Dr. James Beck 00:00:00
Hello everyone and welcome to Expert Briefing. I'm Dr. James Beck, your moderator and Chief Scientific Officer of the Parkinson's Foundation. With this, our third Expert Briefing, we are halfway through our 14th season and we're geared to have a great discussion today. Our topic for today will be centered around understanding gene and cell-based therapies in Parkinson's. So while still in the developmental stage, genetic and cell-based therapies are or soon will be entering clinical trials. These therapies are moving forward because they may hold promise for people with Parkinson's disease. The goal of clinical trials is to understand if that is indeed the case.
We will be reviewing what we hope to expect from these therapies, both in terms of symptom management and disease progression. Before we begin, I'd like to share a little bit about the Parkinson's Foundation. The Parkinson's Foundation is a nonprofit focused on bettering the lives of those living with Parkinson's through improving care and advancing research. Importantly, everything we do is in close concert with our community to ensure that our actions are aligned with the needs and priorities of those living with Parkinson's disease. We're focused on improving care for those living with PD, advancing research towards a cure, and empowering our global community much like we're doing today with our expert briefing.
We have listeners from 22 countries across the globe today, and I want to take a moment to acknowledge this connection and celebrate that our community is coming together in education and engagement. Thank you all for continuing to show up for yourselves and for our community. Feel free to share where you're joining from in the Q&A below, and we'll keep track of that. Before we begin, I'd like to get a sense of where people are, and who they are. So, you'll see a poll just launched and tell us whether you're a person with Parkinson's, a spouse, partner, physician. And if you're joining us from Facebook Live, please respond using the comment section as part of that.
This will tell us what best describes your connection to Parkinson's disease. And we'll be closing this poll in just a few seconds to understand where you are as part of that process.
Okay. Results are in, and not surprisingly, many people here are living with Parkinson's, and many care partners are here as well. We have other family members and a fair number of health professionals are joining us today too. That's fantastic. So thanks to everyone for sharing your connection to Parkinson's. Today's expert briefing is supported by Prevail Therapeutics and the Light of Day Foundation. We want to take a moment to thank our sponsors for supporting the mission of the Parkinson's Foundation through unrestricted educational grants. And then next, I'd like to say for your convenience, we're recording today's Expert Briefing and the recording will be made available on our website, Parkinson.org/ExpertBriefings.
Dr. James Beck 00:02:46
We'll also be emailing a link of the recording and other resources related to today's topic to all who've registered for today's briefing. So no need to worry about that. But feel free to let your friends know if they missed it today that they will be able to watch a recording of it soon. So now, I'd like to introduce Roger Barker. Dr. Roger Barker is a professor of clinical neuroscience at the University of Cambridge and consultant neurologist at Addenbrooke's Hospital. There, he runs the regional NHS Huntington's Disease and Parkinson's Disease clinics. Dr. Barker is also the lead academic scientist of the Drug Discovery Institute in Cambridge, as well as a principal investigator at the John van Geest Centre for Brain Repair. Dr. Barker's research investigates the heterogeneity and its basis in both Huntington's and Parkinson's disease. This has informed his work on studies of new experimental therapeutics for these conditions including cell and gene therapies as well as drug repurposing. So in addition to numerous professional achievements and activities, Dr. Barker is currently running two gene therapy trials for Parkinson's, a fetal dopamine cell transplant trial called TRANSEURO, and he's now just started a new trial with a team in Sweden using stem cell derived dopamine cells called STEM-PD. Clearly, he's well positioned to talk with us today about cell and gene therapies. So Dr. Barker, welcome, and thank you for sharing your time and knowledge with us today.
Dr. Roger Barker 00:04:04
Well, thank you very much. I'm now going to share my screen and I hope that everyone can see my slides in the right format. Thank you very much, Jim, and thank you very much for inviting me to talk. What I thought I would do is I thought I would start off by just introducing a little bit about where cell and gene therapies fit among the new therapies relating to Parkinson's disease. Then I'm going to walk through gene therapies and what they're designed to do and how they're working and where we've got to with trials before going into cell therapies and then concluding a little bit about how we might combine these and thinking about how to use them, in the future.
Just to begin with, my disclosures, I advise a number of companies mainly around cell and gene-based therapy as well as patient-related outcomes, which have become quite an important area for us to investigate not only established therapies but novel therapeutics.
To begin with, I wanted to talk about how do we think of Parkinson's? This is a very simplistic view, but essentially if we think that in Parkinson's, there's a genetic predisposition to the condition that in some way leads to a change in this protein called alpha-synuclein, which then either spreads, causes inflammation, the aggregation of this protein alpha-synuclein, which is a normal protein in everyone's brain, one percent of our brain is alpha-synuclein, but when it starts to aggregate, it causes problems within the cells. Those cells then die, and when a significant number of those cells have died, people start to present with features of Parkinson's.
This is a very simple cascade in which to sort of simplistically think how Parkinson's might come about. But it does help inform us about how people have thought about it therapeutically in terms of novel therapies. So, I don't seem to be advancing my slide. There we go. So, one way is obviously to improve the sort of symptomatic treatments and some of the complications we see in terms of levodopa induced dyskinesias. There are developments of new therapies around that.
There are better ways in which we can deliver deep brain stimulation now, so-called closed loop, where it can learn what's happening in the brain and control the stimulation that's given to the brain and regulate some of the problems and treat better some of the complications we see.
There's also, as you will know, attempts to try and reduce the production of alpha-synuclein. If you produce less of it, less of it will aggregate, will that slow down the disease? This is done by either targeting the production of alpha-synuclein through interfering with its pathway, a so-called antisense oligonucleotide binds to the connection between the gene and the protein, and beta agonists, the salbutamol and other things which are used in asthma. There's some association between that and alpha-synuclein production which people are looking at. There are ways of trying to stop the spread of alpha-synuclein as it moves from one cell to another. This is a very popular hypothesis at the moment.
Dr. Roger Barker 00:06:59
So could we develop vaccines either active immunization or passive immunization to stop that. There is a lot of drug repurposing, so agents which are in current clinical practice for one indication; could we use them for another? In this case to slow down Parkinson's disease around different pathways. That includes stopping inflammation. I'm going to talk about gene therapies around mainly replacing lost dopamine, either in terms of replacing dopamine or regrowing the pathway, but there's also new gene therapies which are coming to clinic around trying to slow down the disease.
I'll talk about growth factors and then finally talk about replacing the lost cells, which is really what I'm going to talk about with cell replacement therapy, the strategy here being to replace the missing dopamine cells that lie at the heart of the condition. Now it's important, I think, to get this global view because you have to position cell and gene therapies in the landscape of what else is out there and as I will come to at the end, they are not mutually exclusive. So all of these therapies in the future could be combined to treat people with Parkinson's. But if we now sort of think about gene therapies for Parkinson's disease, what has been the strategy that people have taken? Well, one approach is to regrow and rescue the dopamine system.
The idea here is that we give a growth factor or fertilizer to the dopamine system. We inject it into the brain and the idea is that the gene which is put into the brain will infect cells in the brain. Those cells will secrete a factor which basically is a fertilizer to regrow the dopamine system, which exists in the brain. So it's not it's not replacing it, it's simply trying to regrow and preserve what's already there. The second strategy which works on a slightly different principle is to say, well, actually, I'm not going to worry about that system that's there. I'm going to assume that that's dying and going.
Can I just put in a gene which will infect cells and those cells will now become little dopamine factories. So I will simply, instead of giving people tablets, I will convert a bunch of cells in their brain to be little dopamine factories to produce dopamine in the brain at the site where I need it. So these are gene therapies which are designed to transfect cells and turn them into dopamine producing cells. And then the final approach, which is as I say, a relatively new approach, is actually put in a gene therapy which is designed to affect the disease pathway, interfere with it, and by so doing,
They can actually slow down the disease process. So truly disease modifying, whereas the others in some ways are more around symptomatic therapy. So those are the three main strategies that have been taken forward with gene therapies for Parkinson's. And this has been going on for about 20 years. So although it's still experimental, it has been around for a while. And the first place where I'm going to start is with the idea of rescuing or regrowing the system. This really became very much a topic in the last end of the last century.
Dr. Roger Barker 00:10:02
And in 1993, a sort of seminal discovery was made that there was a factor called GDNF, glial cell line-derived neurotrophic factor, which was discovered to actually be extremely powerful at regrowing dopamine nerve cells, at least in the lab. And this led to a whole series of trials where people had GDNF, which I'm sure you're familiar with, where GDNF was actually infused into people's brains to try and regrow that system. And that had a sort of checkered history and ultimately it's still unclear whether it works. But linked to this was a gene therapy program which worked on the same principle.
And that was with a gene therapy called neurturin. So neurturin is related to GDNF, it's similar, but it's not perhaps quite as powerful. And the idea here was to take a GDNF-like substance, i.e. Neurturin, connect it to a gene, which is what the AAV2 stands for in that title of that slide, which is an adeno-associated virus, it's a type of virus which is commonly used to infect cells. And then the idea was to inject it into the brain at the site where dopamine is normally released, which is in the bit of the brain called the putamen. And if we inject the gene with the growth factor there, the cells will take up the gene, they'll secrete the growth factor.
That will then promote the growth of the dopamine fibers which are innervating that part of the brain. And so this went to a double-blind placebo-controlled trial, by which I mean that patients were randomized to either have the active treatment or imitation surgery. So they went to theater, they had a hole drilled in their skull, they had the entire procedure done, except nothing was actually injected into their brain. The only person who knew whether anything had been given would be the surgeon. The patient would not know, neither would the physician who was assessing them.
And essentially what this trial showed was that at 12 months, there was absolutely no difference between those that had had neurturin gene therapy injected into their brain versus those who had not. All of the patients seemed to improve to some extent, but being given the gene therapy didn't seem to give you any added benefit. In other words, there didn't seem to be any significant therapeutic benefit for this therapy. At 12 months, everyone was told what they had and then they were followed up for another six months and at the end of that time, 18 months after they'd had the original intervention, interestingly, people who had actually had the active treatment seemed to be doing slightly better.
So that then led people to think, well, perhaps this trial didn't work because we didn't give enough of it at the right sites, and we didn't wait long enough. So a second trial was done, which worked on the same principle, except now that the growth factor attached to the gene was injected into the area where dopamine is released, the striatum, and where the dopamine nerve cells live in the substantia nigra. So they had injections at two sites and they waited for two years. And the outcome of that study, which was published a number of years ago, unfortunately showed there was no difference between the two groups.
Dr. Roger Barker 00:13:05
So using this particular gene therapy approach with a growth factor, it appeared in two trials that actually regrowing the dopamine system whilst in principle a good idea didn't produce any therapeutic benefit. So that then sort of suggests, well, actually this is probably not a useful way forward and that might be a very sensible conclusion to come to. It also sort of resonated a bit with the GDNF infusion studies which tended to show similar results.
We a number of years ago actually, I think it was about, it was pre-COVID, so it's 2019, I think or '18, we held a meeting in Grand Rapids where we brought together all the groups who worked on, GDNF and neurturin to revisit this area to see if we could learn anything from the trials we'd done. And we summarized this in a paper that published in the Journal of Parkinson's Disease. And what we actually came to the conclusion was that whilst these trials didn't give us any convincing evidence that this strategy worked, there were also reasons to believe that it could be improved upon. And one of the areas which we felt that was particularly attractive was the idea to go earlier in the disease course.
And the reason for that is if you look at the number of dopamine fibers in the Parkinson brain as a function of disease duration, within the first one to three years, one still has quite a lot of dopamine fibers existing in the site where the growth factor has been given. After three years, it declines quite rapidly and by five to fifteen years, which is when most patients were entered into this trial, there's almost no dopamine fibers there.
The consequence of that is, if you're putting in a growth factor into an area that has nothing to grow, it's not going to work. And so the analogy I have is you could have the best fertilizer in the world, if you put it on a flower bed with no bulbs in it, nothing will grow. And there's nothing wrong with the fertilizer, there's just nothing there for it to rescue and grow. We feel that if this therapy is to be taken forward, it needs to be moved to an earlier stage of disease. And there are other operational aspects of it which I think also need to be considered. This having now been taken on board, there are gene therapy trials that are now moving forward with GDNF. So uniQure are doing one.
In the UK Parkinson's UK are looking to do a protein infusion, not gene therapy. But Bayer have started a new trial, not using neurturin now but going back to the original GDNF to inject that into the brain with a gene therapy. So gene therapy and growth factors for Parkinson's so far have been a little disappointing, but nevertheless they're back in the clinic and people are rethinking how to administer them. The second strategy around gene therapy is not to try and regrow the intrinsic network but simply to put in a gene therapy that will infect the cells in the brain.
Such as the astrocytes or the glial cells, the non-nerve cells, and give them the capacity to make dopamine. And there are a number of different ways in which they've done this. One is to give the cells the synthetic pathway for dopamine in its entirety. Others did this to give enzymes which only mediate aspects of that pathway and then give people medication which can then be used to convert it into the active agent. This has been the subject of a number of clinical trials and I have been directly involved with two of these.
Dr. Roger Barker 00:16:29
The first was this gene therapy trial that began by Stéphane Palfi in Paris in France and we were then involved towards the end of it in Cambridge in the UK called ProSavin, which led to a second gene therapy trial that we're involved with which only took place in the UK, which was the SUNRISE therapy or OXB-102. The ProSavin gene therapy, which is where I'm going to begin, which was run with my colleague Phil Buttery in Cambridge, involved injecting a different virus, a lentivirus as it's called.
It infects cells, and within that gene therapy are the pathways for making dopamine. They contain the enzymes for making dopamine. And essentially what we did is we looked at different doses, different ways of delivering it, and had this sort of iterative process by which it was delivered. And it was delivered in one single operation on both sides of the brain into the area where dopamine is normally released. The idea being, as I say, to infect that area so it could now produce dopamine from the cells within it. And what we found using three different doses of this agent delivered in slightly different ways was that it did produce a benefit.
So it definitely had some benefit and was relatively safe. The major side effect we saw were actually dyskinesias which could be a sign of efficacy. But ultimately, whilst we saw a signal of effect, it wasn't of a magnitude that made it competitive. So compared to things like DBS and other treatments, it was not as effective. So Oxford Biomedica went back to the drawing board and came up with a new gene therapy called OXB-102, which was then taken on by Axovant who then sold it to Sio Gene Therapies.
And this was a study which was to have three cohorts, of increasing doses. And we treated four patients in Cambridge and two in London, and then unfortunately the company Sio Gene Therapies decided that for financial reasons they would not pursue this therapy further. So they, aborted the trial at this point, stopped the trial at this point, and basically gave the license back to Oxford Biomedica who are currently, not developing this therapy. So unfortunately, we're in a position where we're halfway through or two-thirds of the way through a trial.
And we don't really know, what to make of the data except that the patients we've seen, at least in Cambridge, one of them has stabilized. In London, some of them have gone on to get deep brain stimulation. So, what we can only conclude from this is that there appears to be some stabilization, but it's hard to draw any firm conclusions.
In parallel to these studies which were done by Oxford Biomedica, Voyager Therapeutics in the US were running a trial where they only used one enzyme associated with making dopamine. They did this again in a sort of iterative way, much the same way as we did in the ProSavin study where they gave different doses to different groups of patients, the idea being, can we give more gene therapy, bigger volumes, fill up the area where we're trying to affect the cells and get a bigger response. And that's what they found is that the more they gave, the more they infected the area they were interested in, and the bigger the response they saw.
Dr. Roger Barker 00:19:51
Unfortunately with this study, they also saw some signal changes on the scanning which they weren't quite sure what it meant. They reported that to the FDA and that trial as far as I know has also been stopped. And again, there's no indication that that's been taken on, except in rare cases of children who have very specific genetic forms of Parkinson's with specific enzyme deficiencies where obviously this therapy would, you would predict, have a major benefit. And that indeed has been what was shown in this paper that appeared a couple of years ago.
So overall, I would say that dopamine gene therapies have yet to be shown to really work, but part of the problem is that the investment in this area has slightly nosedived for reasons that's not clear to me anyway. So I don't think we can come to any firm conclusions because in theory this approach should be a sensible and good way to go forward. Now more recently, and including our sponsor for tonight, Prevail, there are two new sort of gene therapies which are coming forward. One is in the clinic and the other is hoping to come to clinic, I think next year or the year after. There may be others, but I don't know.
These are the two that I do know about. So Prevail is working on the assumption that the commonest genetic form of Parkinson's disease or the commonest gene associated with Parkinson's disease is this mutation in one of these genes associated with Gaucher's disease. So I'm sure many of you are very familiar with this. It's called the GBA gene. People with Gaucher's disease have two mutations in each of their genes which gives them Gaucher's disease. About 10% of people with Parkinson's disease have a mutation in one of those genes and that seems to predispose them to getting Parkinson's disease and also seems to predict that they might follow a more aggressive disease course.
This was first picked up by Ellen Sidransky many years ago. We did a study looking at that population in Cambridge and found that five to ten percent of people with so-called sporadic disease, no family history, sort of fairly standard presentation, had this GBA1 mutation. And what we found when we followed these people up long term was it did seem to influence the disease course.
Now, the GBA gene codes for an enzyme called GCase, and so if you have a mutation in this gene, one of the assumptions is that your enzyme activity drops down, and so you have low enzyme activity, and the low enzyme activity not only predisposes you to getting Parkinson's, but once you've got it, it speeds up the disease course. Ergo, if I want to treat it, why don't I put back a gene or put back the enzyme activity? So in Gaucher's disease, that's been done for many years, but that's done with enzyme replacement therapy, which sadly doesn't get into the brain. It can help the problems in the periphery but not in the brain.
There has to be a way of putting the enzyme back in the brain, and one obvious route to do this is with a gene therapy. So Prevail have this trial which is up and running called Propel, where the idea is actually to inject this gene therapy into patients with GBA1 Parkinson's disease. And really at this stage, the idea is to see whether it's safe, which is what you do with all of these first in human studies.
Dr. Roger Barker 00:23:12
They're using some immunosuppression because there is some inflammation with this particular gene therapy and they want to look long-term to see whether it's safe, whether it's well tolerated, how much of an immune response does the patient generate to it, and have some preliminary idea as to whether it's slowing down or having some effect on the disease course. This has just begun and obviously if this was to work, then it would lead to bigger trials and it may be appropriate for large numbers of patients with Parkinson's disease. Now, there is a second trial which is still in the sort of preclinical stage, i.e., hasn't actually gone to clinic yet.
Based on a rare form of Parkinson's related to Parkin. This is typically found in very young people. It doesn't tend to associate itself with the Lewy body pathology you see in people with normal Parkinson's disease, if you like. And it's thought that this problem with Parkin relates to getting rid of the powerhouses of the cell, the so-called mitochondria. There's been a lot of interest in how this informs us about parkinsonism and it's probable that whilst parkinsonism is a distinct entity, parkin is also probably involved in sporadic Parkinson's disease.
There's a company that's working on this particular approach to try and develop a gene therapy which puts back Parkin into the brain. The idea in the first place would be to target people who have no Parkin in the brain, i.e., the patients with the genetic form of it, and then the hope would be if that's shown to be safe and effective, would it have some benefit in people who don't have the genetic form of it. So that's currently in the preclinical space but nevertheless is moving towards clinic in the near future. So those are new approaches with gene therapy which are designed to slow down the disease course.
So gene therapy is just to summarize, they can work on trying to rescue the dopamine system, replace dopamine by infecting other cells in the brain so they produce dopamine, or now moving toward giving a gene therapy that gets into the pathway which drives the disease and slow down the disease itself. An alternative approach, is to actually simply use cell therapies. And what I'm really going to talk about with cell therapies is the idea that you replace the cells that are lost.
In Parkinson's disease. So in your substantia nigra, you have about 400 to 500,000 dopamine cells, and when you've lost half of those, about 200,000 on each side of the brain, you develop the features of Parkinson's, at least the motor features. So what the argument would be is we know dopamine therapies work very well for people with Parkinson's, they have problems, they have off-target effects and in the long term they create complications. But wouldn't it just be simpler, isn't a simpler approach to take people with Parkinson's and just replace their defunct and lost dopamine cells with a whole bunch of new dopamine cells, inject them into the brain where dopamine works?
Dr. Roger Barker 00:26:16
That would have the benefit that I could put dopamine back where it's needed. So you don't with the tablets have all the problem of dopamine drugs stimulating dopamine pathways which are still intact, so you get overstimulation. And secondly, if I put the dopamine cells back as nerve cells, they release dopamine in the normal physiological fashion, so I won't get levodopa-induced dyskinesias. The promise of this therapy is if I put it in, it's a one-off treatment, you would get the maximum benefit that you would see with your dopamine drugs with none of the long-term complications.
You would not be curing people of the condition because the condition carries on, the alpha-synuclein aggregation, but you would be repairing and treating this aspect of the disease. And in that sense, it could be disease-modifying because people forget, I think, that before levodopa came into clinical practice in the 1970s, most people with Parkinson's disease wouldn't live beyond five or ten years, whereas now, of course, people live in the community actually a sort of normal life with Parkinson's disease. This is the strategy that we're interested in. So then the next question you would have to ask is, well, if I'm going to replace the dopamine cells, what could I replace them with?
So where can I find a midbrain dopamine cell of the type lost in Parkinson's disease? Well, one approach is to go and collect them from human fetuses. So women who have termination of pregnancies, abortions, you collect the fetal material that's been aborted, you dissect out the area of the brain that contains the developing dopamine cells, and you use that as your source for transplanting into the brain. And I'll talk briefly about what those trials have shown, which have been going on since the late 1980s.
An alternative which only became possible in 1998 and more recently into 2007 with development of technologies for making human stem cell sources was the capacity to take a human stem cell and turn it into a dopamine cell of the type lost in Parkinson's and use that to transplant it into the brain. So a stem cell, just to sort of remind you, is a cell that divides indefinitely, so it will carry on dividing forever. And what happens is a stem cell will divide, one of those divided cells will be a stem cell which will divide again.
And then what you can do is you can take those cells and you can persuade them to turn into a cell type of any sort. This has been considered for people with diabetes, making islet cells, for repairing the eye and such like. So so there are all sorts of hopes for stem cells and of course they've been used for years in the clinic for people with blood disorders because your bone marrow contains lots of blood cell stem cells. Now, the types of stem cells you have, which I'm going to be talking about, and only talking about, are embryonic stem cells. So these are the stem cells that come from spare embryos in IVF programs.
And currently, BlueRock Therapeutics in New York are using and have done a clinical trial using embryonic stem cells using a particular cell line. The stem cell trial that Jim mentioned we're doing called STEM-PD is using a cell an embryonic stem cell line from Scotland. And Novo Nordisk who we work with are planning to do clinical trials with the same embryonic stem cell line as ourselves. These are called allogeneic, I e they would be like having an organ transplant from an unrelated person. So a standard kidney or liver transplant would be so-called allogeneic.
Dr. Roger Barker 00:29:46
It's from another human, but it's not someone who is related to you. Now, induced stem cell sources came about when Shinya Yamanaka developed the technologies to take an adult cell, like an adult skin cell or an adult blood cell, and convert it into a stem cell. Once you've got the stem cell, you could then persuade that stem cell to become a dopamine cell. And so this offers the potential that you could use the patient themselves as the source of the cells. You take the patient's own skin cell, convert it into an iPS cell, induced pluripotent stem cell, and then you convert that into a dopamine cell.
And that's been pursued by Aspen Neuroscience in California, and has also been the subject of a case report of a single patient transplanted in Mass General and Harvard Medical School. The alternative is to make an induced pluripotent stem cell from some other person and then convert it into dopamine cells and then graft that in. So again, that's like an embryonic stem cell that's not from the person itself, so it's not autologous, but it's from another human, and that's called allogeneic, and that's been pursued in Japan, in Kyoto. It's also going to be the subject of a trial at Arizona State University in people with Parkinson's/parkinsonism.
And FUJIFILM Cellular Dynamics in Chicago have also been looking at this therapeutic approach.
If we just look at human fetal dopamine cells because I think it's been useful, to just see what's been achieved by this whole approach. Just to remind you, the idea here is I'm going to replace the lost dopamine cells that you see in people with Parkinson's disease with a replacement collection of dopamine cells which have been harvested from aborted fetuses. And what's happened with this has been somewhat controversial outside of the ethics. The results have been a bit variable. But importantly, it's shown a proof of principle, namely when it works, it can work extremely well.
The principle of using dopamine cell replacement has a precedent. There are two patients for example in the UK who went to Sweden. They had Parkinson's disease for 10 years, they had fetal dopamine transplants put into their brain and then they were followed up for the next 20 odd years. And on this slide, although it's a bit difficult to see, what happened was that these patients, who have now died because they would now be in their nineties.
Thirty years more or less after they had Parkinson's disease diagnosed, they have a motor score on a standard rating scale, the Unified Parkinson's Rating Scale, which is the same or less than when they first presented thirty years ago, and they are on no medication. So that is a striking clinical response. On imaging of their brains, they have normal dopamine levels in their brains. A patient in Sweden had a transplant on one side of the brain. They did extremely well. Sadly, they went on to develop a Parkinson's dementia. But when they died, they harvested the brain from that patient.
And in that particular patient, on the side where they had the transplant, which is the brown on this slide, every bit of brown you see on that slide is a surviving dopamine cell and fibers growing out of it. This showed that a quarter of a century after you put cells into people's brains, they could survive and innervate the brain. So they have long-term clinical benefit and they can survive long-term. But as I say, not all studies showed this. There were two studies that were done in the United States funded by the National Institutes of Health, which were published in 2001 and 2003.
Dr. Roger Barker 00:33:24
In these studies, patients had sham surgery, so some had no implant. In the first study, they had a small implant. In the second study, the double-blind study at the bottom, they had a small implant or a big implant. And essentially what this showed was that in this study, when you asked the patient a year after they'd had the transplant and measured them on a standard measure, putting fetal dopamine cells into their brain made no difference. And actually, some of the patients were now developing side effects which were these involuntary movements associated with the transplant. In the second study, which published two years later,
There were 34 patients. A third had no transplant, a third had a small amount of tissue and a third had a large amount of tissue. And at two years, there was no significant difference between the groups. In other words, there was no benefit from having the transplant. Interestingly, these patients received immunosuppression for six months after they had the transplant and then it was stopped. And if you look at the graph at the bottom, you can see that the grafted groups were actually improving up to that point and then that benefit was lost, which might imply that the transplant was actually being rejected and that's what caused the loss of the efficacy.
Worryingly, in this study, half of the patients now developed graft-induced dyskinesias, which were so severe in a few patients, they had to go on and have deep brain stimulation. The consequence of this is we have these individual patients in Europe who seem to have done extremely well, and we have these double-blind placebo-controlled trials in America which showed that it didn't really seem to work in slightly larger numbers of patients. The question is, well, how could you actually reconcile this data? We set about trying to do a meta-analysis about 10 or 15 years ago now to try and analyze all of this. And we collected all the data from all of the studies that we could.
And what we found was that there are a third of patients who have had fetal dopamine cells put into their brain who've had a very significant improvement. So on this graph, it's two years after you had a transplant, a 33% improvement in your motor measures. So a third of patients seem to derive a benefit, two-thirds do not. That's not a therapy we can take forward unless we can understand what it is about the third who do extremely well. We tried to analyze this and came up with the conclusion that actually younger, less advanced patients seem to do better. It seemed to have a lot to do with how you prepare and implant the tissue.
As I've already intimated, the amount of immunosuppression after you've grafted to stop the cells being rejected seemed to be important, and long-term follow-up seemed to be important. And it was on that background that we then, received funding from the European, Union to do a study called TRANSEURO, which was to graft a large number of patients in the original, plan, with fetal dopamine cells. And we still have yet to finalize analyzing all this data, but essentially what we found in our study to date is that the use of the fetal dopamine cells did have some benefit on the patients. There was some stabilization of their disease.
Dr. Roger Barker 00:36:33
It varied a bit from site, so eight patients were grafted in the UK and three in Sweden, and we used different devices in those two sites, and there's some suggestion that the devices were rather important. But overall, we didn't see a major benefit. And I think that relates to the fact we gave fewer cells than we should have done, or less than was needed, and that the device seemed to cause problems in terms of survival. However, a more fundamental problem arose in this study, in that it essentially took us eleven years to graft eleven patients. And the reason was we simply could not get enough fetal dopamine cells.
In the time it took us to graft 11 patients, we had another 87 transplant surgeries booked that we couldn't actually use because we didn't have enough tissue. If this therapy is ever to go forward, we're going to have to use a stem cell source. And as I've said, there are lots of stem cell sources out there. The real breakthrough in this field came in 2011 and 2012, when two teams — Lorenz Studer and Viviane Tabar's team in New York, and Malin Parmar's team with Agnete Kirkeby in Lund in Sweden — both developed a technology and a technique that enabled you to take human stem cells and turn them into the midbrain dopamine cells of the type lost in Parkinson's disease.
That has now led to a whole series of trials, which I've already briefly alluded to with the different cell sources. The trial in Japan, using induced pluripotent stem cells not from the patient but from another human, so allogeneic, began in 2018, and they have grafted, I think, seven patients, so we're keenly awaiting the results of their study. The group in New York grafted their first patient with their embryonic stem cell-derived dopamine cells in May of 2021 and their last patient in May of 2022. They're hoping, I think, to publish some preliminary data on what the trial has shown, primarily around safety, at the end of this year.
There was a group at Mass General where they did an autologous iPS. This was a patient who provided their own cells, and this was published a couple of years ago. This was an individual patient. They took the patient's own cells, turned them into stem cells, turned them into dopamine cells, and tested them to check they were safe in animal models. This is one of their studies that was in the paper. The cells do survive, perhaps not optimally, but still, they were surviving.
The patient was then grafted in two different operations, one side of the brain and then the other, with their own stem cell-derived dopamine cells. On the scanning, there wasn't any significant change in the imaging. On the clinical measures, there wasn't any major change, but the patient's quality of life dramatically improved. For whatever reason, this patient felt that the therapy had dramatically improved their condition. What was important for the field is it was shown to be safe. There were no major side effects from this.
Dr. Roger Barker 00:40:05
The trial in Japan, as I said, began in 2018. We're awaiting the results. The trial in New York began in 2021, and we hope to hear something more of that later this year. The group at Mass General have already published their single case. Our own trial in Europe, which is a joint trial between ourselves and Malin Parmar's group in Lund — she's the overall PI of the study — actually began in February this year. We grafted our first patient in February of this year and our second one in March of this year. The next two will be in September, and the last four will be next year.
This study, which is called STEM-PD, is a rather complicated slide just showing essentially what we're planning to do. As with all of these studies in first in humans, the primary objective, the primary aim of this study, is to show whether it's feasible. Can we actually do it? How well tolerated is that therapy when we put it in, and is it safe? Does it not turn into anything we don't want it to turn into? Then there's a whole series of secondary objectives around whether we've got any signs that it might be doing any good. On the back of this, Novo Nordisk, who we work with, a big pharma company, are keen to develop this up and do a global trial around this whole strategy.
Essentially, dopamine cell therapies have been through a very long history of great optimism and pessimism. I think buried in that is proof of principle that they work. The challenge will be getting it to work consistently with a big enough response that makes it competitive.
In the last few minutes, I just wanted to talk about three other ways in which people are thinking of how we can take cell therapies forward or gene therapies forward in Parkinson's. One is the idea that instead of just turning the cells which I began with into little dopamine factories, why can't we convert some of the cells in the brain directly into dopamine nerve cells themselves? Can we persuade non-nerve cells in the brain to become dopamine cells by injecting factors? This has been the subject of a number of preclinical experiments. Ernest Arenas published this a number of years ago.
Dr. Roger Barker 00:41:56
There was this very exciting paper in Nature three years ago, which seemed to show it was relatively straightforward, but a subsequent follow-up paper showed that there were issues around exactly how efficient this worked and whether there was a problem in the way they were labeling the cells. At the moment, this is a very exciting area, that we could actually reprogram cells in the brain directly into dopamine cells rather than transplanting new ones, but at the moment, that's not very efficient, and so we still need to work on that.
A second strategy is to combine growth factors, as I've already talked about. Use a gene therapy that produces a growth factor, such as neurturin or GDNF, and implant cells so you get more cells and you get them to survive better and innervate better. This has been particularly taken on by Lachlan Thompson and Clare Parish in Australia, and they had this paper showing that it worked extremely well in their animal models. This could be another way forward, that we combine gene therapies with growth factors, as well as cell therapies, to try and maximize the benefit from both, rescuing the host system, rescuing our transplants, and having a more efficient way to repair the brain.
Finally, one of the attractions of stem cells is that you can engineer them in ways that might be helpful therapeutically. One such way, as I mentioned right at the very beginning, is the idea that Parkinson's may be related to the spread of alpha-synuclein, and some of the transplanted cells in patients who've had neural transplants have shown alpha-synuclein pathology. How could we prevent that in the future? We could make a stem cell that doesn't have alpha-synuclein in it. We therefore could make dopamine cells that don't have alpha-synuclein. If we transplant them into the brain of people with Parkinson's, they will turn into dopamine cells, but they could never ever die from an alpha-synuclein pathology because they simply don't have the protein there that would allow them to do it.
The alternative way you could engineer cells is to try and get rid of the parts of them that the immune system doesn't like, which makes them immunogenic. You can knock out aspects of the cells that drive the immune response to them and therefore drive the rejection response. We and many others are working on making these so-called universal cells. Gene editing, as I say, may be a very useful way of taking these forward, and we may even be able to gene edit cells to regulate how they release dopamine and such like.
Dr. Roger Barker 00:44:26
There's great potential, but we need to get past base one, which is to show that stem cell-derived dopamine therapies are safe and have some signal of efficacy. To conclude, can we rescue and regrow the dopamine system? There is still some interest with using growth factors like GDNF, and there are still talks of doing protein infusions. I don't think growth factors have come to an end, and gene therapy growth factors have not. I think replacing lost dopamine using a gene therapy approach has, for whatever reason at the moment, not garnered a lot of current interest.
But there is a huge amount of interest in doing this using dopamine cell replacement strategies. The idea of rescuing dying cells, as I've already said, has become something that people are interested in with gene therapy, but obviously, there's a huge amount of work going on with drug repurposing, small molecules and other therapeutics to help that. As I said at the beginning, you could ultimately bring all of these together and say, someone with Parkinson's disease, they present, you give them a cell transplant, you do that with a gene therapy that produces a growth factor, and then you give them a series of agents, either gene therapies or tablets, that slow down the disease course. To all intents and purposes, that combination therapy has solved the problem of Parkinson's, and we can move on to another condition.
With that, I'd like to thank you for your attention. This is the group when we met early this year at our lab retreat. These are the many people who've worked on some of the work I talked about today, and the fantastic STEM-PD team, led by Malin Parmar from Lund, that I've been very fortunate to be the clinical lead of. So with that, thank you very much, and I look forward to your questions.
Dr. James Beck 00:46:11
Thanks very much, Dr. Barker. That was a great presentation. Just for our listeners out there, let me continue to encourage you to submit your questions through the Q&A icon down below. If you're on Facebook, you can use the comments section to do that. My colleagues are organizing questions as they come in, but because a lot of questions are coming, we won't be able to get to everything. We'll certainly do our best and encourage everyone to call our Helpline if your questions aren't answered.
With that, I just want to say it was really fascinating, the comment you made at the very beginning, that all these therapies you're talking about could be combined. Carol, one of our listeners, just asked, if someone has DBS, is there a potential to use stem cell therapy to replace dopamine that's lost in their brain? How do you see this envisioning? I can certainly see us stopping Parkinson's disease with some medication and then relieving symptoms with a stem cell therapy. What are your thoughts?
Dr. Roger Barker 00:47:14
I completely agree with you on that, Jim. Essentially, if you can put back 200,000 dopamine cells, you should, in essence, stop people needing to use dopamine medication. That would be a major benefit if you could do it. At the moment, we give cell therapies to people who've not had DBS, and we're not accepting people onto the trials who've had DBS. The reason for that is it makes it more complicated because they've already had neurosurgery, and obviously we want to do neurosurgery on the brain. Secondly, the regulators will want to know that a deep brain stimulator has no effect on a stem cell transplant. Well, I have no reason to think it would, but I don't know.
For the moment, what we're doing is we're excluding people with deep brain stimulation. Now, it doesn't mean that people with stem cell therapy can't go on to have deep brain stimulation. That would be a bit disappointing because obviously our therapy hasn't worked then. You can do it the other way around. Ultimately, what I would love is if these cell therapies worked, in essence, we wouldn't need deep brain stimulation because that's used for the complications of the medication we give. Apart from people who might have bad dystonia or tremor-dominant disease where there may be a specific indication, the hope would be that ultimately these cell therapies could replace the need for DBS and some of these more invasive Duodopa and suchlike therapies.
Dr. James Beck 00:48:32
Yeah. One of the things you touched on a little bit as we talk about stem cell therapies, and even with the gene therapies, with the first study I think you mentioned with the neurturin, and the ProSavin study, is giving it more time. Even some of the case reports you showed, it takes a long time for these things to start to show effect. Humans aren't mice, where things develop in months. It takes years for cells to grow in the brain and to fully function. When we think about the timeline for trials, is it long enough to be able to see the effects of these therapies? Because there's a tremendous expense to continue a trial.
Dr. Roger Barker 00:49:16
You're absolutely right. Obviously, if you've got high blood pressure and I want to give you a tablet for high blood pressure, you don't really want me to say, 'Well, if you come back in three years, let's see if it's made a difference.' Tablets will work quickly, and they have their effect, and you'll know within a few weeks whether it's working. Gene therapies, if you're just replacing dopamine, would have a similar time frame. It should work quite quickly, so you should see things. But if you're trying to regrow a system or replace it, you're absolutely right. The maximum benefit with fetal dopamine cells was probably three to five years after they were put in.
They take that long to survive, differentiate, make processes, make connections, and to some extent, you have to learn to reuse them. It does take the time, so that is a bit of a problem because how long do you wait before you know whether you've done it right? When we try, for example, to dose in some cells, have we got the right dose? How long do we wait before we think we've got the right answer? Part of it is it's quite difficult to plan trials when you have to wait that long.
It also has major implications to the pharma industry because obviously they don't want to wait three years before you do your next bit of your trial. So it's trying to get a sweet spot where you've got enough information to be predictive of where things are going to go, but not having to wait the full time.
The other important point I would make at this stage is that all of these trials are experimental, and what people sometimes forget is they think you're going to hit gold first time. I always think of cardiac transplantation. When Christiaan Barnard — I don't know how many people remember Christiaan Barnard — he was world famous because he did the first heart transplant. The patient who had that heart transplant, I think, lived for another three weeks. That patient derived essentially no benefit from having that heart transplant. But what we learned from that was that it was technically possible to put it in, that you could get it to work in the short term, and so that advanced the field significantly. Then there were questions about how you stop the immune system and suchlike.
Each trial is very unlikely in these early stages to give you the complete answer. What you're hoping is you'll show it's safe, you've learned something, and you can build on that. Ultimately, you have to have a therapy that's going to give you a consistent, predictable response. Otherwise, it's not really going to be competitive.
Dr. James Beck 00:51:27
I think you really touch on something that's interesting, and it's important for our audience to realize that when we talk about clinical trials, we're really still talking about experiments. We don't know the results. This is why we're doing these studies, to see whether this may work. There's hope, of course. They're not futile to begin with. But as you are a person with Parkinson's who's looking out there, how do you evaluate whether these trials are for real?
We're now talking about the advent of legitimate trials, where scientists have really committed themselves and there's a lot of science behind it, versus other ones where, yeah, I like to say that they take a little liposuction, spin out some of that fat stem cells and re-inject it into your spinal cord and call it a day. People on the call, most people are not scientists or biologists and may not appreciate the difference. What's your advice to them?
Dr. Roger Barker 00:52:29
You're absolutely right. If you wanted to have a stem cell therapy for Parkinson's, there's probably, I don't know, several hundred clinics around the world that could offer you tomorrow, and they would relieve you of a significant amount of money. The first thing I would say is anyone who's asking you to pay for something that is experimental, there's a problem. All experimental trials should be properly funded by charities or national funding agencies. You should not be paying for something that is part of a trial, which is a first in humans to see if it works. That's the first thing.
Secondly, you have to understand the rationale for what we're trying to do. You're absolutely right. I've reviewed papers where people have had stem cells injected under the skin to treat their Parkinson's. Well, how on earth can a stem cell injected under your skin get into your brain and have any effect? It just beggars belief in terms of the mechanism. I think trying to understand what it is they're trying to do and then trying to probe what the data and the evidence is in support of it is important. Don't pay for it. Check on the data before.
Then there's a very good thing that I'm involved with called the International Society for Stem Cell Research. It may be true of your organization as well, Jim, but the ISSCR has had quite a major push there, and they've been very supportive of trying to give information to people to go and look up how you assess whether a stem cell therapy has any merit. Obviously, it's for all diseases with the International Society for Stem Cell Research, but we have specific things on Parkinson's disease. My own view is that there are only a few centers in the world that do this with the confidence that would allow you to go into a trial. I've mentioned those this evening. It's not to say there aren't other groups that could do it, but I think you'd always be suspicious if there's money attached and you can't find the papers in the public arena, in peer-reviewed journals, supporting what they've been doing.
Dr. James Beck 00:54:19
Sorry, I put myself on mute. I think those are really good points. I think the key one is you shouldn't have to pay for it, because the one thing to cure you of a full wallet is not the cure that people are looking for.
What kind of timescales are we talking about? Lots of questions are coming in about that from Facebook, from other lines. And then, as we talked about eligibility too, there are people who are listening with different stages of disease. It seems like this is really geared for earlier onset. But would you then see the hope for broader use once we establish those initial beachheads on how this could work?
Dr. Roger Barker 00:55:01
These first in human studies are quite difficult, actually, because obviously, if you follow my argument to its logical conclusion, you'd say when you present, you get your therapy. No ethics committee is going to allow us to do an experimental therapy in someone who's just been diagnosed, who has a whole selection of agents they could use. Similarly, if you have people who are very advanced, then they can't wait, as we've just discussed, the two or three years for these therapies to work. They're too advanced for us to be able to use this therapy in the first instance. So we're essentially in these first trials. The ethics committees and the regulatory agencies want us to use people who've got moderately advanced disease but who can wait probably a couple of years before they need anything more invasive.
That's who we're choosing at the moment. Probably the most important thing in terms of selection is people who respond well to medication. If you don't respond to dopamine medication, there's no reason you'd respond to a dopamine cell therapy. Conversely, if you've had an excellent response to dopamine medication, there's no reason a dopamine cell therapy wouldn't help you. Ultimately, I would say that this would be suitable for anyone who's got dopa-responsive disease, so who responds to their medication, who doesn't have a major problem in other domains, say major autonomic problems or things of that nature.
But even then, I'm not convinced about that because a lot of the drugs we use to treat Parkinson's — so the Sinemet, Madopar, which I assume is the sort of agents you have in the U.S. — can aggravate autonomic problems. I have patients, for example, where I've used dopa, who have motor problems with quite marked cognitive problems and dementia, because actually to treat their motor side and get a stable treatment transforms how we can manage the other aspects of the disease. Ultimately, I see this therapy as having very wide applicability.
The difference between this and, say, your Duodopa is it is a brain operation. People who have serious cognitive problems or psychiatric problems, brain surgery is not something to be undertaken lightly because it can aggravate that. But I think ultimately, this could have a much wider remit than where we are at the moment in terms of who we're choosing.
The timeframe was the other question. One of the advantages with big pharma being involved is they're not going to wait around. If things go according to plan, everyone always says five years. BlueRock will be planning their next studies. Novo Nordisk are planning their studies. They will want this to, within five years, be either in the final trials to get marketing authorization or to be applying for marketing authorization. They're not going to wait 10 or 15 years. They've also got the money to do it, unlike us poor academics who just have to scrape and beg for what we can to move on to the next stage. I do think that within five years, we will know whether this is a therapy that's got legs or it's just not competitive.
Dr. James Beck 00:57:54
Fantastic. That would be fantastic to hear. And we're talking for people who have idiopathic PD.
Dr. Roger Barker 00:58:02
Yep.
Dr. James Beck 00:58:02
I know we're near the top of the hour, so I want to be conscious of that. What about people with genetic forms of Parkinson's disease? We mentioned the one with Parkin, but that's a relatively rare form of Parkinson's. A lot of people have LRRK2 mutations and GBA mutations. Do you think they can—
Dr. Roger Barker 00:58:23
Yeah, I think so. Although there's this question of GBA patients doing slightly less well, I think when they do less well, it's only a little bit less well. It's not that bad. As I always say, if we can go early enough in these patients and avoid the drugs, then all the neuropsychiatric problems, which often can be a precursor of the dementing process, we can avoid all of that. We might not cure people, and they may all end up in the same place, sadly, with this condition, but we would have bought them five or ten years where they haven't needed to take anything and they've had a very good quality of life. I can't see you being excluded because you've got a genetic form of it.
I think the harder question will be, genetic forms of Parkinson's are now very attractive for drug trials, and you can't be in two trials at once. LRRK2 people are really after that. But as you can see from my talk this evening, Parkinson's has become very attractive as a way of trying to treat people with gene and cell therapies.
Dr. James Beck 00:59:19
I think we're on the cutting edge of what is coming for therapies, and I think it really bodes well for people with Parkinson's in the near future.
Dr. Barker, I really want to thank you for your time with our Expert Briefings today and for talking about understanding gene and cell-based therapies. I also want to thank everyone for joining us today. We had a tremendous response with the Q&A session, and as I mentioned, we weren't able to get to all of them. If you do have a question that wasn't answered, reach out to our Helpline, 1-800-4PD-INFO or 1-800-473-4636. You can find that on our website as well.
Just to mention, this is the third episode of our Expert Briefing. We're going to take a pause right now for summer holidays, and we'll reconvene in September. We'll be talking about Parkinson's disease and the bladder. You can learn more and you can register at our website, Parkinson.org/ExpertBriefings, to do that.
One of the things we'd like to do is just highlight some of the resources and support we have. We have our Aware in Care kit, which is a fantastic tool for those who may enter a hospital for a stay. We have information that is really important through our PD Library, as well as our PD Health @ Home series, which is a virtual way to engage with others in Parkinson's for wellness and health and fitness as part of that process. We have lots of other resources in addition to our Expert Briefings, our Substantial Matters podcast, and professional education we offer.
I also wanted to mention our PD GENEration study, which is providing an opportunity to accelerate clinical trials, as well as have people learn more about their Parkinson's disease, whether they have a genetic form of PD, and can enroll in some of these precision medicine trials.
We're here for you through Parkinson.org, through our Helpline email or through our Helpline number as well. Before we go, I just want to remind everyone that the screen's just going to go black. It's kind of like the TV just gets turned off. But a window will pop up in your browser, and we'll want you to complete a survey. Let us know what you thought of this webinar. We'll share it with Dr. Barker. We'll use that to improve our own series moving forward. With that, I just want to bid everyone adieu, and we'll see each other again in September. Thank you very much. Thank you very much, Roger, for your time. We'll talk to you all again later. Bye.
