Advancing Parkinson's disease research

Video transcript

• 0:24 I'm Roger Barker.
• 0:25 I'm a consultant neurologist at Addenbrooke's Hospital in Cambridge and also the Professor of Clinical Neuroscience at the University of Cambridge.
• 0:33 And in 2019, I suppose one of the questions that I get asked a lot and is very interesting is where are we with Parkinson's disease?
• 0:41 What are the big questions that people are asking about this disease and where are we going therapeutically?
• 0:46 So obviously Parksy's, it's now 201 years since Jane Parkinson described it and I would say there are several trends which are emerging which are exciting as this field is moving forward.
• 0:56 The first is around what do we understand by Parkinson's?
• 0:59 So I would say in the last 10 years there's been a whole sort of new idea emerging around the fact that Parkinson’s disease presents many years before people present with their tremor, their slowness and such like to their GP.
• 1:11 This so-called prodromal or pre-motor Parkinson's disease.
• 1:14 And whilst at the moment we can't accurately predict what that looks like, there are some signals that are emerging, such things as when people act out their dreams at night, so-called REM sleep, behavioral disorder associated with problems with smell, perhaps a little bit of constipation, walking problems and such like.
• 1:31 Now why that's important is it tells us two things really about Parkinson's.
• 1:34 One is that it begins much earlier than we thought.
• 1:37 And secondly, ultimately, if you want to stop this disease, then one of the key things you would need to do is target the disease process as early as possible.
• 1:45 So if we could accurately predict when people are likely to get Parkinson's disease ahead of when they've actually got over features of it, then this is a very attractive target for new therapies to slow down or stop the disease.
• 1:58 So that I would say is one very exciting new development in Parkinson's disease.
• 2:02 I think also around the sort of clinical aspects of the disease has been this idea that whilst we always think about disease as one disorder, it's clear that it's a bit more complicated than that.
• 2:11 It's clear that some people behave in rather different ways.
• 2:13 So some people, for example, have a lot of tremor, some people have a lot of problems with thinking early on.
• 2:19 What is it distinguishes those patients?
• 2:21 What is it that drives the disease process in those patients and what does that mean therapeutically?
• 2:26 Well, we many years ago for example, started a study collecting everyone with Parkes in Cambridgeshire.
• 2:31 We followed them over the last 20 years and it's clear that there are some people who develop early problems with thinking that tend to have probably slightly different genes which seem to drive the disease process once it starts.
• 2:45 Now whilst they might not be the ideal group for some of the therapies I'm going to talk about around cells and genes and growth factors, they may be the very best group by which to try disease modifying therapies as they clearly progress more quickly, often ending up with an early dementia.
• 2:59 And if we could stop that, that would obviously have a major impact on their life.
• 3:03 And it's also probably an easier way of assessing if you're trying a new agent, whether it really is targeting and slowing down the disease process, which to date is largely being done around looking at some aspects of motor control, which as we know, it's very responsive to the drugs we use in the clinic at the moment.
• 3:20 So I think this idea of stratifying Parkinson’s disease having different subtypes is emerging as a very appealing way in which we can be better able to not only tell people in the clinic now what the future holds, but for new therapies.
• 3:33 And I suppose, you know, this has been something which is new to the world of Parkinson’s, but obviously it's been around for a long time with other conditions like cancer.
• 3:41 So when I was training, you know, 30-odd years ago, if you had breast cancer, it was one type of cancer.
• 3:46 Whereas now we know there are various different types of breast cancer, each of which has its own particular type of therapy.
• 3:52 And I see the future of Parkinson’s is very much going down that line.
• 3:56 So then the question arises, well, we've got this exciting new development about picking up proxies before we have the meta features, this pre-meta Parkinson’s, we have this idea of different subtypes of Parkinson’s, stratification of disease.
• 4:07 The next question is, well, what can we do about it?
• 4:09 What are the emerging therapies that may be there to help people going forward?
• 4:14 Well, this is an area which has really exploded over the last decade.
• 4:17 There are lots of exciting new developments in Parkinson’s which I shall now sort of try and briefly summarize as to what I think those are.
• 4:24 So the first I would say is this idea which goes back to what I've said previously about prodromal Parkinson’s, that there isn't the disease begins years before we see it with the tremor, the slowness and the rigidity.
• 4:37 And it may be that those very early features of Parkinson’s disease actually begin not in the brain, but begin outside of the brain.
• 4:43 So whilst we understand that this REM sleep behavior disorder is associated with pathology in the lower part of the brain, the early constipation for example, which seems to be a hallmark of prodromal Parkinson’s, probably has its origin in the gut.
• 4:56 So this has led to this whole theory that Parkinson’s may actually begin outside of the gut, perhaps something we're exposed to.
• 5:02 Of course, there's a change in the protein that lies at the heart of the condition, this protein called alpha synuclein, which causes a problem with your own alpha synuclein in the gut and in the nose, at the top of the nose in the so-called olfactory system.
• 5:15 And that templates on your own alpha synuclein that we all have in our brain too and in our nerve cells into a form which then causes the cell to be unhappy and eventually to die.
• 5:26 So this idea that the disease perhaps begins in genetically susceptible people through some environmental exposure.
• 5:33 It begins in the nose and it begins in the gut.
• 5:35 It then can spread.
• 5:37 So the theory goes up the nerves into the brain, and once in the brain, it passes from cell to cell in what they call a prion-like fashion.
• 5:45 Which means that the protein having become abnormal for whatever reason is passed to another cell.
• 5:50 And when it's in that cell, it then templates that cells own alpha synuclein to become unwell pathological and then 'cause disease in that cell and so on.
• 5:59 Now, if this theory is correct, for which there is a lot of preclinical data, but there is limited clinical data at the moment, then it would imply that you should be able to stop the disease by stopping that protein spread.
• 6:11 And one way in which this has been tackled is to think, can I use an immune system of vaccines, some immune therapy to kill off this abnormal form of alpha-synuclein as it passes from 1 cell to another?
• 6:23 Well, whilst this might sound like science fiction, this has now entered into the clinical arena.
• 6:26 So there are a number of trials in the world going on at the moment which are using people with newly diagnosed Parkinson's in trials to try and see if we can silent that abnormal form of alpha synuclein and stop the disease spreading.
• 6:39 Now whether that is going to happen, whether it really works, we've yet to find out.
• 6:43 But nevertheless, that is a therapy which is currently in the trial and is generating a lot of excitement because it has the potential to actually stop the disease in its tracks and actually even stop it developing into the forms that we recognize nowadays.
• 6:57 So that's one very exciting area.
• 6:58 What are the other exciting areas?
• 7:00 Well, one area which has been really, I suppose, pioneered by the patient charity that cures Parkinson's Trust is around drug repurposing.
• 7:08 So this is a strategy where you take a drug which is already in clinical use for one indication and you use it in another, in this case Parkinson's disease.
• 7:16 So for example, there's trials going on which have been led by Tom Foltynie in London, using a drug which is commonly given to people with diabetes called exenatide, which is a class of drug called a GLP-1 agonist.
• 7:30 Now these drugs are used to treat diabetes, but there's some evidence in animal models that this drug can also slow down the loss of cells in models of Parkinson's disease.
• 7:40 Tom then did a study a number of years ago where he gave people either exenatide or a placebo, followed them over a period of time, and those who are on the active age, i.e. the exenatide, seem to progress less quickly.
• 7:51 Now whether that was truly disease modifying is debatable, but it's opened up the possibility that this drug may have some effect on the disease process.
• 7:59 This is one of many different types of drugs.
• 8:01 So there are currently at least a dozen trials going on that I know of around the world where people are taking a drug which is already in clinical use and trying it in patients with Parkinson's on the hope that it will slow the disease process down.
• 8:13 Now, why is this so exciting?
• 8:15 Well, a) it's very exciting because there's lots of agents being tried, which has great potential for people with this condition.
• 8:21 But importantly, it's obviously a very quick way to get drugs to clinic because we already used them in the clinic.
• 8:26 So we know how well they are tolerated.
• 8:29 We know their side effect profile.
• 8:31 And so it's relatively easy if we get a positive hit with one of these in a trial to quickly translate that into a therapy that everybody could have.
• 8:39 So drug repurposing is really very, very active at the moment in many sites around the world and offers great potential.
• 8:46 And of course, you could imagine that these type of therapies could also be used with the vaccines.
• 8:50 These are not mutually exclusive.
• 8:53 Now, the next area, which I would say has become very exciting as well, has been around these ideas of trying to repair the brain, which is obviously something I've invested a lot of my professional career in trying to develop.
• 9:05 And at the moment there are two main areas in which this is being done.
• 9:09 One is around giving fertilizer to dopamine cells to make them grow.
• 9:13 This is perhaps best known as an agent called glial cell line-derived neurotrophic factor, or GGNF, which has recently been published from a trial in Bristol and was part of a documentary that was shown on the BBC.
• 9:27 And this trial rather disappointingly seem to point a negative outcome in their trial where they gave people this growth factor and followed them over a period of time and those who had the growth factor versus those that did not, didn't seem to change significantly.
• 9:42 However, we buried within that data, there does a clear to be a signal that actually in some people this growth factor works and probably the people in which it works most effectively are those with earlier stage disease.
• 9:54 So the idea of this treatment is you give this growth factor and it stimulates what you have left of your dopamine system to regrow.
• 10:01 Now obviously if you take people with advanced disease, that's not going to work because they've got nothing left to grow because it's all unfortunately being lost to the disease process.
• 10:09 But in the earlier patients where the system is more intact, this type of growth factor should be able to promote recovery.
• 10:15 And in these trials, both this new one and the ones in the past, there is some evidence that this is actually happening.
• 10:22 So at the moment, growth factors have gone into this slightly ambivalent state of whether they're actually going to be useful or not.
• 10:28 But nevertheless, I think there's enough data out there to suggest that perhaps they could be useful in newly diagnosed or early-stage disease.
• 10:36 The other area that has become very exciting is the idea of replacing the lost dopamine cells with stem cell-derived dopamine cells, which you can manufacture in the lab.
• 10:48 Now the idea of replacing dopamine cells with stem has been around for a long time.
• 10:52 You only have half a million dopamine cells on either side of your brain.
• 10:55 When you lose half of those, i.e. 250,000, you develop the major features of Parkinson's disease.
• 11:00 So if you put back 1/4 of a million dopamine cells, in theory you should be able to put someone back to normal, at least around the symptoms and signs relating to the loss of those cells.
• 11:10 Now this has been done with collecting tissue from fetuses, so from termination of pregnancies you dissect out the developing dopamine cells.
• 11:19 But this obviously carries major ethical and logistical problems.
• 11:23 But in the last 10 years, technologies and protocols have been developed where you can now take stem cells, which you can grow into vast numbers of cells and turn those into the dopamine cells of the type lost in Parkinson's disease.
• 11:36 So this was really first done by two groups in New York and in Lund, Sweden, in 2011 and 2012.
• 11:44 And in the last three years, at least half a dozen major enterprises have now entered into the development of a clinical therapy around this strategy.
• 11:54 So the idea would be to grow up the stem cells, turn them into dopamine cells, then freeze them down, and then each patient, in theory, could have a little aliquot of dopamine cells transplanted into the brain.
• 12:05 And this was done for the first time in November of last year in Japan by the team of Jun Takahashi.
• 12:10 It's obviously too early to say whether it works, but as I say, there are many companies and many groups around the world who are now pushing this towards clinical trials.
• 12:19 And I would imagine that in the next two or three years, there will be multiple trials taking place with dopamine replacement cell therapies in people with Parkinson's disease.
• 12:28 Now, this is obviously not a cure because the disease process carries on, But if you were able to repair and restore that system back to normal, then the implications for Parkinson’s would be huge.
• 12:38 In essence, you wouldn't need any of the drugs that we currently use in the clinic because all the drugs we use in the clinic at the moment work around the dopamine system.
• 12:47 And so if we could put cells back which release dopamine in the normal fashion in the place where you want it, you would not need all of the medications we use now.
• 12:55 You would not get any of the complications we see from the medication now.
• 12:58 And then you wouldn't need those rescue therapies, which we also have in the clinic, such as deep-brain stimulation.
• 13:04 So this approach with cell therapies has the potential to change the Natural History of treated Parkinson's disease and could, in theory, be the only treatment you need for that aspect of the condition.
• 13:15 And obviously, if combined with one of these drug repurposing therapies or one of these vaccines could be the answer to how you stop people getting Parkinson's and arrested at the point at which they present.
• 13:26 The final area, which I would say has been very interesting and again has been the subject of recent publications, is the idea that instead of putting cells back to replace dopamine, what you do is you actually put genes into the brain to make the cells which were already there into little dopamine factories.
• 13:43 So this has been done through a number of different approaches.
• 13:45 Perhaps the most famous was the one done by a company called Oxford BioMedica  a decade ago with a drug called or therapy called ProSavin.
• 13:53 In this they injected this vector into the brain of people with Parkinson’s, of which we had three patients.
• 13:58 They converted cells in the brain to these dopamine factories and those patients have then been followed.
• 14:03 Now, not all of them have done well, but some of them have clearly shown a response to that therapy.
• 14:09 The encouragement from that trial then LED them to develop a better gene therapy, which was called OXB-102.
• 14:15 And that therapy has now gone to a clinical trial which began in the autumn of last year with a patient injected with the virus into the brain here and in London.
• 14:26 And we're waiting now to see how that is going to develop.
• 14:30 Now, that is obviously a very exciting area of gene therapy and new interventions.
• 14:35 The company itself has attracted a lot of investment based on what they've seen already.
• 14:39 So this is clearly an area that is emerging as a possible new approach to treating Parkinson's disease.
• 14:45 And indeed, only last week a group in the West Coast of America published a therapy, a paper on a trial in which they'd used a gene therapy showing that they too could increase the production of dopamine in the brain, reduce the dependency of the patients on their oral medication with clinical improvement.
• 15:02 So this idea of using a gene therapy is similar, if you like, to the cell therapy, although it has advantages because you're just injecting the gene and using the patient's own cells, it has the disadvantage that you're not replacing the cells which were lost as part of the disease process.
• 15:18 So in 2019, Parkinson’s is in a very exciting place.
• 15:21 We're starting to understand more about when the disease begins, we're starting to understand more about how the disease follows different paths and how we can subtype patients.
• 15:30 And we're now starting to see a whole plethora of new treatments emerging which can be targeted to these different groups of patients which, whilst they're all being viewed in isolation as ways to treat Parkinson’s Disease, ultimately could be combined.
• 15:44 And they could be combined not only to produce fantastically improved symptomatic benefits to patients, but have the potential to actually cure people of this condition.