you can see here, it's kind of interesting, simply by not pulling the muscle very hard, they get double the amount of force out of the muscle. This is a big deal. And this is why we need objective, physiologically-based surgical training for these doctors who are doing surgical reconstructions and rehabilitation. Now we've also measured other aspects of various transfers, and I wanted to show you two other studies that specifically refer to restoration of elbow extension in tetraplegia. So we have 12 tetraplegic patients who have high neck injuries. And we wanted to understand why, when we were doing this tendon transfer, essentially they ended up weak after a couple of years. We call it an extension lag because the deltoid muscle, the posterior deltoid, which is transferred into the triceps, ends up working as an extensor. But over time, the amount of extension they have goes away. We call it an extension lag. They can only extend their arm maybe 50 degrees instead of the normal 90 degrees. So step one was to ask the question, is the posterior deltoid even a good donor muscle? And so we did quantitative anatomy of the posterior deltoid. And here you can see the picture on the right is the posterior deltoid, the classic delta shape of the deltoid. It's been unwrapped from the shoulder. You can see the innervation zone of the axillary nerve. And then that shaded area in gray is where the posterior deltoid is and where the tendon is sutured to create this tendon transfer. So for the transfer, we then predicted what amount of force the posterior deltoid could create. Now, the green line in this graph is the link tension curve of the posterior deltoid. And the yellow line is the link tension curve of the triceps. And two things are immediately obvious. One is the triceps muscle group is huge and strong. So for the posterior deltoid to restore the function of the triceps, it's going to have to be operating at its pretty much optimal force. But the other thing that's pretty interesting, again, from a physiological point of view, is that the green line is actually pretty broad. So why is it that a muscle, the posterior deltoid, with such a broad link tension curve would end up with an extension lag? That's what we didn't know. So we did a bunch of things. Step one was we really refined our intraoperative procedures. So here you can see in these three panels, three different steps, three different very important steps of the transfer. In the upper left, we've taken a tibialis anterior tendon out of the leg. We've sutured it to the distal aspect of the posterior deltoid with an interrupted suture back and forth above and below the anastomosis site to give the tendon the maximum grip on the posterior deltoid muscle. In the upper right, you can see we're testing that grip. And then in the lower panel, you can see that distal tibialis anterior tendon has been sutured into the triceps tendon to restore extension. Now we also did a clever thing. It wasn't my idea. It was my colleague, Jan Frieden. Jan inserted small stainless steel sutures at all those regions I just showed you. So you can see stainless steel sutures one and two are at the proximal deltoid. Between two and three are the graft itself. And between three and four are the distal triceps insertion site. And by having these suture sites, we can figure out the integrity, if you will, of the various portions of the tendon transfer. And so we measured the distance of the proximal deltoid, the tendon graft, and the distal triceps at four weeks, three months, and six months. And now we've got even two-year follow-up data. And I'll just tell you, the two-year follow-up data are close to the six-month data. But here's what you can see. When you look at the amount of elongation of the overall muscle tendon unit six weeks after surgery, you can see it elongated about 15 millimeters. And six months after surgery, it elongated 23 millimeters. And in the deltoid world, that's quite a long distance. We knew that that elongation was going to allow shortening of the deltoid and therefore weakening of the deltoid. So in good rehabilitation fashion, we changed our rehabilitation strategy. We immobilized the elbow in about 10 degrees of flexion, and we put orthoses in with the patient's wheelchair four weeks and eight weeks after surgery, and only allowed them to flex their elbow 10 degrees every two weeks. And that orthosis looks like this. You can see that by having that protective arm rest, the shoulder is prevented from AD ejecting, and the elbow is prevented from flexing. Both of these had significant impact on the muscle tendon unit, as shown in this slide. So now the yellow data are the data I just showed you without the arm rest or the orthosis. The blue data are with the arm rest, and the key finding is shown in the right-hand side of the graph at six months. You can see that blue bar shows that there's essentially no elongation of the muscle tendon unit if you use that arm rest, which is pretty cool. What it means is the muscle is not allowed to shorten, and therefore it generates more force over the entire range of motion. And when we break down the location of that elongation, we see what's shown in the next slide, and that's the story. And the story is for surgeons that without the arm rest, as shown in the bottom bar graph, the proximal anastomosis elongates tremendously. In other words, the tendon is essentially slipping off of the deltoid over time as it's used. The middle and distal areas are much smaller, but with the arm rest, the majority of that slippage is deleted. So now the standard protection for the posterior deltoid to triceps transfer includes this orthosis, which is part of the wheelchair. Now getting back to the physiology of the situation, what's going on? Well, as shown here in this slide, this is that same link tension curve. It turns out that as that muscle is allowed to shorten, again, 23 millimeters down the ascending limb of the link tension curve, it gets much weaker. And when it gets much weaker, it finally just doesn't generate enough force to extend the elbow, which is pretty interesting. Now we also, to make sure this explanation worked, we actually did mathematical modeling. So in the horizontal axis, we have elbow joint angle, and this is work that we did in New Zealand with Alistair Rothwell. In the vertical axis, we have elbow extension torque, and you can see normally as you flex the elbow, torque increases slightly. That's the measured torque values in 23 to 31 patients. That's a huge number of patients from Sweden and from New Zealand measured over time. The white line is the predicted value based on the mathematical model I just showed you. And if we alter that model and try to ask our question, okay, now that we understand the biomechanics of this system, what if we simply allow the muscle to shorten 23 millimeters? We have what's shown here. The yellow dots are the model that I just showed you. The blue dots are what happens if that transfer slips 23 millimeters. And isn't it interesting that the elbow extension leg now shows up? The blue dots on the lower left-hand portion of the graph show you two things. One is there's almost no deltoid force produced when the elbow is at a very short length. And secondly, the slippage results in an overall significant drop in deltoid force. What these data tell you is that a tendon transfer is not simply a tendon transfer. You can't just grab a distal tendon, suture it into the appropriate site, and expect the site to work. You have to understand the physiology and anatomy of that particular tendon. You have to have some kind of knowledge of the appropriate length for that tendon. And you also have to perform, I would say, vigilant rehabilitation to allow that tendon to heal prior to excessive use. In the next two videos, I'm just showing you an example. This is a gentleman who has not had a tendon transfer. He has a high cervical injury. And you can see he's trying, but he can't extend his elbow. And that's not surprising, because the triceps are no longer innervated. Whoops. Oh, sorry. This is the other side of the same gentleman. You can see it's really easy for him to extend his elbow. That's a great amount of elbow extension. He can swim with that arm. He can reach up above gravity. He can grab things off a shelf. And what's really exciting is, when these procedures are performed bilaterally, here's a bilateral high cervical injury patient who's going up a ramp with bilateral posterior tendon transfers, posterior deltoid to triceps tendon transfers. And you can see he could go up that ramp with not too much effort. So to summarize, surgical tendon transfers provide an inexpensive, I put it in quotes, and dramatic approach to restore function in spinal cord injury. I say inexpensive because, of course, surgery is expensive. But when you do a tendon transfer appropriately, you save nursing care, you save rehabilitation care. Of course, as we show with the gentleman, if you can run a manual wheelchair instead of a power wheelchair, you have greater access to the community, transportation, et cetera. So you save money in the long run with these surgical tendon transfers when they're performed appropriately. An understanding of the muscle basic science principles that I showed you, specifically at the link tension curves, can be exploited to optimize surgery or provide innovative alternatives. My partner and I, Dr. Preetend, have developed other tendon transfers that aren't typically used. Once you understand the biomechanics of the transfer and the physiology of the muscle, you can get pretty creative in restoring function. And physiatrists really need to team with experienced and humble surgeons to bring this out to our patients. I say humble because surgeons often are trained a certain way and they don't want to change things. So what we've done is we had whole tendon transfer educational courses to show them the appropriate way to do these transfers. And then the more they do them and the more successful they are, you can see the incredible amount of function regained by these patients, the more likely they are to do them and want to do them in partnership with physiatrists. So thank you very much for your attention. I do acknowledge the tremendous amount of funding we get from the United States National Institutes of Health and the Department of Veterans Affairs Rehabilitation Research and Development Service. Have a great day. Hi, everyone. My name is Dr. Nassim Rad and I'm an assistant professor at the University of Washington. And today I'm going to be providing an update on the rehabilitation management of adults with spinal muscular atrophy, which has become an ever more important topic in the era of gene therapy. I have no relevant financial disclosures to make. In today's lecture, I hope to review the clinical phenotypes and pathophysiology of spinal muscular atrophy, understand how SMA expands beyond just the motor neuron, and finally end with standard of care guidelines for rehab management of those with spinal muscular atrophy. So spinal muscular atrophy results from the degradation of alpha motor neurons in the spinal cord, which leads to progressive muscle atrophy and weakness. The most common form of SMA, which I'll be discussing in this presentation, is due to a defect in the survival motor neuron 1 gene, which is localized to chromosome 5 and accounts for about 95% of all SMA diagnoses. Its incidence is 1 in 11,000 births. Now there are two SMN genes that exist. SMN1 gene is a telomeric copy and SMN2 is a centromeric copy. The SMN1 gene is transcribed into a full mRNA transcript that, when translated, produces a normal functional SMN protein. The SMN2 gene is nearly identical to the SMN1 gene with the exception of a C to T substitution at position 840. What this results in is an mRNA transcript that excludes exon 7 and results in a truncated nonfunctional SMN protein that's rapidly degraded. Now, fortunately, exon 7 is not always excluded. So about 10 to 15% of the time, exon 7 is included, and this means that about 10 to 15% of the time, functional SMN protein is produced through the SMN2 gene. In 1991, there was an international consortium on SMA, and they classified three types of SMA based on age of onset of symptoms and the maximum motor function achieved. This was later expanded to include type 0 and type 4. So type 0 is a prenatal onset with a death that occurs within weeks. Type 1 is an onset that occurs between 0 and 6 months. These patients are unable to sit, unsupported. Type 2 patients develop symptoms prior to the age of 18 months. These patients are nonambulatory, but they are able to sit independently. Type 3 patients develop symptoms after the age of 18 months, and they do achieve ambulation. Type 4 is considered adult onset. So these patients develop symptoms typically greater than age 30. Now, we now know that there is a significant correlation between SMN2 copy numbers and clinical phenotype, which makes sense if we go back to the previous slide, because if you have higher copy numbers of SMN2, you would therefore make more functional SMN protein and therefore have a less severe phenotype. Now, we know this isn't perfect because there are patients out there who have higher copy numbers of SMN2 and more severe phenotypes and vice versa. So there must be other genetic modifiers at play. But typically, type 0 patients would have one copy of SMN2, type 1, two copies, type 2, three copies, type 3, three to four copies, and then type 4, four to six copies. So SMA results from a deficiency of the SMN protein. The SMN protein is found within the nucleus and cytoplasm as part of the SMN complex. And we know that the SMN complex plays a role in RNA splicing in all cells, which has made us question, well, if it's in all cells, why is it that SMA is classified as a motor neuron disease? Well, we do know that expressions of SMN are highest in the motor neurons. And it's been postulated that the SMN complex that plays a role in all RNA splicing may in effect, may therefore have an effect on the development of healthy motor neurons. So while motor neurons remain the primary pathological target, I just want to take a moment to recognize that beyond the motor neuron and the skeletal muscle atrophy that then develops, the most severe forms of SMA type 1 have seen autonomic nervous system involvement, heart, liver, pancreas, intestine, and metabolic dysfunction. The schematic on the right on the top portion is very similar to what we previously discussed on the bottom, just reinforces the fact that the loss of SMA protein affects the motor neuron, inhibitory and excitatory synapses, as well as the neuromuscular junction itself. The natural history of SMA is becoming more and more important, especially in the setting of gene therapy, when we have to take into consideration clinical trials that need to monitor for improvement that would occur or improvement that would be better than compared to natural history or prognosis. So in 1997, about 500 SMA patients with type 1 and type 2 muscular atrophy, as well as type 3, were analyzed. And in the top portion of this chart from that study, we look at survival probability in SMA type 1 and type 2. So if you can look at the chart, you'll see that 32 patients that were alive with type 1 SMA at age 2, by the age of 20, unfortunately, none of those patients were alive. Of the 100 patients with type 2 alive at age 2, 77 remain alive at age 20. For type 3 SMAs, who we predict have a more normal lifespan but a high morbidity, we are looking at probability of being ambulatory. And in this study, they divided type 2 between, I mean, I'm sorry, type 3 to type 3A and type 3B, the difference being onset of symptoms before or after three years of age. And so we can see that ambulation is lost as we reach adulthood. And certainly, by the age of 40, a significant number of these patients have lost their ability to ambulate. So this segues nicely into talking about aging in SMA, which is important to recognize what happens to motor units, normal motor units without spinal muscular atrophy. So the normal aging motor units, hallmarks of aging are motor neuron loss, neuromuscular junction instability, and repeating cycles of de-innervation and re-innervation. So if you take a look at this schematic from the Journal of Physiology, at the top, we have a younger motor unit. So we see the motor neuron itself, and then we see the muscle fibers it innervates. And then the next schematic is an older motor unit. And so the hyphenated lines show the de-innervation that's happening and then with collateral sprouting on the, what I'll say, blue motor neurons, as I don't have an indicator here, but it's a blue motor neuron. I don't have an indicator here to point onto the slide. There's collateral sprouting, and it changes those muscle fibers towards the same muscle fibers that were previously innervated by that motor neuron. So you have group muscle fiber typing. And then in the very old motor neuron, motor units, you see the fact that that complete motor neuron has died off. So in addition, you have muscle fiber atrophy. Now, a similar process is ongoing in SMA patients at the onset of disease. And so it's important for us to recognize that in patients that are aging with SMA, they're going to have concomitant aging motor neurons to deal with. So what do advances in gene therapy and treatment mean for patients with SMA? And so in this particular talk, we're not going to go over the actual treatments, but the treatments are focused at improving SMA protein production. And what this means is that SMA types 1 and 2 that were not predicted to live into adulthood now will have increased survival into adulthood. We also predict that these more severe phenotypes will mimic more milder phenotypes. The reason being is that, unfortunately, these treatments do not aim at reversing nerve loss. And so there still will be some motor neuron loss that the patients have started out with. Ultimately, these in combination means that there'll be more management of chronic disease, and that means that we need to have a more proactive approach to management. So this schematic was taken from the Standard of Care 2018 consensus. And I think it nicely illustrates the need for multidisciplinary approach for treatment. So we have the SMA patient at the center of this schematic, surrounded by their family who play an important part of giving caregiver support. And as you can see, their care is needed from multiple sides. Their care is needed from multiple specialists, from the neuromuscular neurology and rehab physicians to orthopedics, nutrition, endocrine, including bone health, pulmonary support, medication management, and ongoing acute care needs. Now, in adults that age with spinal muscular atrophy type 2 and type 3, it's now becoming more evident that these patients have plateau periods where their yearly functional change is minimal. And when we do see functional loss, this is primarily occurring because they've had an increase in joint contractures, sudden scoliosis deterioration, and excessive weight gain. So our job as their physicians is to make sure that we are proactive about reducing these complications so that patients can enjoy a maximum level. On monitoring and managing weakness, contractions, respiratory dysfunction, and scoliosis. Assessing function in SMA is important because in patients who've had chronic disease for long periods of time, the traditional neurological exam and manual muscle strength testing is not as useful for picking up progressive loss of function. We know that our current rating scales are not as sensitive for those patients that are on the extremes of clinical spectrum. So for those that are very low functioning or very high functioning. But some of the ones that we wanna be familiar with, especially in the era of gene therapy, where again, we're seeing clinical trials that need to be able to have accurate rating scales to monitor for improvement. Is the Hammersmith functional motor scale expanded? Functional motor scale expanded. This is primarily useful in SMA type two and type threes, who have more preserved function. The revised upper limb module, which is great to use in patients who no longer have movement in the lower extremity, it consists of about 20 entry items that evaluates what patients are capable with, with their upper extremities. The motor function measure test has a variety of forms most commonly used in SMA and in recent clinical trials is the MFM 32, which looks at function in three domains. So standing, transfers, proximal, and distal muscle. We don't wanna forget about the utility of mobility time test. So in those ambulatory patients, a six minute walk test can be useful in determining their function, assessing their improvement in function. So important interventions for maintaining independence and monitoring for contractures are orthoses for the upper and lower limbs. Educating patients and their caregivers on regular stretching for at-wrist joints, including the hip, knee, ankle, wrist, and hands. For those that can continue to ambulate, supporting that ambulation with knee, ankle, foot orthoses, AFOs, or RGOs, consideration of wheelchairs, so lightweight manual wheelchairs, or power assist wheelchairs in stronger patients. And then power wheelchairs for those that are losing their ability to ambulate. An important attention needs to be paid to their custom postural support and seating systems that should include tilt and recline. Now, the standard of care that I mentioned before, so a consensus on treatment was first developed in 2007 and most recently updated in 2018. The consensus paper has recommendations for everything from orthopedic involvement to nutrition and pulmonary. But I wanted to spend a little bit more time in this talk not focusing on everything but on exercise, as more patients are on gene therapy. Many patients have asked, can exercise, one, how should they be exercising? And two, can exercise reinforce any improvement that they've made while on gene therapy? So for all patients with SMA type 2 and type 3, so regardless of whether they're on treatment or not, the recommendations for exercise for type 2 include swimming, horseback therapy, wheelchair sports, stretching, and range of motion is recommended at a minimum of five to seven times a week. And then supported standing up to 60 minutes with a minimum frequency of three to five times a week, optimally five to seven times a week. And so this does require significant dedication from caregivers. For SMA type 3s, aerobic activity for 30 minutes with a variety of different activities. The stretching frequency is less than in type 2, because we would predict that these patients would be less at risk for developing contractures. Using active assisted stretching and orthoses and lower limb orthoses for posturing. In general, we counsel patients with spinal muscular atrophy to avoid resistive exercises and muscles with less than anti-gravity strength. To avoid overuse and fatigue that develops 24 hours a day, fatigue that develops 24 to 48 hours after exercise. And to pay attention to which exercises are painful. Now to answer patient's questions on whether or not exercise in combination with the gene therapy or without gene therapy will resolve an improvement in strength, we unfortunately don't have many great paper randomized control trials on exercise in spinal muscular atrophy. So we're gonna take a look at the ones that we do have in regards to strength. So in 2014, 12 participants with SMA type 3 were randomized to using hand ergometry and a strengthening program. Unfortunately, no improvement in function or strength was identified with only modest improvements in aerobic capacity. They did note though that the peak oxygen uptake was lower in SMA patients compared to other neuromuscular disorders. In 2015, nine children with SMA type 2 and type 3 completed resistive based training three times a week. This was determined to be safe and well tolerated, but limited improvement in strength and motor function was recorded. Though of note, they did have some significant results with one particular patient who was not able to climb stairs at the beginning of the study and was able to do so independently at the end of the study. In regards to survival, prolonging survival, we don't have any human trials on exercise and survival. But we can look at mice models. And so in 2005, exercise training was evaluated in about 45 SMA-like two mice that were subjected to exercise which consisted of forced running on a wheel. They showed sustained motor function and increased lifespan by 57.3%, which in mice age was equivalent to eight days. At 10 days, they had 14.8% loss of neurons in their ventral horn of the spinal cord, so they did count those cells. And at 13 days, they had 35.1% loss, but that was only compared to 19.6% in the exercise group. So significant improvement. And a 34-time increase in Exxon 7 containing SMN transcripts in the spinal cord. In 2016, so more recently, SMA-like type 3 mice were subjected to running or swimming for 10 months, and significant benefits were seen to resistance to muscle damage, metabolism, muscle fatigue, and motor behavior. Interestingly, in this paper, the benefits were different depending on whether the mice was in the running or swimming protocol. So I wanna conclude with, we've made a lot of recommendations to our patients about what we think is most important to prolonging their life. But it's also important to pay attention to what's most important to our patients. A recent study on quality of life in SMA did a fantastic job of interviewing 15 SMA adult patients from the ages of 18 to 59 with extensive phone interviews. They got over 1,000 quotes describing how they feel about different aspects of their care. Everything was ended up breaking down into four categories, physical health, mental health, social health, and then other areas of spinal muscular atrophy. And as you can see, there is a plethora of things that are considered important to these patients and make up the burden that the spinal muscular atrophy patients carry. So I hope that today we've learned a little bit about the most common form of SMA resulting from the homozygous deletion and mutation of the SMN1 gene, leading to progressive motor neuron loss. That we remember clinical severity can be correlated to the SMN2 copy number, but it's not perfect. Right now, pharmacological treatments for adults aim at increasing SMN2 expression. So we cannot reverse the nerve damage that's already occurred. And we need a multidisciplinary approach to address these long-term complications of our aging SMA population. And more data is needed on specific exercise regimens in this population. So I wanna thank you guys for your attention today. Hello, my name is David Arnold. I'm one of the nerve and muscle disease specialists at the Ohio State University. I have the great privilege to be able to build off the talk that was just given by Dr. Rad. And I'm gonna be able to talk about genetic-based therapy development in the field of neuromuscular medicine and I'm going to particularly focus on spinal muscular atrophy. So before I begin, I do have a few disclosures in regards to funding as well as previous work as a consultant for some companies that are in this space. So we just heard about the strategies for diagnosis and treatment of spinal muscular patients and so what I'm going to focus on is the development of genetic-based therapies and as these therapies have been developed, we're going to learn about maybe new challenges and unmet needs in this space that these therapies are dramatically effective and I'll show you some of that data but they also raise new challenges that I think as physiatrists we are really optimally trained to kind of fill these gaps and so I kind of hope to set the stage and kind of pose some potential challenges for our field in this regard. So we already learned about the genetic basis but what I find truly remarkable and incredibly exciting is that this gene, so SMA is related to homozygous deletion or loss of the SMN1 gene. There's a second gene that also produces the protein that is produced by the SMN1 gene that's SMN2 and really if you boil it down to the most simple fact is SMA or spinal muscular atrophy is caused by low levels of SMN protein or survival motor neuron protein. These levels are insufficient for normal motor neuron function and with low levels of SMN, you have motor neuron dysfunction, degeneration, and loss leading to muscle atrophy and muscle dysfunction which has a whole host of complications related to motor dysfunction. Fortunately, we have now three therapies that have been FDA approved for use in patients with SMA and what I'm going to do is kind of go through these and present some of the data that has been demonstrated in patients with spinal muscular atrophy. So the first therapy that was approved is nusinersen. So this is an antisense-based oligonucleotide therapy. It's an intrathecal delivered intervention. So it does require repeated injections in patients. The second one that was subsequently approved is basically a gene therapy. So this is an adeno associated viral delivery to replace the SMN gene and the third approved just as of 2020 is risdoplam which is a small molecule-based therapy that is an oral delivered treatment. So there's really two main strategies that these three different interventions that are now FDA approved leverage to basically restore SMN protein levels and so nusinersen and risdoplam are very similar in the way in essence how they increase SMN protein. So in the healthy state, most people have two SMN genes. So the SMN1 gene and the SMN2 gene. So the SMN1 gene is a gene that produces close to 100% of full-length normal SMN protein whereas the SMN2 gene is I like to call it the wimpy backup SMN gene only produces about 10% of full-length normal SMN protein. So nusinersen and risdoplam in essence are trying to get more SMN protein from this wimpy backup SMN2. So they do that by changing splicing and to basically produce full-length protein from that gene. In contrast, the gene therapy-based treatment is really replacing that's a little bit of an oversimplification but replacing the SMN1 gene. So the adeno-associated viral vector is delivering the cDNA of the SMN gene and that cDNA produces full-length SMN protein. So kind of in a way replacing the missing SMN1 gene. So before I go through the details of the data from the trials from each of these therapies, I'm really just going to have time to just give you a highlight of each. But before I do that, I want to step back in time just a little bit to highlight some work, some of which was performed by a PI at our center, Dr. Stephen Kolb. So this was a multi-site trial that was designed really to mimic the anticipated interventional trials that would come along. So this wasn't an intervention trial but it was trying to mimic that condition. So I want you to focus on the panel on the left. So the CHOP-N10 is a motor scale that's commonly used in infants with spinal muscular atrophy. So these infants came in, were enrolled at diagnosis of spinal muscular atrophy. The majority of those infants were diagnosed based on clinical symptoms. We had a few that were diagnosed earlier based on pre-symptomatic treatment, but most were symptomatic. And what this graph highlights is even at enrollment, you have this dramatic loss of motor function. So you know, there's already a big separation. And the infants actually by three months of age are already maximized on the CHOP-N10. So they went to another motor scale where you see the progressive decline of function, although kind of gradual. So it's dramatic loss at baseline. So I want to direct your attention to the panel on the right, which is basically highlighting compound muscle action potential. So this is basically a motor nerve conduction study looking at amplitude. So EMGers out there will be familiar with this, but this is a measure of just kind of neuromuscular function. An average CMAP from the ulnar innervated hand muscle, the adductor digiti minimi, at diagnosis is 0.5 millivolts in SMA. Chronically, the average CMAP value is 0.3 millivolts. So really, really low. Where this is, this graph is highlighting five pre-symptomatically diagnosed patients with SMA, showing that early actually the CMAP is above normal, which you would expect for an infant. So two millivolts or higher would be considered normal in an infant. And so these infants show normal CMAP, but then this dramatic decline. So that green window that I've highlighted is suggesting or questioning whether there's this pre-symptomatic window of opportunity. And so these are data piecing together that we really need to diagnose early and deliver the treatments early. And I'm going to show you data that further supports this concept and highlight some needs for implementing these therapies very early. So the first therapy I'm going to talk about is the first that was approved. So in late 2016, late December, nusinersen was approved for all types of SMA, intrathecal delivered antisense-based strategy. And so I want to direct your attention to the left panel. And this is basically looking at a Kaplan-Meier curve. So the probability of an event-free survival, which basically means not needing permanent ventilatory assistance. And so you see a dramatic separation there. So normally without any intervention, the natural history is death by age of two in spinal muscular atrophy type 1, which is what these infants were. And so very effective. I would also like to highlight that 8% of these infants achieved independent sitting. As we heard from the last talk, independent sitting should never be achieved by type 1 SMA. So this was a very exciting finding, published in 2017 in New England Journal of Medicine, and one of the major pieces of data that led to the approval of this treatment. Another study that was done, started a little bit later, and the results are more recent, so published in 2019, is where they took infants in this earlier window, as I suggested or pointed out earlier, is they treated before the symptoms were as overt. So they had to have a CMAP amplitude of one millivolt or higher, and a certain level of motor function, and also very young age. And what they show, and you can see this, so the chop in 10 graph on the right panel there, they are hovering right around 60, and 64 is the max. And so that's dramatically improved compared to the natural history that I pointed out earlier. Also, you can see that the CMAP amplitudes between two copies and three copies of SMN2, which modulates phenotypic severity, you can see that those, the two copy patients, their CMAP is roughly 10 times what it normally is based on natural history data that's available. Moving on to gene replacement therapy, so adeno-associated viral vectors to deliver the SMNcDNA. So this was a study that I had the privilege to be involved in directly, so I got to see these infants every three months. And I would like you to focus first on the panel on the left, and so these infants are stratified by age at time of enrollment and treatment. And this also highlights dramatically that the earlier the treatment occurs, the more dramatically effective the intervention. And you would see that there's a dotted line on this graph at 40, and so what that is indicating is, based on several natural history studies, we never expect a patient with type 1 SMA to achieve a CHOP-10 score of 40 or greater. And you can see the majority, all but one, that was actually, that infant was treated much later, closer to eight months, achieved greater than 40 on the CHOP-10, and some even maximized that score, so dramatically effective. A subsequent analysis that compared the natural history study that I mentioned earlier performed, led by our site, comparing to this cohort, you can see dramatic separation of CHOP-10 between those cohorts. The last therapy that I want to talk about is Ristaplan. So this is a small molecule therapy that's orally delivered once a day, different doses based on age and weight. This is unpublished data. It's available online, but it's not in publication format yet, as far as I know, at the time of this recording. So the FireFish study studied type 1 SMA patients, and those infants should not be expected to achieve sitting unless there's a treatment intervention. And you can see that 41% of these infants achieved sitting without support, so dramatically effective. And survival equal or greater than 15 months without ventilation was seen in the vast majority of those infants. And so very, very exciting developments in these three spaces. And so it's tempting to compare across the different treatments, but I think the key points that I want to point out are the impact is dramatically affected by the number of copies of SMN2, which some of these studies varied between, and the age at intervention has a major impact. And so you really have to be careful to compare between the three. And so deciding which treatment is the best for each individual is still a little bit unclear. So some things to point out is gene therapy in the U.S. is only approved up to the age of two. So after the age of two, that's not an option. There's some ongoing studies looking at CSF-based interventions that would allow treatment at later ages, theoretically, which may expand that population that could receive gene therapy. Rizoplam is approved after the age of two months or older. And then, as I mentioned, Nuslinersen is approved for all types, all ages. And so early on, the possibility of delivering gene therapy is exciting because you have a one-time injection in theory. And if you miss that window, then they don't receive that therapy. So a lot of people currently are kind of putting gene therapy kind of first in line when it comes to infants that are diagnosed early at younger ages. But there are things that have to be considered when you consider different possibilities. And of course, at later ages, the Nuslinersen and the small molecule-based therapy Rizoplam are the only options that are available. So when Nuslinersen was first approved in late 2016, the bulk of the research that was available was actually in infants and children. Really, the oldest participant was age 15. So we didn't know a whole lot about the effects in adults, even though it was approved for all ages and all types. So we basically started an open-label study to learn more about what happens with SMN restoration in older patients, so ambulatory and non-ambulatory adults with SMA. And we did a whole battery of outcome measures. And I'm going to show you just a really high level of some of those responses. You know, this is an intrathecal-based injection. So a lot of these individuals have spinal fusions and difficult intrathecal access. And so it wasn't a very easy study to get off the ground. But we developed a multidisciplinary clinic to kind of address all these issues of getting, you know, insurance approval, having the expert to do the specific injections, and doing the battery of outcomes that we were interested in. And so very challenging process that really took a whole village to get this off the ground. So some of the high-level effects that we've seen. So this study is now closed. The data is locked. And we have actually it's in review currently. The high-level thing from a physiological standpoint, which I found most fascinating and we were most curious about, was when you restore SMN at a late age, you see increases in compound muscle action potential, which is like a neuromuscular functional readout. And then we also saw enlargement of motor units. So that could suggest potentially improved collateral sprouting, improved connectivity at neuromuscular junction. And so this was consistent across all types of SMA. So we had more severe to less severe affected, really stratified by ambulatory status. And really on the other functional outcomes that we measured, we saw more consistent improvements in the more mildly affected individuals. But the electrophysiological evidence of increased collateral sprouting in large CMAP and large motor unit potential size was consistent across all cohorts. Another thing that we're trying to develop is better biomarkers. These patients with SMA really don't like the shocks of nerve conduction studies and other assessments. And so we're trying to develop some surface recording strategies for electromyography readouts to assess the health of the motor unit pool. One thing that has fallen out of this data is actually very interesting is if you look at the sizes of the motor units, these are all chronically treated patients, so at least 10 months of nusinersen. You can see that the non-ambulatory patients, the more severely affected patients, have smaller motor units compared to controls. And interestingly, the opposite is true for ambulatory. So there's kind of this bimodal response to the motor units. So SMA may actually be associated with defects of collateral sprouting as well, which may be a target for future therapeutic development. Some additional findings. We had patients that were treated with cervical injections as well as lumbar. And some of the readouts and some of the outcome measures actually tracked with which route of injection was delivered. I don't have time to go into detail for that, but like for instance, upper limb function as measured by the revised upper limb module showed more effect with cervical delivery. So it suggests maybe the SMN levels are getting higher in the cervical myotomes as compared to the lumbar myotomes. That deserves further research, but I think it's something we have to keep in mind when we're thinking about delivering distribution of these therapies. We have also found that even with therapy, there's a dramatic neuromuscular junction transmission defect, which may be a target for some additive therapies to improve that transmission at the junction to improve the signaling to the muscle. And so this may be a target that can be further developed for future therapeutics. So I focused on spinal muscular atrophy, but there are a lot of other areas where this is being developed. One of my main areas of interest is myotype dystrophy. Antisense oligonucleotides have been studied in myotype dystrophy type 1. The issues were is the antisense molecules did not get to the target, so there was problems with distribution, and so those are trying to be worked out by several different groups across the world. There are approved antisense-based therapies, in particular for hereditary amyloidosis, to break down basically our target, the messenger RNA, and so these are approved and also for the dystrophinopathy, just DMD. So some take-home lessons that I just want to highlight is really exciting advances in the field of spinal muscular atrophy, and I think these will spill over into other areas of neuromuscular and other genetic-based diseases. I think I emphasized the point that early diagnosis and treatment is going to be really critical. So newborn screening is getting implemented now. It's in over 30 states currently, and so as that gets ramped up, we're going to see earlier interventions, and it's going to be exciting to see how much more effect we have with these therapies. With these therapies, you can see from the data that it does dramatically improve phenotype, but there's still residual deficits, and so these patients with improved survival are going to have new challenges from a physical function standpoint, and so I think that's where our specialty and our expertise will really need to be leveraged to optimize function and prevent long-term complications, and I think it's possible that the motor units that are partially rescued may be more dramatically affected by aging, and so addressing those issues and monitoring these patients is going to be really, really critical. We still want better therapies that can treat and have better impact when they're delivered later in the course of disease, but until then, we have to use all the tools available to optimize function. We do need better biomarkers, and I think that's an area that will continue to explode, so we can kind of validate biomarkers better now that we have an intervention that changes phenotype. So I really thank you for your attention. There's my email. Please don't hesitate to shoot me a message or ask me a question if you have something. That was a very high-level review. There's a lot more published data out there on all these things. This field is really exploding in regards to the data that's available, but thank you for your attention.

neuromuscular medicine

spinal muscular atrophy

nusinersen

gene therapy

rizdeplam

survival motor neuron protein

clinical trials

early diagnosis and treatment

physiatrists