← RealTalk MS
RealTalk MS
Episode 463: A Novel Approach to Treating MS-Related Depression with Dr. Robert Motl and Kelly
00:37:06
Loading summary
Transcript34 lines
- [00:01]
A
I'm john strum and this is real talk, mississippi. It's July 14th and we have a lot to talk about. Depression stops people from engaging in life. It can stop them from showing up at work, meeting up with their friends, even staying connected to their family. One out of every two people living with Ms. Will experience depression at some point in their Ms. Journey. But there may be an effective treatment that doesn't require another infusion, another injection, or even another pill. Welcome to Real Talk Ms. This week I'll be joined by Dr. Robert Mottl, the principal investigator in a study that's taking a novel approach to managing Ms. Related depression. And Kelly, who lives with progressive ms, participated in this study and realized her depression had vastly improved. But before we get to my conversation with Dr. Mottle and Kelly, there are a few other things that you should know about. Last April, the Ms. Community was excited to see Fernando Mendoza taken as a number one pick in the NFL draft. Fernando's mother Elsa lives with Ms. And it was everyone's hope that Fernando would raise awareness of Ms. As he had been doing all throughout his college career. Well, that's how it started. Let me tell you how it's going. Last Thursday, Fernando and his family donated $500,000 to the university of Miami Miller School of Medicine to support Ms. Research through the Mendoza Family Fund. This half million dollar donation will be used to help launch a first of its kind Ms. Stem cell transplantation trial this fall at the Miller School's Ms. Center of Excellence. Training camp hasn't even opened and Fernando Mendoza is already walking his talk demonstrating that he's a lot more than your average rookie. We'll look forward to hearing more from him as his NFL career kicks into gear. The good news is we have over 2020 FDA approved disease modifying therapies to treat Ms. But the not so great news is they all have the same limitations. You have to take these drugs for life, or at least most of your life. They offer incomplete protection against disability progression, and they struggle to hit the chronic inflammation deep inside the central nervous system. That's why the California Institute for Regenerative Medicine has just awarded a $7.49 million grant to Dr. L. Yang and her research team at UCLA to further their development of a treatment for Ms. That flips a script. It's a universal off the shelf car NKT cell therapy that fights Ms. On two fronts. So let's break down what this is really all about. Traditional car t therapies, which have done wonders in cancer research and are currently undergoing multiple Clinical trials for Ms. Well, these therapies work by wiping out the bad B cells that produce the antibodies that mistakenly attack myelin in an individual with Ms. Dr. Yang's therapy does that, too. It engineers cells with a chimeric antigen receptor to target a protein that lives on the surface of B cells called CD19. But here's why this therapy is a double threat in Ms. B cells aren't the only problem. There are also inflammatory myeloid cells that attack the damaged areas in the central nervous system and drive progression. Regular CAR T cells ignore these myeloid cells. But Dr. Yang's platform uses natural killer T cells, or NKT cells. And these cells have a natural receptor that detects and attacks those inflammatory myeloid cells. So you have one therapy that kills those misbehaving B cells and clears out the chronic inflammation that's causing the actual damage to the nervous system. And because these cells can survive in the body for months or even years, the goal isn't just to manage symptoms. The goal is to cause an immune system reset. And that reset could keep Ms. Disease activity in the central nervous system on hold indefinitely. Now, if these benefits weren't enough, there's more. In traditional CAR T cell therapies, scientists have to take a patient's individual cells, alter them in a lab for weeks, fly them back, and reintroduce them to the patient. It's an expensive process, making CAR T cell therapy a very expensive treatment, costing hundreds of thousands of dollars. Now, NKT cells are naturally compatible with anyone's immune system. Dr. Yang's team can mass produce them using donated cord blood stem cells, freeze them, and ship them out to treat any patient. And one single cord blood stem cell donation can create thousands of doses. They're estimating the cost could drop as low as $5,000 per dose. Compare that price to the cost of the disease modifying therapy you're currently on. The research team has already seen very positive results of their CAR NKT cell therapy in pre clinical mouse models where it actually prevented paralysis. They've already met with the FDA and over this two and a half year grant period, their goal is to reach the point of human clinical trials with hundreds of doses ready to go. I try to avoid hyperbole, but this is what a cure could look like. And we'll keep you updated as Dr. Yang and her team continue their work. The good news isn't only coming from the west coast. On the east coast, Dr. Yaoying Wu, an assistant professor of biomedical and chemical engineering at Syracuse University, has been awarded a National Institutes of Health or NIH grant to develop an innovative class of nanoparticles particle therapy to treat Ms. Today's Ms. Disease modifying therapies broadly suppress your immune system to stop it from attacking your myelin. It works, but it creates a massive side effect, leaving you more vulnerable to everyday infections and other complications. But what if scientists could find a way to re educate the immune system instead of just turning it off? That's exactly what Dr. Wu's project, officially titled Tolerogenic Dendritic Cell Membrane Coated Nanoparticles for Precision Multiple Sclerosis Therapy is designed to do. So let's take a minute to break down this project with the rather long and somewhat confusing name. In our bodies, we have a specialized class of immune cells called tolerogenic dendritic cells. Think of these cells as the Peacekeeper in your immune system. Their natural job is to look at the body's own tissues and tell the rest of the immune system, well, this stuff belongs to us, so don't attack. In other words, they promote peace and tolerance. What Dr. Wu is doing is creating synthetic nanoparticles and then disguising them in the actual physical cell membranes harvested from these peacekeeping dendritic cells. Now, because the nanoparticles are wearing the native cell membrane like a coat, literally like a disguise, they carry all the same surface proteins and molecular keys. And when these disguised nanoparticles enter the body, they mimic the Peacekeeper cells perfectly. They interact directly with rogue B cells in the immune system and deliver a highly specific molecular message. They say myelin is a friend, not a foreign threat. Do not attack. That's what immunoengineers call a cell memetic strategy. Instead of shutting down the whole immune system to protect your nervous system, you're target training the immune system to tolerate myelin again, leaving the rest of the body's natural defenses fully intact. To fight off normal colds, viruses and more serious infections. Dr. Wu has received an NIH R21 grant. R21 grants are specifically designed for high impact, exploratory, novel research. It's the ultimate proof of concept. Funding Dr. Wu and his team at Syracuse University's Bioinspired Institute are using this grant to build out the preliminary data required to take this to larger scale manufacturing and eventually human clinical trials. This cutting edge Ms. Therapy represents a paradigm shift away from broad immunosuppression toward total precision. We'll be tracking Dr. Wu's progress as he and his team create a new class of nanoparticle therapy for Ms. Early treatment with a high efficacy disease modifying therapy is increasingly being recognized as an important step when it comes to improving long term outcomes for people living with Ms. But the astronomically high cost of these DMTs creates a serious barrier to access. Not just here in the United States, but around the world that could be changing. A major Scandinavian clinical trial called Overlord Ms. Has provided the first high level randomized double blind proof that a low cost off label therapy is just as effective as one of the leading high cost standard standard disease modifying therapies on the market. We're talking about Rituximab versus Ocrelizumab or if you prefer to use their trade names, it's Rituxan versus Ocrebus. First, let me share some quick background. Both of these drugs are monoclonal antibodies that do the exact same basic job. They deplete B cells, which are the immune cells that are most responsible for driving the inflammation in relapsing Ms. Ocrevus of course is FDA approved specifically for Ms. And it's been shown to be highly effective. Rituximab on the other hand, is an older drug that was originally approved for lymphoma and rheumatoid arthritis. For years, neurologists in places like Sweden and Norway have been prescribing rituximab off label for Ms. Because it's so much cheaper. But there's never been a gold standard randomized double blind head to head trial to definitively prove that rituximab works just as well as Ocrevus. That is, until now. The Overlord Ms. Trial followed newly diagnosed relapsing Ms. Patients across Norway and Sweden for 30 months using both clinical assessments and MRI. And the result? Total clinical equivalence. Rituximab showed comparable efficacy and safety to ocrelizumab. It protects the brain and stops relapses just as well, but at a tiny fraction of the cost of Ocrevus. The Overlord Ms. Trial proves that highly effective Ms. Treatment can be delivered without compromising patient outcomes or breaking the bank. And there's another story to report here. Because both of these drugs wipe out B cells and because B cells are the primary hiding place for Epstein Barr virus, which we know is a major trigger for Ms. The biomaterial collected from the Overlord Ms. Trial is being funneled directly into the broader European EBV Ms. Research Initiative. Scientists are using these exact same patient samples to map out how B cell depletion alters the EBV related immune mechanisms that drive Ms. Well, this story represents a real victory for publicly funded, independent academic research. It proves that scientists can design a more sustain, equitable path forward for the global Ms. Community. And it gives doctors the hard evidence they need to advocate for affordable, early, high efficacy treatment for everyone, no matter where they live or what their insurance looks like. If you'd like to review the details of the overlord Ms. Clinical trial, you'll find that link in today's show. Notes. You know today's episode has focused on evidence based, cutting edge biomedical breakthroughs. Well, I have one more breakthrough to share with you, but this one doesn't involve cell transplants. It doesn't even involve medicine. The Mood and Exercise Training Study for Multiple Sclerosis is designed to analyze the effects of two different remotely delivered and monitored exercise training programs for managing major depressive disorder among people with Ms. Joining me today is the study's principal investigator, Dr. Robert Mottle, along with Kelly, who was a participant in the study. In a moment, we'll meet my two guests. When we think about physical exercise, we often think of its physical benefits. But for someone living with ms, the benefits can go far beyond just feeling good physically. Depression affects one in every two people living with ms, and the Mood and Exercise Training Study for Multiple Sclerosis, or METS for ms, is designed to analyze the effects of two different remotely delivered and monitored exercise training programs for managing major depressive disorder among people with Ms. Joining me to talk about METS for Ms. Is a good friend of the podcast and the study's principal investigator, Dr. Robert Mottl, along with Kelly, who was a participant in the study. Dr. Mottl is the director of the Exercise Neuroscience Research Laboratory at the College of Applied Health Sciences at the University of illinois, Chicago. Kelly Dr. Mottl, welcome to the podcast.
- [14:59]
B
So glad to be here. John.
- [15:01]
A
Dr. Mottle, we've long known that exercise is good for the body, but this research specifically targets mood. What was that aha moment or the specific data gap that led to the creation of the Mood and Exercise Training study?
- [15:16]
B
That's a great question, John. There were really two things that motivated the METS for Ms. Study. One of the observations was that there is a wealth of research showing that exercise can improve depressive symptomology in people with multiple sclerosis. Yet none of the studies that we reviewed specifically focused on people with Ms. Who had major depressive disorder. So we don't actually know whether or not exercise would work in that population of individuals. And there's a lot of reasons to think it will. But there are also some Reasons to think that it might not work. You know, when we look at medications, when we look at talk therapy, those seem to not work quite as well in people with Ms. Who have major depressive disorder as they do in the general population. Then at the same time, we were looking at the research in the general population, and when you look at the general population of the United States, there's a lot of studies that have examined different therapeutic modalities for treating major depressive disorder. And there was this really large meta analysis and systematic review of all the therapeutic interventions for managing major depressive disorder. And of all the interventions, exercise came out on top for treating depression in people with major depressive disorder. So when we saw these two really important things in the literature, me and my colleagues, we pulled them together and wrote this grant to the multiple sclerosis research program that's now back and with us. And we were fortunate enough to receive the funding and be able to do this critically important trial for people living with multiple sclerosis and major depressive disorder.
- [17:03]
A
Well, let's drill down a little bit. Can you walk us through the type and intensity of exercise that was used in the study?
- [17:10]
B
Yeah. So just to be clear, the study is still ongoing, so we're not done yet. And we have two different exercise programs, and I'll explain both of them. One of the exercise programs is what people will typically think about with exercise. We have individuals engaging in aerobic exercise, and we have them also engaging in resistance exercise. So the aerobic exercise, we have them doing walking, and they do walking three days per week. They start really low at 10 minutes on each session, and then they ramp up to about 30 minutes of walking on each session. And that occurs over a 16 week period of time. The intensity is structured based on the rate at which they take steps. So we want them to walk at about a hundred steps per minute, because that's the threshold for moderate intensity. Then on the other with that, we also do resistance training. So we give them resistance bands, and again, we start them with the lowest amount of resistance, and we start them with five exercises that target the upper extremities, the core, and the lower extremities. And then over time, we increase the number of exercises and we increase the resistance by the bands such that they do 10 resistance exercises or target 10 different areas, and they're using a much heavier resistance to where when they're done, they're kind of getting to the point of they can't do more repetitions. So that's one of the exercise approaches the Other exercise approach that we've learned that a lot of people with Ms. Like is stretching to improve range of motion and flexibility. And a lot of people tell us that they have a lot of stiffness, it impacts their ability to do everyday life tasks, and it's really something that they struggle with. And so this other program is very, very specifically developed based on guidelines that the National Multiple Sclerosis Society put together. And we give people a simple set of exercises to start with, and we start with, you know, a small amount of time on those exercises. And then we build, we give them more exercises and give them more options and allow them to choose more exercises, more duration of each of those exercises, like holding a stretch and doing more sets of those exercises. So we're trying to compare whether or not these two different forms of exercise have similar benefits on major depressive disorder. Or maybe there might be one program that works a little bit better than the other. We don't know. And we're hoping to find that out.
- [19:53]
A
Are you finding that there's a specific dose of activity that seems to trigger a positive change in mood for someone with ms?
- [20:03]
B
So in both of these programs, we try to get people to what we would consider to be the clinically effective dose of exercise. For the traditional exercise program, that means 30 minutes of walking and doing two sets of 10 repetitions of 10 different muscles. And we try to get people there by about halfway through the 16 week program. In the stretching where we're trying to promote flexibility and range of motion, again, we believe that the proper amount of exercise is about 10 different muscle groups and doing two different kind of stretches of those muscle groups lasting for about 30 to 60 seconds. And that seems to help with range of motion and flexibility. That would have the benefits that, that we would hope that they would experience. But again, we don't know the right dose yet because we're not quite done with the study.
- [21:07]
A
From a physiological standpoint, do you know what might be happening in the brain of an Ms. Patient when they engage in this specific training, and how is it counteracting the biological basis of Ms. Related depression?
- [21:21]
B
Yeah, so if we think about some of the root causes of depression in Ms. And overall, you know, there could be a biological basis of it. So dysregulation of neurotransmitter systems like serotonin, norepinephrine, or there might be the, the kind of lack of confidence, lack of self esteem, things like that, that come from living with a chronic debilitating disease that's really hard to manage when we look at the literature, there actually are some data that exercise works in people with major depressive disorder by changing around neurotransmitter systems and levels that have to do with serotonin and norepinephrine. In fact, there's a very classic study comparing exercise versus an ssri, a serotonin selective reuptake inhibitor, and the two combined and showing that they all have similar effects, suggesting that exercise is working on that neurotransmitter system. On the other hand, we know that exercise is a great stimulus for helping people to physically feel better about themselves, to evaluate themselves more positively, and that translates into an overall, more positive evaluation. We call that self esteem, and self esteem is a major contributor to managing depression and preventing depression in society and people with multiple sclerosis. So it could be biological, it could be psychological, it could be both operating at the same time.
- [22:59]
A
Many people with Ms. Deal with profound fatigue or mobility issues that make the idea of physical exercise seem like it's out of reach. How does the METS Ms. Study account for these very common symptoms?
- [23:14]
B
Yeah, we hear that a lot when we ask people to start an exercise program that is, is this going to make my fatigue worse? And if it makes my fatigue worse, that's going to make everything I do worse and ultimately make my depression worse, I think is a reasonable extension. So we start everything with a very, very low amount of exercise. We start it with, you know, something that's akin to about 10 minutes of exercise, you know, three days per week. And we start low because we want to see how people respond to that. Some people, that's the perfect amount, right? And we're just going to start them there and slowly build them up. Some people will tell you after the first two weeks of doing 10 minutes, three times per week that this is not enough, it's not pushing me. And we build them faster. And some people will tell us, like, wow, you're really pushing me, you know, to the limits here. And we give them a slower build over time. So we do that because we don't want to drain someone's physical and mental reserves and ultimately cause them to have more fatigue, and that translate into more problems in everyday life. I will say that one of the things that we're looking at in this study, because we are measuring fatigue as a secondary outcome, we're trying to examine whether or not if we improve depression, do we also get improvements in fatigue and kind of maybe can we discern which is the chicken and which is the egg in the outcomes of this trial?
- [24:58]
A
Kelly I want to thank you for being patient. Now I have some questions. Now I have some questions for you. Before you join Dr. Model's study, how would you describe your general mood and how would you describe your relationship with exercise?
- [25:13]
C
So my general mood, I would say pretty positive overall, but definitely doubting myself and my ability. As I've progressed in my disease, um, I've definitely, my struggles have become more apparent and so my self esteem is fairly low. Um, as far as my, you know, my depression, I don't know that I ever saw my lower self esteem as part of the depression. But after the study I definitely see the correlation. So that would be my, my effect as far as mentally, as far as physically. Fatigue definitely has always been an issue for me since diagnosis. So it was hit or miss on exercise. You know, if I was feeling really good, then I was really optimistic about what I could do, what I could achieve that day. If I was feeling woke up particularly fatigued, that wasn't even on my radar that day. So there was no structure, to put it that way. No, no real structure, no organizing my day around it to see how that affected the rest of my day by doing it daily. So that was definitely kind of where I was going in.
- [26:40]
A
As you went through the training, was there a specific week or a particular moment during the training when you realized, hey, my mood feels different, I'm, I'm feeling a little better about things?
- [26:54]
C
Yes, definitely. Um, I was at about week one, maybe 10 days in. And what I realized when I was, when I was doing the stretches on that day, every day prior, it was kind of just like a job, you know, I was going to do it and whatever the effect was from doing it, great, you know, if it was positive, I felt better, great. If I didn't, okay. On like about the 10th day, I realized I was actually excited. Like I got up a little bit earlier, I had breakfast, you know, and I was, I was treating it like a job that I loved on that day. And that was the difference for me, that was where it kind of turned from. I'm participating in this study just to see, to me actually seeing the difference.
- [27:53]
A
So did you notice that change carry over into your daily life either, I don't know, in relationships, your work, or even just your overall outlook?
- [28:04]
C
Yes, I actually did. So, you know, part of, I don't work in outside jobs, so I've been on disability. So my days are, they tend to be a little bit mundane. You know, a Tuesday is like a Friday and it's not much difference for Me, I was noticing that once that change kind of happened, I was, I was eager to shower, to get dressed, to figure out something to do. I was painting more than I was prior. I was, I was definitely more engaged in every activity for the rest of the day and it was, I felt more accomplished and I haven't felt that, you know, when you don't work a actual 9 to 5 job and things like that, you struggle to find ways to feel that you're contributing. And I think that that was my big, big depressive element for me is that I don't, I didn't feel part of the human race, you know, I didn't feel part of that rat race. You know, everyone's trying to get out of it when they're in it, but I was like aching to get back in. And this gave me a little bit where I could find my new purpose and I could find things in my day that made me feel complete. It made me feel less disabled, less dependent and more independent.
- [29:43]
A
That's amazing. For someone who is listening to our conversation right now, maybe they're feeling stuck in Ms. Related low mood, physical inactivity. What's the one thing you wish someone had told you before you started this training?
- [30:01]
C
I wish that someone told me that it doesn't have to look the same for everyone. I'm very spastic, you know, I'm very spastic on my right side and I'm not going to be able to complete these stretches the same way that the next person will. But it doesn't matter. I'm not competing against other people. I'm just doing things that are really good and beneficial for me and I think I saw it as well. But I can't do the exercise like this person can, so why bother, right? I'm going to fail. But it's not about that, you know, it's about, it's about doing it for you. And it may look different, you know, I walk different than other people. That doesn't mean I shouldn't walk, you know, I, I eat different than other people, it doesn't mean I shouldn't eat. I exercise and stretch differently, but okay, and, and that's fine. And however that looked for me was okay. And I didn't know that. I didn't give myself permission to feel that prior.
- [31:11]
A
Dr. Mottle, have you had an opportunity to observe how participants maintain these habits and after they finish their part of the study?
- [31:21]
B
So we are following people up for four month period of time after the program ends and our hope is that we've delivered the goods, we've given them a great program like Kelly has talked about has meaningful changes for them. But we've also given them tools and resources that they can keep this program in place, maintain the behavior and maintain the benefits. And we're going to study them for four months after the program is over. I do want to make a comment that falls into what Kelly was saying. Our coaches who deliver this program always work with our participants where they are, we meet them where they need to be met. We listen to them, we pay attention to them. We try to understand what they need and how things will work for them. We try to make sure we're not using a one size fits all approach to everybody. Because as Kelly said, she had very specific needs. She had very specific ways of doing the exercises, very specific ways of when she would do them and how they made her feel. And meeting her where she was was key for her to be able to do this, make the change and stick with it. And that's key for everybody to learn.
- [32:46]
A
So the big question, how do we move this from a clinical study to a lifetime standard of care?
- [32:52]
B
Great question. And first, we need the data, right? You know, nothing moves into clinical practice and daily care until you have the data to move it there. So that this trial is going to be fundamental for having good, high quality data. The once we get it there, you know, neurologists, healthcare providers, they're always itching to recommend exercise and they'll generally say stuff like exercise will just be good for you. It'll be helpful for you. Because we don't have the data to be able to say exercise will help you manage your mood and you need that because we think you have major depressive disorder. So once we get the evidence, I think it will help healthcare providers to be able to make that recommendation. And the whole thing with METS is METS is a home based program. People don't have to go to a gym for completing the Mets program. They can do it in the comfort and safety of their everyday home environment.
- [33:57]
A
I guess I have one more question. Are you still recruiting participants for this study?
- [34:02]
B
We are still recruiting participants for this study. We are hoping to recruit about 20 to 25 more people so that we reach our sample size estimates that we provided when we wrote the grant and then we have full statistical power to be able to determine that these treatments are both working and to be able to be clear on whether or not one treatment is superior to the other.
- [34:30]
A
And how does someone get involved?
- [34:32]
B
There are two ways of contacting our team one you can send us an email and the email would go to M E T S F o r m s uic edu. That's mets4msic.edu. Or you could contact Ariel. Her number is 312, 3551790 and we will get back to you next day.
- [35:03]
A
We'll make sure that information is on the Show Notes for this episode as well to make it easy for people to find Dr. Robert Model Kelly, I want to thank you both for contributing to our understanding of the value and importance of exercise in mitigating Ms. Related depression and delivering real measurable benefits to people living with Ms. And thanks so much for talking with me today.
- [35:28]
C
Thank you.
- [35:29]
B
Thank you John. And we're so grateful to have Kelly with us today. She's a rock star.
- [35:34]
C
Thank you guys.
- [35:36]
A
That's going to wrap up this episode of Real Talk Ms. Real Talk Ms. Is powered by the National Ms. Society and you can share this episode of the podcast by letting your friends or family members know that all they have to do is point their web browser@realtalkms.com and 463. You'll find that link in today's show notes so you can easily copy and paste it right into an email or a text. Liat Shalom was diagnosed with Ms. In 2021 at the age of 30. Rather than letting her diagnosis define her, Liotte picked up her pen and began documenting her journey in a graphic memoir titled Unraveled. I hope you'll join me next week when we'll meet this self described award winning graphic novelist, Mississippi advocate and professional smartass. I'm John Strum. Thanks for listening. Stay safe and make healthy choices.
- [36:44]
C
Sam.