The long awaited results of a bone marrow MSC stroke trial were published recently, and the results were quite striking (with caveats that we’ll get to). This topic is near and dear to my heart, as using MSCs for stroke recovery is my field of expertise, and the preclinical work that led to this trial was pioneered by my mentors. I’m not an unbiased observer, so to speak, but the results of this trial speak for themselves, so I’m unafraid of my inherent pro-MSC bent. The trial was small; only 18 patients were recruited, two of whom dropped out before its completion. That means that only 16 patients had results reported, but the results for those patients were quite positive on the balance. The authors, who were led by an outstanding physician Dr. Gary Steinberg of Stanford, report that 13 of 16 patients saw clinically meaningful improvements in 4 of 5 measures that they tested for. The measures are all commonly used clinical scores that measure patients’ ability to move freely and conduct daily life, so this type of improvement is indeed impressive. Before we get into the nitty-gritty of the results, let’s first talk about what they did and how they did it.

In this study, patients were recruited who had suffered a stroke at least 6 months prior to cell treatment; the patients also needed to show no clinically meaningful improvement over a period of months before treatment. Both of these criteria are important because of what they were trying to measure. Specifically, they wanted to measure regeneration of the nervous system. As a patient recovers from a stroke, inflammation resides, swelling decreases, etc, and these things all contribute to recovery. However, after a period of weeks to months, this recovery stalls, and the patient is considered to be finished recovering. It is generally accepted that after 6 months, little to no further recovery is likely. So by treating patients outside of 6 months, the researchers could be reasonably certain that any clinical improvements they measured would be due to new growth of brain cells, blood vessels, other types of support cells, etc. That is, by measuring patients’ clinical improvement, they were really measuring whether MSCs were contributing to brain growth. In this trial, four different doses of MSCs were administered, and they were delivered to patients by direct injection into the brain.

First, let’s talk about what’s good and right with this trial. The most important thing is that patients improved (obviously). Stroke affects a lot of people (almost 800,000/year in the US), and most do not have any treatment options beyond physical therapy. The standard treatment for stroke is to try to remove the clot that is causing the stroke, either by physically removing it or by using an agent that dissolves clots called tPA. This strategy suffers from the fact that they need to be administered within hours of a stroke, and many patients don’t even know they’re having a stroke for long after this brief window has expired. This combined with other safety concerns means that only 3-5% of stroke patients get any therapy at all. Over the years, many, many drugs have been proposed to stimulate regeneration. So far, none has worked. MSCs are the best hope ever for stroke patients that they might improve beyond their brief recovery period. As stroke is the leading cause of adult onset disability, affecting literally millions of people, this would be welcome news these survivors and their families, who of course often double as caretakers. Just how well did it work? In the press release that Stanford sent out as a companion, one patient, a woman in her 30s, was quoted as saying, “My right arm wasn’t working at all. It felt like it was almost dead. My right leg worked, but not well. I used a wheelchair a lot. After my surgery, they woke up.” Let that sink in for a minute. MSCs helped resolve hemi-paralysis, one of the worst outcomes one can have from a stroke. Her limbs “woke up.” This is nothing short of a giant leap forward in regenerative medicine, and we have MSCs to thank for it.

This patient may have had the most dramatic recovery of all the study participants, but others did well, too. The researchers used 5 common measures of recovery to determine how their patients fared over the course of one year from injection. They found that in 4 of the five tests, patients improved significantly, and that the improvement continued for 6 months on average, before plateauing. They did not observe regression after the plateau, meaning that the effects were lasting. The one measure they did not see improvement on, the Modified Rankin Score, is geared more toward acute recovery, so even that was not entirely unexpected.
The second most important thing was safety. They did not observe any adverse effects that were attributed to the cells. A few patients had minor “adverse events” that could not be definitely ruled out as having been caused by the cells, but all serious adverse events that patients experienced were determined to have been caused by the surgery itself or else unrelated to the treatment.

This is good news, but it brings us to the first interesting point on which I tend to disagree with the designers of the study. I can’t quite figure why they chose to inject the cells into the brain. Their reasoning is based on a meta-analysis(a study of studies) that showed that in all the qualified animal studies, intra-parenchymal (IP; brain injection) was the most efficacious method of delivery, followed by intra-arterial (IA), then intra-venous (IV) injection. Case closed, no? Well, not exactly. In the meta-analysis on which the study design was based, the authors themselves state that the difference between IP and IV injection was small, and both are vastly superior to no treatment. It seems to me that the risk factors associated with doing a brain surgery would be outweighed by the small benefit that might come from avoiding IV injection. One can only speculate as to why they chose the route they did, but my guess is that it had something to do with really needing this trial to succeed, so they wanted to use every advantage they could get. I don’t blame them, if that’s in fact the case. This work is 20 years in the making, and it represents a leap forward that the stroke community has been waiting on since Paul Broca first described brain lesions in the 19th century.

The other curious thing was their choice of cells. The authors chose to use a cell line from a single donor, which had been modified to express a portion of a protein call Notch-1. Their choice of using a single donor cell comes from two places. First, they needed to keep the treatment as standard as possible. Second, a company called SanBio sponsored the project, so it’s likely that they have some money interest in these cells for future use. That’s ok; that’s how drug research works. But it may not be the best science that could have been done. Notch-1 has been shown to force MSCs to behave like neurons, the conductive cells of the brain. So the thinking goes that we should pre-express Notch-1 before injecting the cells so that they are more neuron-like, and can therefore help repair better. Sounds reasonable, no? Two distinct facts torpedo this idea. First, the cells all disappeared within one month of injection (one can track this by MRI), but the patients didn’t hit peak recovery until three months! (Not to mention that they stayedbetter for 12 months.) Second, they could not detect any dose response in their cohort. Granted, the sample size was small, but the smallest to largest dose was a factor of 4, which is a large difference. If Notch-1 was helping the MSCs to make new neurons, one would assume that neither of these observations could be possible. Again, I think this might have been an intellectual property play by SanBio and not a science-based decision. This is further evidenced by the fact that the entire rationale in the study design was based on one paper from 2004 (the one referenced above), and there is not a robust body of literature showing that Notch-1 does much to improve outcomes.

​All in all, there is nothing in the study that leads us to believe that they wouldn’t have had better outcomes with a patient’s own, young cells, were that an option for any of these study participants. Also, I don’t want to say too much on the negative side. This was a fantastic study, and it will help the field of MSC-based regenerative medicine along greatly. The study was registered for two years, so it will be fantastic to see next year what the final result it. I can’t imagine that they won’t move to a much bigger trial based on these results, however.

The long awaited results of a bone marrow MSC stroke trial were published recently, and the results were quite striking (with caveats that we’ll get to). This topic is near and dear to my heart, as using MSCs for stroke recovery is my field of expertise, and the preclinical work that led to this trial was pioneered by my mentors. I’m not an unbiased observer, so to speak, but the results of this trial speak for themselves, so I’m unafraid of my inherent pro-MSC bent. The trial was small; only 18 patients were recruited, two of whom dropped out before its completion. That means that only 16 patients had results reported, but the results for those patients were quite positive on the balance. The authors, who were led by an outstanding physician Dr. Gary Steinberg of Stanford, report that 13 of 16 patients saw clinically meaningful improvements in 4 of 5 measures that they tested for. The measures are all commonly used clinical scores that measure patients’ ability to move freely and conduct daily life, so this type of improvement is indeed impressive. Before we get into the nitty-gritty of the results, let’s first talk about what they did and how they did it.

In this study, patients were recruited who had suffered a stroke at least 6 months prior to cell treatment; the patients also needed to show no clinically meaningful improvement over a period of months before treatment. Both of these criteria are important because of what they were trying to measure. Specifically, they wanted to measure regeneration of the nervous system. As a patient recovers from a stroke, inflammation resides, swelling decreases, etc, and these things all contribute to recovery. However, after a period of weeks to months, this recovery stalls, and the patient is considered to be finished recovering. It is generally accepted that after 6 months, little to no further recovery is likely. So by treating patients outside of 6 months, the researchers could be reasonably certain that any clinical improvements they measured would be due to new growth of brain cells, blood vessels, other types of support cells, etc. That is, by measuring patients’ clinical improvement, they were really measuring whether MSCs were contributing to brain growth. In this trial, four different doses of MSCs were administered, and they were delivered to patients by direct injection into the brain.

First, let’s talk about what’s good and right with this trial. The most important thing is that patients improved (obviously). Stroke affects a lot of people (almost 800,000/year in the US), and most do not have any treatment options beyond physical therapy. The standard treatment for stroke is to try to remove the clot that is causing the stroke, either by physically removing it or by using an agent that dissolves clots called tPA. This strategy suffers from the fact that they need to be administered within hours of a stroke, and many patients don’t even know they’re having a stroke for long after this brief window has expired. This combined with other safety concerns means that only 3-5% of stroke patients get any therapy at all. Over the years, many, many drugs have been proposed to stimulate regeneration. So far, none has worked. MSCs are the best hope ever for stroke patients that they might improve beyond their brief recovery period. As stroke is the leading cause of adult onset disability, affecting literally millions of people, this would be welcome news these survivors and their families, who of course often double as caretakers. Just how well did it work? In the press release that Stanford sent out as a companion, one patient, a woman in her 30s, was quoted as saying, “My right arm wasn’t working at all. It felt like it was almost dead. My right leg worked, but not well. I used a wheelchair a lot. After my surgery, they woke up.” Let that sink in for a minute. MSCs helped resolve hemi-paralysis, one of the worst outcomes one can have from a stroke. Her limbs “woke up.” This is nothing short of a giant leap forward in regenerative medicine, and we have MSCs to thank for it.

This patient may have had the most dramatic recovery of all the study participants, but others did well, too. The researchers used 5 common measures of recovery to determine how their patients fared over the course of one year from injection. They found that in 4 of the five tests, patients improved significantly, and that the improvement continued for 6 months on average, before plateauing. They did not observe regression after the plateau, meaning that the effects were lasting. The one measure they did not see improvement on, the Modified Rankin Score, is geared more toward acute recovery, so even that was not entirely unexpected.
The second most important thing was safety. They did not observe any adverse effects that were attributed to the cells. A few patients had minor “adverse events” that could not be definitely ruled out as having been caused by the cells, but all serious adverse events that patients experienced were determined to have been caused by the surgery itself or else unrelated to the treatment.

This is good news, but it brings us to the first interesting point on which I tend to disagree with the designers of the study. I can’t quite figure why they chose to inject the cells into the brain. Their reasoning is based on a meta-analysis(a study of studies) that showed that in all the qualified animal studies, intra-parenchymal (IP; brain injection) was the most efficacious method of delivery, followed by intra-arterial (IA), then intra-venous (IV) injection. Case closed, no? Well, not exactly. In the meta-analysis on which the study design was based, the authors themselves state that the difference between IP and IV injection was small, and both are vastly superior to no treatment. It seems to me that the risk factors associated with doing a brain surgery would be outweighed by the small benefit that might come from avoiding IV injection. One can only speculate as to why they chose the route they did, but my guess is that it had something to do with really needing this trial to succeed, so they wanted to use every advantage they could get. I don’t blame them, if that’s in fact the case. This work is 20 years in the making, and it represents a leap forward that the stroke community has been waiting on since Paul Broca first described brain lesions in the 19th century.

The other curious thing was their choice of cells. The authors chose to use a cell line from a single donor, which had been modified to express a portion of a protein call Notch-1. Their choice of using a single donor cell comes from two places. First, they needed to keep the treatment as standard as possible. Second, a company called SanBio sponsored the project, so it’s likely that they have some money interest in these cells for future use. That’s ok; that’s how drug research works. But it may not be the best science that could have been done. Notch-1 has been shown to force MSCs to behave like neurons, the conductive cells of the brain. So the thinking goes that we should pre-express Notch-1 before injecting the cells so that they are more neuron-like, and can therefore help repair better. Sounds reasonable, no? Two distinct facts torpedo this idea. First, the cells all disappeared within one month of injection (one can track this by MRI), but the patients didn’t hit peak recovery until three months! (Not to mention that they stayedbetter for 12 months.) Second, they could not detect any dose response in their cohort. Granted, the sample size was small, but the smallest to largest dose was a factor of 4, which is a large difference. If Notch-1 was helping the MSCs to make new neurons, one would assume that neither of these observations could be possible. Again, I think this might have been an intellectual property play by SanBio and not a science-based decision. This is further evidenced by the fact that the entire rationale in the study design was based on one paper from 2004 (the one referenced above), and there is not a robust body of literature showing that Notch-1 does much to improve outcomes.

​All in all, there is nothing in the study that leads us to believe that they wouldn’t have had better outcomes with a patient’s own, young cells, were that an option for any of these study participants. Also, I don’t want to say too much on the negative side. This was a fantastic study, and it will help the field of MSC-based regenerative medicine along greatly. The study was registered for two years, so it will be fantastic to see next year what the final result it. I can’t imagine that they won’t move to a much bigger trial based on these results, however.