Stem Cell Therapy for Parkinson's Disease Reality Check

Medscape

14-07-2025

This transcript has been edited for clarity.
Indu Subramanian, MD: Hello, everyone. Welcome to Medscape. I'm so excited to have Prof Roger Barker here, who is a professor of clinical neuroscience and honorary consultant in neurology at the University of Cambridge in England.
I am Indu Subramanian. I work at UCLA, and I'm excited to speak about the very hot topic of stem cells, and specifically today, about stem cells and Parkinson's. We may end up talking about stem cells in general as a focus, so keep watching and you'll learn a lot.
Prof Barker, I know that you are an amazing fount of knowledge in this space. Perhaps we can start with you describing a minute or two of your background and the history of stem cells.
Fetal Dopamine Cells
Roger A. Barker, MBBS, PhD: I started on cell-based therapies to repair disease of the brain many years ago — probably best to leave it at that rather than be too specific, otherwise it gives away my age. I'm essentially a neurologist here in Cambridge. I see patients half the week and the other half of the time I do research.
My original work was with Steve Dunnett here in Cambridge, and we were looking at how we could better repair the brain in Parkinson's. Particularly, the premise is, as you know in Parkinson's, you critically lose this population of dopamine cells. You have half a million on each side of your midbrain. When you lose half of those, you get the first features.
In theory, if you could transplant back a quarter of a million healthy dopamine cells of the type that are lost in Parkinson's, you should be able to put that bit of the brain back to normal. It's not a cure, but you should be able to repair that. This has been a topic people have looked at since the 1980s, and I came into it and did my PhD in the early 1990s to look at this.
Those early studies showed that you could put dopamine cells into the brain. They weren't stem cells; they were fetal dopamine cells. In some cases they survived, and in some cases they had very marked clinical benefits to the patients.
Best-case scenario, patients could go 20 years off medication with normal dopamine levels in their brain and looked normal, for all intents and purposes. It was a minority, and it was ethically a big problem because fetal tissue was being used. In different parts of the world, that receives different types of concerns. There was also a problem with logistics.
We recently published a trial called TransEuro, which used human fetal dopamine cells to treat Parkinson's. We found that there were major problems with getting sufficient tissue. With the 21 transplants we did, we had another 86 that were canceled because we didn't have sufficient tissue.
Regardless of the benefits from using fetal dopamine cells, logistically it's not possible. It's ethically very contentious. That work laid the foundation for the recent stem cell work because it showed that it could be done. When it worked well, it worked very well. It was just rather inconsistent.
Pluripotent Stem Cells
Subramanian: That brings us to the nonfetal type of stem cells. What are those exactly and why are we using them?
Barker: The main problems with the fetal tissue were, as I say, with logistics and ethics. It was very difficult to get sufficient amounts of them because you needed tissue from at least three or four fetuses to transplant one side of the brain, so the numbers needed were quite high.
Each person had their own individual product, so what we needed was a source of cells where we could manufacture large numbers of the dopamine cells that we needed, we could do it consistently, and ideally we could then freeze it and you could say we've got a standard package of therapy we could give any patient.
This was the ambition, but there wasn't much scope for it really until 1998 when human embryonic stem cells were first made by Jamie Thomson. Obviously, in 2006-2007, Shinya Yamanaka and the team in Kyoto made induced pluripotent stem cells and human pluripotent stem cells.
Now you have the capacity to make human lines of embryonic and induced pluripotent stem cells. The next trick was, could you turn those into the dopamine cells you needed for Parkinson's?
That was really solved by the labs of Lorenz Studer in New York and Malin Parmar in Lund, who both came up with protocols in 2011-2012 to show that you could convert human stem cells into dopamine cells of a midbrain type.
That started a whole process of work about taking these therapies to the clinic from that starting point. It was also shown at around the same time by the group in Japan, led by Jun Takahashi, that they could do it as well. They could make human induced pluripotent stem cells into dopamine cells.
Just under 15 years ago, we now had all the substrates to make the dopamine cells, which we could then use in clinical trials. Obviously, a large amount of work needed to take place before we could get to the clinical trials, which have recently just published.
Subramanian: Can you explain the pluripotent stem cells? How do you make them make dopamine? How does that work?
Barker: It's an interesting question because obviously an embryonic stem cell is a stem cell you get from an embryo. We were all at some point an embryonic stem cell. Those cells can turn into any cell in your body.
When you do an induced pluripotent stem cell, you get an adult cell, skin cell, or a blood cell, you reprogram it back to a stem cell state, and then you try and flip it into a dopamine cell. The trick is, can you work out what you need to give a stem cell to convince it to become a brain cell and then convince it to become a dopamine cell?
Now, I'm not clever enough to do that, but there are various people who are. That, in part, relates to knowing what happens in normal development. One of the challenges that put the field back for a number of years was thinking that human development in terms of dopamine cells was the same as you'd see in a mouse.
People could convert mouse stem cells into mouse dopamine cells quite easily, and that was established over 25 years ago. People thought it'd be the same with human, but it proved not to be the case. It was a different developmental program you had to follow.
Once that was cracked, then people could add this cocktail of factors, convince your stem cells to become a neural stem cell, and then to become a dopamine stem cell. Then, the idea is when you put in a dopamine stem cell precursor, which is what we do, that will then mature into the dopamine cell that you want once it's put in the brain.
Recent Nature Studies
Subramanian: Tell us about the most recent trials, because they're very exciting to many people but I think there's still some caution to be had. Tell us what your thoughts are.
Barker: It's been very interesting. Obviously, from those original discoveries back in 2011-2012, the next 10 years was spent trying to show that you could make human stem cells into dopamine precursors of the type needed to replace those lost, and it could be done at clinical grade.
That involved an enormous amount of work to show you could manufacture these things to a standard necessary to put into a human. You had to show that they were safe so when you transplanted them, they didn't form tumors or they didn't go and make the wrong type of cells.
That was done by the team in Japan, it was done by the team in New York, and we've also done it in Europe. More recently, the two teams led by Viviane Tabar and Lorenz Studer in New York, who set up a company called BlueRock, published their data, and the group of Jun Takahashi and his team in Kyoto published theirs. Both of them published papers in Nature .
The Japanese study took seven patients and they used two doses of cells, and the group in New York used 12 patients. They grafted some in New York, some in Toronto; five at one dose, seven at a higher dose. Those studies both showed, if you look at them in totality, that it was safe. Of the 19 patients that were grafted, there were no major problems within them. It wasn't that they weren't without side effects, but there was nothing serious that would give one concern.
The patients could tolerate the procedure, they could tolerate the immunosuppression, which they had to make as a result of having this therapy. There were no abnormal signals on the scan that would worry you that they were forming tumors or that things were happening in the brain.
It was feasible and it was safe. The question is, was it effective? That, I think, is a little more questionable in the sense that these are very early studies.
One of the big challenges is knowing what dose of cells to give, because you can only guess how many you need to put in to make the number you want. Those are often made from assumptions you've made in the lab, so in rats or mice, which is difficult to then translate into the adult human brain. They had to guess how many cells to transplant, which is why there were two doses.
If you look at the efficacy and you look at the survival of the cells, which is done using special imaging, using PET imaging, particularly with F-DOPA, which is picked up by dopamine cells, you find that the clinical response in the Japanese study was a bit variable. The response in the New York group, the BlueRock study, was that the higher dose seemed to have more of a clinical response than the lower dose.
In the PET imaging, looking at dopamine survival, in the Japanese study, there were little hotspots. There was some evidence that the cells survived, but it was a bit hit-and-miss. In the New York BlueRock study, the signal changes were relatively small. Although there was a clinical response, the imaging was less impressive.
The other way, then, to look at it is to ask how much medication did people take. Obviously, if the transplant's working very well, then it's replacing the dopamine and you need less medication. Actually, in both studies, there wasn't a huge reduction in the amount of medication that people took.
My conclusion from those trials would be that it was safe, it was feasible, and it was encouraging, but we haven't quite solved the problem. We haven't quite solved the problem of how many cells to give. We certainly haven't restored patients back to normal. There are other things we need to do before we could say that this therapy is ready for a big trial or for primetime in the clinic.
Do We Know Where in the Brain to Put Stem Cells?
Subramanian: I appreciate that analysis because that's very helpful. I think people are always wanting to jump to conclusions that we're ready for real time, and I think it's still some time away. Just one or two other last thoughts. Where are we putting those cells in the current studies?
Barker: It's a very good question. Obviously, at the bottom part of the brain is the substantia nigra at the top of the stem of the brain. They project up to a thing called the striatum, and the striatum has two parts called the caudate and putamen.
In Parkinson's, the putamen takes the biggest hit. That's where you lose most of the dopamine and the cells die off in the nigra. The transplant itself is not put in the nigra because we're not convinced the fibers will grow back.
We put the cells where the dopamine is lost and where the dopamine is lost the most, so we transplant them directly into the putamen, into the place where we think dopamine will have its maximum effect if these cells survive and innervate.
Linked to that is, of course, we're not quite sure how to do that either because there is no device for injecting cells into the brain because no one's done it before. As I say, we don't quite know the dose. We don't quite know how many deposits to put in.
The two groups who've published have used slightly different doses, slightly different cannulae to put the cells in the brain, and a slightly different number of tracks. Those may be critical factors. In our own trial, which is yet to finish, we've used slightly different doses, slightly different devices, and slightly different numbers of tracks.
I think the other important message to get across is that these trials are not all the same. There are subtle differences between them. They're fundamentally tackling the same problem, but they're not exactly the same.
Putting them all together and saying that, together, they show this, is a useful headline, but the detail is actually quite important.
Subramanian: Absolutely. The devil is always in the details, isn't it? Thank you so much, Prof Barker. I so enjoyed this conversation. Thank you for joining us today.
Barker: Thank you very much.