← MS Living Well: Key Info from Multiple Sclerosis Experts
MS Living Well: Key Info from Multiple Sclerosis Experts
Repair, Reset, Reimagine: Stem Cell Therapies for Multiple Sclerosis
00:45:40
Loading summary
Transcript83 lines
- [00:02]
A
Greetings, all. Welcome Back to the Ms. Living well podcast. I'm your host, Dr. Barry Singer, director of the Ms. Center for Innovations in Care at Missouri Baptist Medical center in St. Louis. Today's episode is Repair, Reset, Reimagine Stem cell therapies for multiple sclerosis. This episode is sponsored by TG Therapeutics. Today we're delving into the promising and complex of stem cell therapies for multiple sclerosis. We'll explore innovative new approaches, including treatments designed to reset the immune system, as well as regenerative and neuroprotective therapies aimed at repairing and preserving nerve function. We'll also discuss clinical trials, ethical considerations, and practical guidance for navigating emerging treatments. Later on the show, we'll be speaking with Dr. Stefano Pluchino from the University of Cambridge in UK where he's been leading groundbreaking research neural stem cells and their potential for treating secondary progressive Ms. But first, I'd like to head north to Canada and introduce Dr. Mark Friedman. Dr. Friedman is a professor of medicine in the field of neurology at the University of Ottawa, director of the Multiple Sclerosis Research Unit at Ottawa Hospital, and a senior scientist at the Ottawa Hospital Research Institute. He's a lead investigator in the Canadian Bone Marrow transplant study in Ms. & Co Chair of the International Mesenchymal Stem Cell transplantation study group. Dr. Friedman, welcome to the Ms. LivingWell podcast.
- [01:40]
B
Glad to be here.
- [01:42]
A
Great. So let's start with the basics. What exactly is autologous hematopoietic stem cell transplantation, or ahsct? And how is it used to treat ms?
- [01:53]
B
Yeah, that's a bit of a mouthful for sure. Autologous just means from yourself. So if you're receiving an organ or cells from someone else, there's always the possibility that the cells or the organ will be rejected by the body. So it's important that the cells are coming from the individual patient. Hematopoietic is just a word for the blood system. So in ms, we are concerned that the immune system is rejecting myelin, which is, of course, the insulation of the wires of the central nervous system. And if it's part of the blood system, we can eliminate the old blood system and replace it with a new system that's derived from the blood cells or the stem cells. And that's where the hematopoietic being the blood system and the stem cells come from.
- [02:47]
A
Excellent. That's very clear. So can you walk us through the process of undergoing autologous hematopoietic stem cell transplant? Age SCT from like the pre treatment phase all the way to recovery. What's involved?
- [03:01]
B
There's actually quite a bit involved. It's not a simple procedure and your patients really need to be medically well to sustain this. And there are different techniques, but let me just sort of put it into the three phases that we really focus on. The first is the preparative phase, which gives us the stem cells to use. So you have to derive these from the individuals. And that requires a fairly high dose of chemotherapy which has side effects. As you know that we use cyclophosphamide. And most of the techniques, and there are several around the world that are being used, will generate the stem cells using this same technology. A big bolus or dose of chemotherapy followed by a hormone that's injected by the patient for four to five days. It's called gcsf. It's a hormone that essentially drives the stem cells out of the bone marrow and into the blood system, where it can be collected using what's called a leukophoresis machine. And essentially it's a line in one arm and a line out the other arm. Blood flows through this machine and the stem cells, along with many of the other white cells, are then pulled off and the rest of the blood is given back to the patient. And then you have a collection of cells which includes your stem cells. And some groups like ours will take that to a next step, which purifies the stem cells and in so doing, not only gives you a purified stem cell collection, but also eliminates any of the possible disease causing immune cells that might have been in that graft. That's phase one. Now, some very rare cases, you can't generate enough stem cells to do the graft, and then the whole procedure stops right there. Because the next phase is the most difficult one, and that's the conditioning phase. And in that phase, patients are often brought into hospital. And then depending on where you are in the world and which technique is being used, your old immune system is knocked out with a combination of different types of chemotherapy. We use what are called myeloablative therapies. So we are really eliminating everything, all the bone marrow cells, and we use in particular high doses of busulfan and cyclophosphamide, because those are two chemicals that actually get into the brain. Those chemotherapies can then eliminate the immune cells that may have gotten into the central nervous system and caused the dis. So it's sort of important that all of these cells be eliminated because then you're left with no hematopoietic system that includes all your white cells and red cells, because there's no way of selectively knocking out just some followed by the third phase, usually within five to six days, we know that we've given enough chemotherapy that the old system is gone. And then the final step is to remove the purified frozen stem cells that have been collected at stage one and simply hook it up and the stuff drips into the patients. And within two or three days, they start that same hormone that generated the cells to begin with, and that enhances engraftment. Some people will also give, just immediately following that, something called ATG is antithymocyte globulin, and that is essentially an immune antibody. It's usually derived from other animals that kills T cells. So just in case some of those T cells that may cause the disease got into the graft, you're eliminating them even more before the stem cells then go in, repopulate the bone marrow, and within days the white cells come out, we start to count them, and we throw the patients out of the hospital because they're at a risk of getting all sorts of infections. In that point, we get them out as quickly as possible and they're followed.
- [07:12]
A
Yeah, that's an amazing process that people have to go through. And I guess you have to have a good understanding of what's involved before you jump into going through a stem cell transplant. So the interesting thing is you're knocking out the immune system, rebuilding the immune system. How do you know that it's not going to cause the same disease? I mean, it's the same person that had Ms. Why is the immune system different after we reset it?
- [07:36]
B
Great question, Barry. And that was asked of us probably when we embarked on this and wrote our first grant in 1999, believe it or not, everyone said, well, this is a genetic disease. If the genes haven't changed, then you're going to get the disease all over again. And there were a lot of naysayers who told us that that was the reason why we shouldn't go ahead with the whole process. So I said, well, here's a great way. This is like hitting reboot on the computer. Let's eliminate the old system, put the cells back in, and if the patient redevelops the disease, we're right on the scene with all our immune techniques to pick up that first event. And I have to tell you, that experiment was a complete failure because nobody redeveloped the disease.
- [08:23]
A
So it worked well.
- [08:25]
B
That was not the expectation, but we also put to rest the notion that the geneticists were telling us this is a fait accompli.
- [08:33]
A
Yeah. And then one of the big questions is, okay, so if they don't develop it again, I think there's this perception that it's an actual cure. Would you consider this a cure?
- [08:43]
B
I hate to use the C word. If you want to define a cure, as these are patients who no longer have any evidence of ongoing inflammation that we can detect, then yes. Did it stop the progression in 100% of people? No, there's that other sort of inflammation so going on in the background in the brain that's driving the progressive phase of the disease. We're calling it various things now. We're calling it pira, which is like progression in the absence of any obvious relapses. Are we able to drive that? I can tell you that most of the patients that we have done using our technique of ahstt, they do progress a bit afterwards, at least some of them, but then they level off and they plateau. So I think what we've been able to see is that that progression probably started well before we did the procedure and was sort of ongoing, but then it stopped, it leveled off and maybe we've stopped the contribution to ongoing progression. We've done what, something like 150 patients at our center now over the last 10, 15 years. We're very selective, obviously. And none of those patients have ever developed a new MRI lesion in attack. Most have either plateaued or improved. Actually regressed.
- [10:08]
A
Yeah. That's astounding.
- [10:09]
B
Totally unexpected.
- [10:11]
A
Have you seen any MRI activity, breakthrough over time for your patients?
- [10:15]
B
Zero.
- [10:16]
A
No enhancing lesions, no new T2 lesions.
- [10:19]
B
Exactly. And we're just reviewing everything. We'll probably send in a publication later this year. Our 25 year follow up of our entire cohort had repeated MRIs over the years and they've had a few pseudo attacks, as one would expect. I can tell you we can stop the disease, but I can't tell you we're repairing the damage. And so these patients have continued to have whatever symptoms that were left from the damage that can every once in a while get worse when you have like a cold or a urinary tract infection. So they continue to have that, but no new lesions have formed in any of these folks.
- [10:53]
A
That's amazing. So let's talk about clinical trials. Has anyone compared AHSCT directly to other disease modifying therapies since it's so effective?
- [11:04]
B
Do we have the data to do that properly? As you know, you would have to Do a randomized controlled study. Now there are two large ones ongoing, as you know, one of them in the US called Beat ms, they've been randomizing people who they've deemed eligible for this procedure to either the best therapy that's out there, that's available for the patient versus the ahsct. But the AHSCT technique is the one that uses the drugs coded by the letters B, E, A, M beam, followed by atg, which is the antithymocyte globulin, which is not myeloablative. It means it doesn't knock everything out. It's sort of immunoablative. So it knocks out most of the immune system, but it's not knocking everything out. And using that type of conditioning regimen over the years we've seen a return of disease activity in up to 25% of patients. So 75% of people are essentially what we call NEDA. No evidence of disease activity. That's so much better than any of the best medicines that we have today. But it's not 100%. So if you're going to undergo a procedure like this, which is essentially a bone marrow transplant, I don't think you want to do this more than once in your life. So our attitude is let's use a conditioning regimen that gives you 100%. So the myeloablative approach, but it's also riskier. Right? You have to have the right people. So this is a really experienced transplant team. This is not a fly by night center. There are lots of those around and patients need to be aware. Buyer beware. Look where you're going. And what's the expertise that's present wherever it is that you're going to undergo this technique.
- [13:02]
A
So who are the right candidates for this treatment?
- [13:06]
B
Well, everybody's a responder and that's the problem. So you could say, why not just do this on everybody? That's true for many of our disease modifying drugs that have a very strong response. The so called higher efficacy therapies. Why don't you just give them to everybody? But we also know there's such a variability of the disease that there are patients who really do have very mild disease and a very mild course and have had Ms. For 30, 40, 50 years and it's a nuisance disease for them at best. And then of course you have the other extreme where patients could be almost disabled within a year or two. So the recommendation in general is yes, we know they exist and the decision to undergo a therapy is usually discussed with the patient. And how risk averse they are, et cetera, et cetera. And if they truly do have mild disease, they don't have any of the indicators of aggressiveness, then it's okay to go with a moderate efficacy therapy that's very safe with close vigilance, so that if that disease suddenly changes, you know, we can hit right away with those higher efficacy therapies and then, you know, that makes sense. If you have can start ticking all the boxes of all the things that may indicate a more aggressive course to begin with, then chances are someone's already given them a high efficacy therapy, they're going to fail it, and they'll probably fail it fairly quickly. And by the time we see them, we go, oh my goodness, you got such a disease. And I'll go right away to the ahsct. And those patients have done very well to say, what is that perfect patient? I can't tell you. But I can certainly tell you that if they're on the more aggressive side and they're not so risk averse, because you still have to consider the possibility that this could be a fatal outcome. Everyone needs to know that these are chemotherapy drugs that put you at high risk for some very serious infection or complications that in rare cases will kill you. It's very low. We quote a risk of less than 1%, but it's not zero.
- [15:16]
A
Yeah, yeah, that's important to know and we'll dive into those risks in one minute. But I did see some guidelines that said people that are better responders tend to be less than 45, disease duration, less than 10 years, more mild to moderate disability, no cognitive impairment. Relapsing.
- [15:34]
B
That's correct. Age is important because of the possibility of complications. So the younger you are, the better the chances that you'll have a lower risk for complications due to the lower risk of comorbidities. That's just a given. Right. The younger you are, the better the chances your reparative mechanisms are higher. We know that your ability to remyelinate and fit the nervous system drops as you age. The still relapsing is an indication that that inflammation, which really is the target of the conditioning regimen, that it's still there, there's a fire still burning. And if the fire is not burning, there's no point in bringing in the water bombers. As long as there's a fire burning, you can eliminate it using hsct. So that's why relapsing is put in there.
- [16:25]
A
Yeah. I think the big question comes up is relapsing Ms. Ver secondary progressive. Do you see a difference in your outcome when you treat patients if you've.
- [16:34]
B
Been remote from inflammation? MRIs have been quiet for a couple years, there's been no relapse, and all you've had is pure progression. The results have not been very good. There's a group in Scandinavia that claims that they can still treat secondary progressive Ms. And slow the progression in that group. But when you go back and look at the patients, they still had some activity of some sort. And we've seen that even in our studies of drugs. We have some drugs that are approved for progressive ms, but as you know, the effect is so much greater in the patients that still have some ongoing activity. So that's kind of the key here.
- [17:14]
A
Well, this is important because if it doesn't make sense and you're not going to get much out of it, it's a lot to go through.
- [17:19]
B
It breaks my heart to turn patients away like that. They've had Ms. For 15 years now they're in a wheelchair and they want to reverse all this because they've heard some miraculous stories. And it's true for some of the patients who've ended up in a wheelchair very quickly and still have all that inflammation. After an HSCT, they've recovered. But 15 years later, typical progressive disease, in the absence of any kind of inflammation, you're probably not going to have a great response to an hsct. So it's not worth the risk, at.
- [17:52]
A
Least for this procedure. We need something else, hopefully BTK inhibitors or remyelination or whatever's next. All right, great. Let's talk about safety a little bit more. How significant is that mortality risk? Today? You were saying less than 1%. I saw numbers that were much lower.
- [18:07]
B
There are so many potential problems depending on the chemo agent that's being used. And that's the key. Some are using low dose cycloatg, some are using the beam atg, some mix of two, or we're using busulfan cyclophospham. Every one of these drugs has an issue and they're well known and we're using very strong doses of it. So what we talk about are the acute risks, the risks around the time of the procedure, the ones that are a little bit later, so within a year to 2 of the procedure. And then the long term risks, anytime you manipulate the blood system with chemo drugs, you run the risk that at some point you could get a malignancy like a leukemia or a lymphoma. That's the long term risk. It's very small. What are the upfront risks? Well, you've knocked out your entire hematopoietic system. You don't have any blood cells. You have to regenerate your red cells, you have to regenerate your white cells, and during that time, you're at risk of everything. So we cover our patients with antibiotics, antiviral drugs, antifungal drugs, ivig, which is essentially pooled antibodies for some of the cases up to a year or more. They'll get IVIG as a minimum for six months. They'll get antivirals for at least a year to two years. They'll get antibacterial drugs for at least the first three months until they start to regenerate all their white cells that are capable of defending that. But then there's all these other things that can occur at the same time. The drugs affect all the biological structures of your body, which includes your blood vessels. So you can get something that's very serious, called a capillary leak syndrome. Sometimes patients need ICU care for that. We get autoimmune conditions that arise so you can get suddenly reactions against different blood elements. It's rare, but it happens, and you have to be ready for that type of thing. There's a lot of things that are exclusive to the type of chemo drug that is being used that I can't really go into now. But the hematologist you're working with knows all about that and the team knows all about that, and that's the key. You've got to be with that hematology team so you have the expertise on board ready to deal with this should any of those problems arise.
- [20:40]
A
What about fertility, Mark? Is that a concern?
- [20:43]
B
Oh, yeah, 100%. Because if the doses of chemo that we're using, patients are rendered sterile, the men not so much as the women. The ovaries are very sensitive to the chemo drugs. You're virtually eliminating a possibility of generating an egg. Many of the men start to get their sperm back, but we recommend, if possible, to make a sperm bank donation before the procedure. For and for women, it's a costly procedure, but if they have the ability to do an ovarian harvest and freeze them and maintain them, we've had several patients be able to do that, and they've given birth to their own children through the technology that's available today. It's really quite spectacular to see that.
- [21:31]
A
Yeah, that's a huge win. In fact, it's given me chills that you can, you know, so Many treat their Ms. And they still can have their family. I mean, that's amazing.
- [21:39]
B
When that first patient came in with her baby, she got an egg and that was fertilized with her husband's sperm, and they implanted it into her. And she showed up and said, oh, yeah, I got something to show you. And she holds up this little baby, and I almost burst into tears right there. And then she's been so well from her ms, she was one of the original cohort. She's been free of disease for years.
- [22:02]
A
All right, so we just talked about this entire amazing process and the great response. So what about access to this? You're in Canada up there in Ottawa. Is this open to people to get stem cell transplant, or is it covered by the health care system?
- [22:18]
B
Fortunately for us, it is 100%. The federal government has what's called the Health Canada act, and as long as you abide by the rules, then there's 100% portability, which means it doesn't matter where you are. If you're an Ms. Patient in Vancouver and you need a transplant and you come to Ottawa, 100% is covered. And I think it works very similar in Europe. It's in the States, where it can be quite costly.
- [22:43]
A
Yeah, unfortunately, that's where we need more advocacy. The National Ms. Society has proposed that this should be available. Interestingly, I just looked at some of the major insurance companies, and actually there's clauses now to allow hsct, but it's under very specific guidelines. So it is important that we can circle back and try to advocate for it. There are clinical trials as well, as you mentioned, in the United States. So that would be another way, potentially getting access. So with all the patients that you've treated with hsct, would your patients do it again?
- [23:18]
B
We've asked that question, Barry, to all of them. And even though it's a year out of your life, they've all said 100% they would absolutely do it again, especially when they're free of all these drugs. Many have recovered somewhat substantially, especially if we can get them early. That's why the timing is so important, to get in there for those patients who are having that more aggressive disease. And I think they'll turn around. So 100% of them would have said yes.
- [23:50]
A
All right, well, we got to keep doing that advocacy here in the United States to have more access to it. And clearly you need a team that knows what they're doing. Their life is on the line. So you want to make sure that you have the right people with the right experience.
- [24:03]
B
I can't stress that more. I think that's a very important point.
- [24:07]
A
Excellent. Well, thank you, Dr. Friedman, for all your commitment to the Ms. Community over the years and being the leader in stem cell transplant. I appreciate it.
- [24:15]
B
Thanks, Barry. It was great talking with you.
- [24:29]
A
Next up, I'm excited to bring onto the show a pioneer in the world of stem cells for multiple sclerosis. Professor Stefano Pulchino is a clinical professor of regenerative neuroimmunology, an honorary consultant in neurology within the Department of Clinical Neurosciences at the University of Cambridge in the United Kingdom. Professor Pulchino, welcome to the Ms. Living well podcast.
- [24:52]
C
Thanks very much for the very kind invitation, Barry. I'm happy to be here.
- [24:56]
A
Superb. So, Stefano, let's start from the beginning. What are stem cells and what makes them different from other types of cells in the body?
- [25:04]
C
Keeping the description of stem cells very high level, we can say that stem cells are special cells in our body that can become in principle, many different cell types. And that applies also to brain cells, blood cells, or tissue cells. And stem cells have an amazing ability to renew over and over, over time. And this makes them very different from most non stem cells of our body, which instead have a very limited lifespan and are not able to change into other cell types. What's remarkable is that in adult mammalians, including human beings, nearly every tissue in the body has some kind of stem cells, which in principle have been made by Mother Nature to help repairing and maintaining tissues. In Ms. Research, specifically, we are exploring quite actively different types of stem cells for advanced therapeutics, for understanding also new mechanisms of disease. And for example, stem cells on the bone marrow, which are called hematopoietic stem cells, are being studied to reset the immune system in relapsing, remitting, refractory, very severe Ms. Other stem cells, including mesenchymal stem cells, can also regulate immune responses. They can support tissue repair. And in my case specifically, neural stem cells can also develop into brain cells and they can produce protective molecules and helping repairing nerve damage and preserve nerve function.
- [26:20]
A
So when we talk about stem cells. So you said hematopoietic stem cells. So those are cells that come out of the bone marrow, right? Yeah. And then you mentioned mesenchymal or mesenchymal. Potato. Potato. Where do the mesenchymal stem cells come from?
- [26:33]
C
Several tissues, including in bone marrow, but also including the adipose tissue, the dental part also contain a small fraction of mesenchymal stem cells, which can also be extracted out of the tissue. They can be manipulated in the laboratory and they can be also expanded to be used for a number of applications, including the development of advanced therapeutics. So the most significant difference between hematopoietic stem cells and mesenchymal stem cells and bone marrow is that hematopoietic stem cells are those responsible for making new blood cells, while mesenchymal stem cells are not responsible for making new blood cells.
- [27:04]
A
You said adipose tissue, which is our fat, right? Dental pulp. How do you get them out of your dental pulp?
- [27:09]
C
Usually like small biopsies.
- [27:10]
A
I think I'd rather have it taken out of my fat than my dental pulp.
- [27:14]
C
Yeah, yeah.
- [27:15]
A
All right. So can you walk us through mese stem cells, how they're collected, prepared and then reintroduced into the body? How do you do that?
- [27:24]
C
In general, the process begins by collecting these non hematopoietic fraction of cells from the bone marrow, applying a simple aspiration of the bone marrow from an accessible bodily site, and then once collected, there is a huge amount of quality controls and the use of chemically defined media in the laboratory to allow MSN gamma stem cells to expand while undergoing relative enrichment. And once they are ready to be used for therapeutic applications, they are reintroduced in the body. And this has been done extensively in animal models of different diseases, including neurological diseases and Ms. Like diseases, and in humans in pioneering clinical trials.
- [28:05]
A
Yeah, so speaking of clinical trials, so one of Those was the MEASMS or MESEMS clinical trial, studied 144 patients with Ms. From nine countries who either received an infusion of their own bone marrow derived mesenchymal stem cells or placebo. So what insights did this study provide?
- [28:24]
C
Yeah, we can say that The MESEM or MESEM Survey clinical trial was the largest academic, not for profit mesegamma stem cell based clinical trial ever run in the world. As you said, they incorporated different centers worldwide. So it was a gigantic adventure enterprise to uniform all the protocols and procedures to characterize, expand and reinfuse the cells across different centers. It was a phase two trial. So in a CICASIB trial where participants were randomly assigned to receive either an infusion of autologous bone methodide mesenchymal stem cells or placebo, basically a dummy injection of non cells. The exclusion criteria at the time were not super rigid. As a matter of fact, participants to the mesen trials had for the great majority relapsing remitting Ms. But there were also individuals with secondary progressive Ms. And individuals also with primary progressive Ms. Even the expanded disability status scale was very broad. Between 2.5, which is almost invisible type of Ms. To 6.5, which is walking with a stick for a limited distance. And the key insight of the study, which was, again, we have to remember, it was an efficacy study, showed that yes, the infusion intravenously or mesenchymal stem cells was safe, was doable, was feasible, but it basically was unaffective in reducing the risk of developing new MRI based lesions compared to placebo. There was no clear benefits in disability progression and there were no clear benefits in brain atrophy either. So I think the conclusion was a little bit disappointing. There were lots of expectations from the Messem study for the international nature of the trial, for the amount of financial and human resources devoted, but I think the authors in the published papers, which were published in the lance Neurology in 2021, was a quite honest assessment of the limitations of the study. So basically they were very honest, saying that although safe and well tolerated, the type of study they conducted was not in support of using bone marrow DMS and gamma stem cells to treat active forms of Ms. So I think this is important moving forward and it is important because it allows a very deep reflection on the type of cells used for advanced therapeutics, the route of injection, the methods of delivery, the type of preparation for the transplantation.
- [30:39]
A
Yeah, so those are some important insights trying to figure out why this trial failed and if there's still hope there. So speaking of hope, there was another study that was done at Hadassah Hospital in Jerusalem and then about 48 patients that had active or progressive Ms. And in that study, about 59% of patients treated with intrathecal mesenchymal stella. So that means in the spinal fluid and 41% treated with I mesenchymal stels had no evidence of Ms. Disease activity. And they actually used a sham group that did not get actual real mesenchymal stem cells and they only had 10% of patients were disease free in that category. So does the route make a difference if you had given into the spinal fluid versus giving it directly into the vein?
- [31:29]
C
I think that that's one of the key differences between the two, two trials to consider. I think the route of injection is important because it is important where we deliver the cells. So indeed, intrathecal delivery of mesenchymal cells in the ADASA consecutive trials showed a very relevant effect on patient outcomes. There is also some intrinsic biology. As I said at the beginning, one of the most important challenges of the mesem study was to coordinate those nine or 10 international centers participating to the trial to adopt the very same QC controls and quality checks across independent cell factories. The Hadassa trials were much less ambitious in terms of number of centers recruited. And they were applying a confidential still protected protocol which eventually is able to enrich mesenchymal stem cells. So basically, in addition to their intrinsic properties, the cells from the Hadassah center were also able to protect the brain through some intrinsic features that the protocols applied were able to exaggerate. So route of injection, type of cells, patient selections. And also another important aspect which is still very early days, is also the number of injections. The mesen studies heavily relied on a one off injection. And there is established agreement and evidence that the lifespan of mesenchyma stem cells in vivo is very short. So instead the Hadassa group proposed to repeat these it injections of mesenchymal stem cells showing a combination add on effect. The more injections were made on two patients. So there is a number of key aspects of developing an advanced cell therapy that we have to consider when either closing a chapter or when investing too much in another chapter.
- [33:16]
A
Yeah, that's really interesting that the cells use it. It also have neuroprotective qualities. So that's pretty fascinating. And just for our audience, you know, when we talk about giving it in the spinal fluid, this is done through a lumbar puncture and then the cells are given through the low back into the spinal fluid. So that's how these are being administered. So mesenchymal stem cells have been available. You know, many clinics out there propose to give you mesenchymal stem cells. I've had people get them out of their fat or adipose tissue and out of their and then given back intravenously. Generally is how I've seen people get it. And many patients have gone and spent over $10,000 to get a treatment. You know, frankly my experience, I've never seen anybody have some like major improvement with this. So what's your perspective on this option?
- [34:07]
C
I do not recommend these options. These clinics are in fact promoting unproven stem cell interventions as a cure not only for ms, but for a number of diseases. Even with other without providing a rationale, the complications which are described can or cannot occur. And they include infections, include strokes, they include even cancer. There is in fact among all these clinics a lack of standardization and regulatory oversight. And many of these clinics require patients to pay in cash. They don't provide any documentation in support of what's being injected. The type of procedures. They are not very much transparent. So I strongly, strongly advise patients to seek care from qualified medical professionals, to participate in regulated clinical trials where potential risk and benefit are studied, they are monitored and they can be mitigated. So it is crucial to prioritize evidence based medicine and protect vulnerable individuals from exploitation.
- [35:04]
A
Right, Those are really important pieces of advice there. Again, we're talking about mesenchymal stem cells. This is not hematopoietic stem cell transplant, but this is really just these mesenchymal stem cells. So let's dive on into another important topic. A lot of people out there have ethical or religious concerns about stem cells and I think it's primarily driven by the use of embryonic stem cells. So are embryonic stem cells actually used in Ms. Research or treatment today?
- [35:33]
C
No, not really. At the moment, not much human ESL research is applied to the development of clinically applicable medicines. And I think the major discovery is the possibility to reprogram somatic, even from minimally invasive biopsies into es like multipotent or pluripotent cells, which is basically what most of academics and even private companies are doing at the moment.
- [35:56]
A
Yeah, so let's dive into that. So you can take a mature cell and kind of backtrack and make it into a stem cell. How does that work? Can you explain it simply to our audience?
- [36:09]
C
I think it's a fantastic discovery which first experiment started by me 50s by John Gordon in Cambridge, when basically he put in close contact extract from the cytoplasm with nuclear material in frog cells, showing that the memory of the cells which is contained in the DNA in the nucleus can be resetted and even an old cell can be rejuvenated, they can be reprogrammed. And basically the principle, this new concept is called cell reprogramming, implies that if we take a cell of our skin, we deliver mechanically into that cell a combination of transcription factors which are competent for making a pluripotent stem cell. That cell will become a pluripotent stem cell.
- [36:48]
A
What does a pluripotent stem cell mean?
- [36:51]
C
So basically it is the most immature of the stem cells, which in principle possess all the information to become any cell of our body.
- [36:58]
A
Right. So pluripotent could turn into any type of cell and you can do that from a mature cell. So you could take a skin cell and make it into a pluripotent cell, which is kind of amazing because you kind of think you got to start at the beginning and then work, work your way out, but you can actually re engineer these backwards. So you've been at the forefront of this work with neural stem cells. What type of cell do you use to make your neural stem cells from?
- [37:20]
C
We created in collaboration these induced neural stem cells, which are not alike, the pluripotent embryonic stem cells. They have a little bit lower potency because we reprogram somatic cells towards directly neural stem cells. So basically, instead of becoming embryo like first and then becoming brain, we make the brain out of the skin to make it very simple for the lay audience which is listening to us. And that's done by a number of very, very complex technical tricks that we apply to the cell. So we deliver the factors, then we play with the ph, with the acidity of the tissue, culture media, with the temperature. And instead of making embryo like structures which are very difficult to control in terms of their ability to become anything, we make brain stable, expandable stem cells out of skin cells.
- [38:08]
A
That's amazing. So let's dive into the groundbreaking research that you've been involved in. So you did a phase one trial where you took these neural stem cells and they were transplanted into the brains of 15 people with progressive Ms. So can you explain what was involved in getting these stem cells in and what the goal was?
- [38:29]
C
The trial I participated to, which was the acronym is HNSC spms and that's already telling that it is a trial made of human neural stem cells transplanted in individuals with secondary progressive Ms. It is a phase one trial. We were able to recruit total 15 people with active and non active secondary progressive Ms. Which were offered treatment through ICV injection. So the cells were delivered via a microcannula inserted in the left lateral ventricle of the brain. Still using the cerebral spinal fluid and the cerebral spinal fluid circulation for a proper distribution of the injected cells in the whole brain and spinal cord.
- [39:12]
A
Let me clarify that for our audience. So there's a catheter attached to a little reservoir reservoirs under the scalp. Catheter goes in the brain and inside the brain there's fluid filled spaces called ventricles. So the stem cells are transmitted right down the catheter into the brain through this reservoir that's underneath the skin. So you can access it, you know, just with like an injection into the scalp and then get the stem cells right into the brain.
- [39:40]
C
Yeah, yeah. Thanks very much for clarifying. The patients were patients with long standing advanced secondary progressive Ms. So the disability at recruitment was between 6.5 and 8 PDI cells were delivered through this catheter that you mentioned. And we also associated with the treatment a low dose Six months only, which is half of the whole duration of the trial. Immune suppression with tacrolimus and low dose steroids. What is important to keep in mind is that this was also a dose escalating clinical trial. So basically those 15 individuals participating in the trial were randomized between four ascending doses of allogeneic neural stem cells, starting from low dose and ending up with high dose. Because the aim was to check for the feasibility, the safety, the tolerability, but also eventually identifying what we call the maximum tolerated dose.
- [40:39]
A
And when you talk about dose, you're talking about just the number of cells.
- [40:42]
C
Number of cells, yes.
- [40:43]
A
So what was the maximum number of cells that you implanted?
- [40:45]
C
The maximum was 24 millions of cells per individual. They are somatic adult neural stem cells.
- [40:51]
A
So what did you find out?
- [40:52]
C
We found out that it was possible to establish clinical grade and clinically applicable neural stem cell medicines, that the injection was well tolerated, there were no side effects, not even at the maximum cell number injected into individuals. And also we started observing a number of very interesting outcomes of the trial, which however is difficult to over speculate because of the nature of the trial. There was no control group. So basically we found that in a subgroup of patients, those receiving the highest number of cells, there was a trend towards reduction of brain atrophy. So basically the more the cells we injected, the least brain shrinkage and then another set of data which are very exciting, but again, not, not fully controlled is the way we looked at biological fluids. Without knowing what to expect from this advanced therapy in a group of patients with very high levels of disability, we decided to collect longitudinally multiple blood and cerebral spinal fluid samples per patient. So we managed to get five TSF samples per patient, up to seven blood samples per patient in 12 months of follow up. And we found a dose dependent and time sustained increase of markers of lipids, oxidation and catabolism, which we have no idea what it means, but it might imply, or it might suggest an increase in brain energy and homeostasis, kind of resolution of the chronic inflammatory process which was affecting these patients, inflammation and degeneration. But again, we need to repeat the data in a fully controlled clinical trial.
- [42:39]
A
Excellent. So this was phase one. Does this go forward with phase two?
- [42:43]
C
We have put together a fantastic international consortium of investigators. So there is people from the uk, people from the state, people from Switzerland, we have the best scientists for mri, the best statisticians, and we have created the RESTORE consortium which has just received pilot funding from the International Progressive Mass Alliance. Through this specific call, which is called Experimental Medicine Medicine Trial Exercise and we have been awarded a development award. The RESTORE consortium is co led by myself and Professor Angelo Vescovi. The other avenue is that we can use stem cell technologies to model Ms. In a dish and to make specific new interrogations on potentially new mechanism of disease.
- [43:25]
A
That's very exciting. We're so grateful as an Ms. Community for your leading research there in Cambridge in collaboration with Italy and around the globe. So we really appreciate your insights that you provided. And I know our audience has a lot of questions about stem cells, so this was really fantastic.
- [43:44]
C
Thanks very much for the opportunity for the questions and for time.
- [43:56]
A
Thanks to our listeners for downloading this episode of the Ms. Living well podcast. Repair Reset Reimagine Stem Cell Therapies for Multiple Sclerosis as shared by Professors Freedman and Pluchino. There is significant progress in the development of stem cell therapy for multiple sclerosis. AHSCT can be a powerful Ms. Treatment option for the right candidate, but comes with significant risk and requires an experienced medical team. On the other hand, mesenchymal stem cells have had mixed results. Future clinical trials on neural stem cells offer new hope. As always, we recommend staying informed, discussing all your options with a trusted healthcare team and only pursuing options backed by solid science. Thanks again to TG Therapeutics for sponsoring this episode. Keep in mind that the topics we discussed on the show are strictly informational and not medical advice. Any change in your treatment should be discussed directly with your own healthcare team. Our show is hosted by me, Dr. Barry Singer and Dr. Jamie Heilman and produced by Carriette Harmon. Our theme music is the Gold Lining by Broke for Free. If you like the show, please share with others living with Multiple Sclerosis and if you get a chance, please post a positive review on Apple Podcasts really helps more people find out about the show. You can follow on X at DrBarry Singer and Dr. Jamie Hallman at BrainBoyNeuro. One more information about our guests and their websites can be found in the show notes for this episode in the blog section on mslivingwell.org thanks so much for listening. This has been an Ms. Living well podcast.