Episode 16: Can an Asthma Drug Prevent Parkinson’s?

Dan Keller (00:08)
Welcome to this episode of Substantial Matters: Life and Science of Parkinson's. I'm your host, Dan Keller at the Parkinson's Foundation. We want all people with Parkinson's and their families to get the care and support they need. Better care starts with better research and leads to better lives. In this podcast series, we highlight the fruits of that research, the treatments and techniques that can help you live a better life now, as well as research that can bring a better tomorrow. One study that holds great promise for people with Parkinson's appeared recently in the journal Science. In the paper, researchers identified some drugs already approved by the U.S. Food and Drug Administration for other purposes that appear to decrease the production of alpha-synuclein. Alpha-synuclein is a normal protein in the human brain. Everyone has it, but in people with Parkinson's, there is too much of it, and it accumulates, contributing to the development of the disease. In this study, people who used the highest doses of a drug called salbutamol, taken by inhaler to treat asthma, were about 1/3 less likely to develop Parkinson's as people who never took it. Dr. David Simon, director of the Parkinson's Foundation Center of Excellence at Beth Israel Deaconess Medical Center in Boston, explains the investigators' approach and the significance of the findings.

Dr. David Simon (01:44)
I think this is a potentially very important paper, although we'll only truly know the importance with hindsight when more work has been done, but the quick summary of what they've done is identified a novel pathway with potential drugs that target that pathway that could be used in theory for slowing the progression of Parkinson's disease. We don't know for sure that these drugs will do that, but they've provided quite a bit of evidence in many different ways that at least support the importance of testing that possibility.

Dan Keller (02:22)
They screened more than 1,000 drugs and came up with drugs that—some of them are already approved. Certainly how these drugs are used—they're asthma drugs, they're inhaled. So do you think if this pathway and this route to a treatment is viable, that it's going to be a little faster than if they started with an absolutely new kind of molecule and had to do it from the beginning?

Dr. David Simon (02:48)
Yes, that's absolutely true, and that's specifically why they chose to screen this panel of over 1,000 drugs. They weren't randomly selected drugs. They were drugs that are part of a panel of drugs that have already been FDA-approved for some other indication, and that's a huge leap forward in the clinical process. It still takes time and is slow, but this means we already have extensive data regarding dosing and safety in humans. If you start with a new drug that's just been developed in the lab, there's a huge amount of testing that needs to be done in animals, and then early testing in humans that takes years, and many of those drugs will turn out to fail due to toxicity issues. Here, it's a huge leap forward that will cut off many years of research and improve your chances of success in the end.

Dan Keller (03:40)
These drugs are currently approved to treat asthma. They're beta-adrenergic agonists, as they say. What are they doing in terms of Parkinson's?

Dr. David Simon (03:53)
We had not anticipated that these beta-two adrenergic agonists, these asthma drugs, would have an effect on Parkinson's. They found it, as you said, from this screen of a huge number of compounds to see if they would have an effect on a protein that we know to be relevant to Parkinson's disease. And these just popped out of that screen. They tested the ability of drugs in cells in a dish in what's called a high-throughput assay that's amenable to screening large numbers of drugs like this to see which drugs would reduce levels of a protein called alpha-synuclein. And alpha-synuclein is a normal protein. We all have it, but in Parkinson's patients, there's too much of it, and it tends to accumulate and aggregate, and it causes toxicity that actually contributes to the progression of the disease. So the idea is that if they can reduce levels of that protein, then it might have a protective effect in Parkinson's. So that's why they did that particular screen, and these drugs popped out.

Dan Keller (04:58)
So I suppose you don't want to eliminate alpha-synuclein entirely, because we assume that if there is some protein in the body, it must have some natural function. How much did these drugs knock down the levels of alpha-synuclein, either in the lab or in animals or in people?

Dr. David Simon (05:18)
I mean, that's an important point. We don't really know what would happen in people if we completely eliminated alpha-synuclein. These drugs don't completely eliminate it. They reduce its expression. The threshold they used in their assay—they paid particular attention to drugs that reduced it by at least 35%. I don't know the specific percentage of reduction for each of the compounds they identified, but in none of the cases did it completely eliminate alpha-synuclein. It just reduced the levels. So I think that adds a bit of safety for the reason that you said.

Dan Keller (05:51)
Do you think that these drugs, if they're developed and brought to market for Parkinson's, would have to be inhaled, or is there another route? It's certainly easier to take a pill.

Dr. David Simon (06:02)
Although for asthma, where you're targeting the lungs, it makes sense that they would be delivered in an inhaled form. In Parkinson's, we don't know. There are oral available agents that are actually longer-acting. The typical, common versions, like salbutamol that's used for asthma, are short-acting agents that are inhaled. But it might make sense in Parkinson's to use one of the longer-acting oral agents. It's actually one limitation of this study. I mean, it's a wonderful study that addressed this issue in many different ways, but one thing it doesn't tell us for sure is which is the best agent. It gives a lot of evidence that beta-two adrenergic agonists are promising and should be tested in the clinic in Parkinson's patients, but it's still unclear which of the various ones would be the best one to move forward with.

Dan Keller (06:49)
It seems like this is a very new approach. In the past, it's been—and currently—it's replacing dopamine through using levodopa. Some studies are looking at reducing the amount of accumulated aggregates of alpha-synuclein, but this one is aimed at stopping the production. So is this, I won't say a breakthrough, but a very new way of thinking about it?

Dr. David Simon (07:15)
Yes, it is. It's not the first study to try to identify ways to reduce the expression of alpha-synuclein, but to my knowledge, it's the first one to clearly show the potential of beta-two adrenergic agonists for achieving that. And you're right. There are other studies actually further along, already in phase two clinical studies, looking at various strategies to try to clear away the clumps of protein. Here's an idea at an earlier stage: just prevent the protein from being produced in the first place—or, as you pointed out, reduce it, not completely prevent it. So yes, that's a novel aspect.

Dan Keller (07:50)
As we discussed, these drugs have proven to be tolerable and safe when they're used for asthma, and I suppose research would want to use compounds that are already approved for something, cutting the development process way down. But do you think that there may be even some of these compounds which may be even more effective?

Dr. David Simon (08:13)
Well, it's possible, although that relates to the issue I brought up earlier—that we don't know which compound is the most effective. It's always possible we could find a variant of one of these that could be modified in a way, for example, to achieve better penetration into the brain or to have some other feature that makes it more potent. But we don't know. I mean, there are reasons to think the agents already available are worth testing. One example is from the same study. In addition to screening and finding these compounds, they also did an epidemiologic study where they looked at basically data from the entire population of Norway that they had access to and found that patients who were treated with existing agonists, including salbutamol, had a lower risk of developing Parkinson's disease. And so that suggests that, for example, salbutamol itself might have protective effects. That's only an association. That kind of study in patients—that's not a randomized, prospective study—can't prove that salbutamol actually prevented those people from getting Parkinson's disease, but it's encouraging, and it's consistent with the other data in the paper that it might have a protective effect. So I think there are reasons to think that the agents already in existence have potential value and are worth testing.

Dan Keller (09:26)
In that same study, they looked at agents that also block the beta-adrenergic receptor. The drugs we've been talking about actually activate the receptor. The drugs that are commonly used for, say, blood pressure block the action of the receptor. Some of those drugs are also used for essential tremor. Is there some caution here that one must be really sure of a diagnosis—that it's either essential tremor, in which case those drugs would be appropriate, and not Parkinson's, in which case those drugs may be harmful?

Dr. David Simon (10:04)
Yeah. So that's a complex issue and an important one. It's a strength of the paper and of this entire hypothesis that this pathway is important that they found complementary results. As you say, when they block these receptors rather than activate them, they found the opposite effect. Blocking these receptors actually leads to increased levels of that protein, alpha-synuclein, which would be bad. And they showed in cells and in mouse models that blocking it with drugs like propranolol increases expression and has toxicity. And actually, in that Norwegian epidemiologic study, people who took propranolol had a higher risk of Parkinson's disease. So the data all seems to fit. So scientifically, that's nice, but as you pointed out, clinically, that raises a question: do we need to be concerned about using propranolol, actually, in anybody, including essential tremor patients and Parkinson's patients? Are we potentially causing some downside in terms of increasing the risk of Parkinson's or causing some other negative effect? I think the answer to that is it raises an important question that needs to be addressed, but we don't know. And just like I think it would be premature and inappropriate at this point to treat Parkinson's patients with beta-two adrenergic agonists, because we don't yet have data in Parkinson's patients to show that they're safe and effective, likewise, I don't think we know enough yet to say that people need to avoid beta blockers. It needs to be studied, but we don't know right now.

Dan Keller (11:31)
I suppose at this point, that's a pretty strong caution not to proceed without actually having the data in hand, doing the right trials. What needs to be done before these things would be either approved for this use or appropriate?

Dr. David Simon (11:46)
I mean, the reason for that caution is history. We've seen this problem before. For example, coenzyme Q10 and creatine are both agents that looked very promising and worked in animal models, but when they ultimately went to a definitive phase three study, they proved not to have any benefits in Parkinson's patients, so we need to wait for the proper studies. The first step here would be probably a phase two clinical study, which means an early phase focused mostly on safety and tolerability, which may be different in Parkinson's patients compared to asthma patients. For example, tremors can be one of the side effects of these drugs, beta agonists. And since tremors can be a side effect of beta agonists, that might be a particular problem for Parkinson's patients, especially those for whom tremor is a problem. So we need to figure out how much of a problem that is. Maybe it'll be less so with the longer-acting oral forms compared to the short-acting inhaled forms. But we don't know, and we'll have to see that. And the phase two study also gives a preliminary look at whether or not there seems to be a signal for efficacy, but it won't be definitive in terms of telling us if it slows progression. So if things look good after a phase two study, it goes on to a phase three study, which means an even bigger, larger, usually longer study that is designed to definitively tell us whether or not it slows the clinical progression of the disease. So that process is going to take several years to get those studies done, and until they're done, we just don't know for sure, even though this study shows that it's promising and certainly should be studied.

Dan Keller (13:20)
So those studies would have to look for slowing down or halting progression. There are no real biomarkers for this, I assume—imaging or blood test or anything like that—to say, oh yeah, there's an immediate effect?

Dr. David Simon (13:33)
Unfortunately, what we're really trying to do is reduce alpha-synuclein expression in the brain, and there's a huge effort and interest in identifying a strategy for imaging non-invasively alpha-synuclein levels in the brain. A similar effort was made successfully for imaging a different protein called amyloid that accumulates in the brain of Alzheimer's patients, but there are difficulties in developing a similar test for Parkinson's patients. So right now, we don't have any way to tell if it's reducing alpha-synuclein levels in the brain. To determine if it slows progression, similarly, we don't have a way to count neurons in the brain, so we rely on clinical exams. We know how the disease normally progresses, and we see if this alters that progression by clinical exams. It's not perfect, and a better biomarker would make that screening test much easier.

Dan Keller (14:27)
Finally, is there anything interesting or important that we've missed, or a take-home message?

Dr. David Simon (14:33)
One take-home message, I'd say, is we've been talking about this one area that looks very promising—beta-two adrenergic agonists. It's one of several different targets and pathways that look very promising, and right now we are pursuing several different strategies in clinical trials, and this will become one of them soon, I hope. I don't think they're all going to work. We've seen some failures in the past. I'm sure we will again, but I don't think they're all going to fail either. I'm very optimistic that with additional time, we are going to find strategies that do indeed slow clinical progression of Parkinson's disease, and that will change the way we treat it. So I'm cautiously optimistic, and that optimism is partly based on this paper and this pathway, but not entirely, because there are many other pathways that also look promising.

Dan Keller (15:24)
I was impressed with the consistency of the results that they showed in this paper, all the way from in vitro to mouse models to the epidemiologic study in Norway. Everything seemed to be consistent—the controls. It seemed they did those things every which way. I thought it was quite a definitive paper, as far as it went.

Dr. David Simon (15:43)
Yeah, I completely agree. This is really sort of what I call a tour de force. And, you know, the first author, Mittal, and the senior author, Clemens Scherzer, really should be congratulated, along with quite a lot of collaborators who put together this body of work. It is very unusual in a single paper to have such a wide array of different ways to have tested the hypothesis, as you said, starting with drug screening—unbiased—that came up with this pathway, then finding epidemiologic data in the Norwegian population to support that hypothesis, testing it in cells, including confirmatory and replication tests, then moving into animal models, showing similar effects in brain. And also—we didn't talk about it—but against a toxin called MPTP that can cause the same neurons that die in Parkinson's, at least some of them, to die in the mice. These agents had the same protective effects that you'd predict in that mouse model. So it's a remarkable body of data that all is consistent with the idea that beta-two adrenergic agonists should be tested in clinical trials in Parkinson's patients. I was going to mention one other model they used, which is not in vivo, meaning not in brain, but in cells in a dish, still may have some direct relevance to its potential in humans. And that is they used stem cells from humans who have a triplication of their alpha-synuclein gene, which is an unusual type of mutation that causes them to make too much alpha-synuclein. And in those cells, in a dish—these stem cells—they converted them to neurons and then treated them with these agonists and showed that the agonists could reduce the levels of synuclein in those cells. And those are human cells from humans who have this genetic predisposition to making too much alpha-synuclein, which causes them to get Parkinson's disease. So maybe even more so than the protection against MPTP in that mouse model, the effect of reducing alpha-synuclein in these human cells might be at least as predictive. Hopefully—at least I hope it's as predictive—that it might have efficacy in humans. But again, as promising as it all is, until we do the proper tests in patients, we won't know the answer.

Dan Keller (18:01)
Well, there is still a lot of testing to be done before any of the therapies Dr. Simon described can be used by people with Parkinson's. It's an exciting time in Parkinson's research. New studies come out every year from the Parkinson's Foundation's Parkinson's Outcomes Project, the largest-ever clinical study of Parkinson's, and the foundation invests millions of dollars into research to help improve the lives of everyone affected by PD. To find out more about what research is going on in Parkinson's, call our toll-free helpline at 1-800-4PD-INFO or go to parkinson.org and click on Research. If you have any questions about the topics discussed today, or if you want to leave feedback on this podcast or any other subject, you can do it at parkinson.org/feedback. We'll respond to some questions in future episodes. At the Parkinson's Foundation, our mission is to help every person diagnosed with Parkinson's live the best possible life today. To that end, we'll be bringing you a new episode in this podcast series twice a month. We'll continue our focus on research next time with a conversation about stem cells with Parkinson's Foundation National Medical Director Dr. Michael Okun. Till then, for more information and resources, visit parkinson.org or call our toll-free helpline at 1-800-4PD-INFO—that's 1-800-473-4636. Thank you for listening.

To understand why this study is exciting, it is helpful to be familiar with alpha-synuclein, a normal protein found in the human brain. People with Parkinson’s have too much alpha-synuclein. When it aggregates and accumulates it contributes to the development of the disease. These abnormal clumps of alpha-synuclein are called Lewy bodies. They are found in the dopamine-producing brain cells of people with PD. Lack of dopamine leads to many of the symptoms of Parkinson’s, including movement and mood problems.

Another term to know is beta2-adrenergic agonist, the class of medication researchers looked at in this recent study. These drugs cause smooth muscle relaxation. This helps open the bronchial passages, so beta2-adrenergic agonists are mostly used to treat asthma and other lung conditions.

Dr. Simon earned MD and PhD degrees from Washington University in St. Louis and completed the Harvard-Longwood Neurology Residency in Boston, followed by a Movement Disorders Fellowship at Massachusetts General Hospital. He then joined the faculty at Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School, where he is now a Professor of Neurology. He is the Chief of the Division of Movement Disorders at BIDMC and Director of the Parkinson’s Foundation Center of Excellence at BIDMC.

Dr. Simon is involved in clinical studies as well as laboratory research to study agents that may have neuroprotective effects in Parkinson’s disease. He was a recipient of the George C. Cotzias Award from the American Parkinson Disease Association and has received additional research funding from the American Federation for Aging Research, National Parkinson Foundation, Michael J. Fox Foundation, and two institutes of the National Institutes of Health (NIH) – the National Institute on Aging and the National Institute of Neurological Disorders and Stroke (NINDS).

Dr. Simon completed a four-year term as a member of the NIH Molecular Neurogenetics study section and currently serves on the NINDS Biospecimen Review Access Committee (PD-BRAC). He is on the Editorial Board for Annals of Neurology. He is a member of the Cure Parkinson Trust’s Linked Clinical Trials Committee and is on the Scientific Advisory Board for the Weston Brain Institute. He also has served as Chair of the Scientific Review Committee of the Parkinson’s Study Group (PSG) and currently is an elected member of the PSG Executive Committee.