Episode 7: Genetics as a Guide to Neuroprotection in Parkinson’s Disease

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.

For many years, levodopa has been the treatment of choice for Parkinson's because of its effect in reducing motor symptoms, but the disease still progresses regardless of treatment, and attempts to protect neurons in the brain and slow the progression of Parkinson's have not been successful. Advances in modern genetics now open a new window on possible ways to look at the underlying causes of the disease. They can also help select people for clinical trials who have the most likelihood of benefiting from a particular experimental treatment.

Today, Dr. David Simon, director of the Movement Disorders Center at Beth Israel Deaconess Medical Center in Boston — a Parkinson's Foundation Center of Excellence — explains how genetics can be a guide to developing new drugs that might preserve nerve cells and potentially keep Parkinson's from progressing.

In our discussion, he mentions two terms that may not be familiar to everyone. One is biomarker, a shortened term for biological marker. Biomarkers are characteristics of the body that you can measure. They are important to medicine in general and to drug development in particular. Biomarkers tell us how the body is doing and can help identify disease risk or disease progression. The other term is alpha-synuclein, a protein found in the human brain that is associated with the development of Parkinson's, so it is a potential target for drug therapy.

Dr. Simon sets the stage for the situation today and how scientists are moving the field ahead to try to find ways to slow the progression of Parkinson's.

Dr. David Simon 02:25 It would really dramatically change the way we treat Parkinson's disease if we could find one — or preferably more — strategies that can slow progression.

Dan Keller 02:34 So what are some strategies? How can we gear up to know better how to attack it?

Dr. David Simon 02:41 So the first step, of course, is understanding what causes the disease to progress. In some cases, what causes people to get the disease in the first place will also be a mechanism relevant to why it progresses, although in other cases, causes of progression may be distinct from triggers of the disease. I think one of the important clues is genetics, where we can have a very clear causal association of a change in a gene with high risk of developing the disease, and that can give us a great clue into a target for neuroprotection. But there are other strategies as well for identifying promising mechanisms.

Dan Keller 03:17 The genes that are being looked at now — are they associated 100% with Parkinson's disease, or are they just one factor in the mix that raises the risk or modifies it?

Dr. David Simon 03:28 Yeah, so the genetics of Parkinson's are very complex, and both types that you just named have been identified, although there's still a lot about the genetics of Parkinson's we don't understand. In terms of a single gene in which a mutation is found that puts you at very high risk for getting the disease, it's only a very small percentage of patients in which we can identify such a mutation. There are common variants — sometimes in the same genes that have one of those other types of mutations I mentioned — where a common variant has a small impact on your risk of the disease. And then there's some in between, where a variant puts you at high risk of the disease, but not everybody who carries that mutation will actually get the disease. I can give examples of those if you wish.

Sure. One would be a gene called LRRK2 — or "lurk two" as some call it. Maybe 2% of all Parkinson's patients have this mutation, which is actually relatively common as far as high-risk genetic mutations go. It's a mutation that we're still working to understand exactly why it causes a high risk of Parkinson's, but it's probably due to increased activity of the enzyme produced by that gene, and that gives a great clue as to a possible neuroprotective strategy in patients who have a mutation in this gene. We know that high levels of this enzyme cause people to get the disease, or at least have a high risk of getting the disease, and we can measure the activity of that enzyme. So many pharmaceutical companies are designing drugs that specifically inhibit that enzyme. It makes a lot of sense that those drugs might help to slow the progression.

Now, we can't know that until we test it properly in placebo-controlled trials, and it takes a lot of work to get a drug like that even to the beginning stages of trials. But that work is being done, and I think one reason this approach has greater promise than some of the past strategies is that it's targeting a very specific mechanism in a subset of patients who we can identify as having the greatest chance of benefiting from the drug. So if we tested one of these LRRK2 kinase inhibitors in all Parkinson's patients unselected, we might not see any effect, because it may be only that 2% with the mutation who could benefit — but we have a way to select them. We can test patients and enroll only those with the mutation for the initial clinical trials.

Disappointingly, that means if it works, we've got a great strategy, but only for 2% of Parkinson's patients. On the other hand, given so many failures with promising agents that have not shown efficacy in clinical trials, if we can make progress in a small percentage of patients, that would be a huge victory. And then we just do it again in another subset, and again in another subset, and eventually, hopefully, we'll reach a large group of Parkinson's patients.

Dan Keller 06:16 That gene would be a biomarker for who may best be suited for a trial or benefit from it. But are there biomarkers to follow the therapy itself, or do you have to wait years to see whether something is working or not?

Dr. David Simon 06:31 There are many different types of biomarkers. You can have a biomarker of the drug effect, and you can measure that very quickly. As I mentioned, you can measure the activity of this enzyme — treat cells in a dish, or maybe even a person — draw a blood sample, and measure to see if the drug is having the desired effect. That's very quick, and that's great. That we can do for several drugs, and it's important because some drugs have gone into neuroprotection clinical trials that have failed, where we don't really know for sure what the mechanism is. The drugs failed, but we don't even know if the drug was having the necessary mechanistic effect in patients, because we either can't measure it or we don't know what to measure.

With LRRK2 kinase inhibitors, we can measure the activity of this enzyme — we know it's having the desired effect. That doesn't guarantee the trial will work, but if it doesn't, we have good arguments as to why this mechanism isn't what we thought it was. And with genetic data, I think we have strong reasons to believe we're on the right track with that mechanism.

So other biomarkers that would be hugely valuable would be a biomarker of progression. Thankfully, Parkinson's does progress relatively slowly in most patients — that's great for patients — but we want to make it progress even slower. To do that, we can't just treat patients for a month and see if they progress slower, because that's really not enough time to detect progression. If we had a biomarker of progression that was more precise than our clinical exams, we might be able to detect changes in a shorter amount of time. With some strategies, the biomarker could tell us we're on the right track even before we've had time to detect clinical progression.

One example: there are vaccine studies underway to clear away alpha-synuclein. There's an overwhelming body of evidence implicating alpha-synuclein in the degenerative process in Parkinson's. So it could be that, in a short period of time, if there were ways to image alpha-synuclein in the brain — which, by the way, don't exist yet, though there's a huge amount of work to develop that type of biomarker — we might treat patients for that one month I mentioned and show that we've cleared away alpha-synuclein. If we do that, it's not exactly a biomarker of progression, but it's a biomarker that the drug is affecting a relevant pathophysiological pathway. Then you'd know that's worth pursuing in a bigger, longer, more expensive phase trial. On the other hand, if you had a drug or vaccine that you hoped would clear away alpha-synuclein and you see no evidence of that, maybe you stop there and put your resources toward a more promising agent.

Dan Keller 09:02 So where do we stand now in terms of prospects? We have all these tools in hand — are these going to open up the field in a different way from what we've seen in the past?

Dr. David Simon 09:15 One way it's different is, as I mentioned, we're now targeting defined subgroups. A couple of examples of trials that failed — that didn't do that — would be Coenzyme Q10, which affects mitochondrial function, meaning energy metabolism, and may have antioxidant and other mechanisms. But there weren't specific patients who we would think were more likely to benefit compared to others. Same thing for creatine, a drug with some overlapping mechanisms, also involving energy metabolism and antioxidant defenses. Both drugs were tested in pretty much all Parkinson's patients — there were some entry criteria, but nothing specific to the mechanism of these drugs. And although they looked promising in preclinical data, they both showed no benefit in phase three clinical trials.

I think a drug like an inhibitor of LRRK2 kinase, where you can identify specific subsets of patients who are likely to benefit, has a much greater chance of success. Another example would be another gene — the glucocerebrosidase gene. This is a gene involved in Gaucher's disease, a completely different disease, but it was noted that people with Gaucher's disease have a high risk of later developing Parkinson's. This became clear especially after treatment for Gaucher's disease improved and people were living longer. But people who are carriers of a Gaucher's mutation — they don't get Gaucher's symptoms — were also noted to be at higher risk of Parkinson's, and these mutations cause loss of the enzyme activity.

Some companies are working on drugs that increase the activity of that enzyme. I'm actually working with one company doing that, but there are others as well, including one that's moving into clinical trials right now. There you could identify patients either by having a mutation in this gene — where you know they have very low enzyme activity — or even some patients who don't have a mutation in the gene but still have low activity. You can enroll patients with this low enzyme activity and hope that they would have a greater chance than others at responding to a drug activator. So that's another example where you can identify a subset of patients — again, just a small percentage of Parkinson's patients — but where we might have greater success in slowing progression.

And although some trials have failed, there are a couple of others ongoing now. One in particular — and our site is involved in this — is a clinical trial funded by the NIH of a drug called inosine, which increases uric acid levels. This is led by Dr. Michael Schwarzschild at Massachusetts General Hospital, who has done a lot of the background work, along with many others. Inosine increases uric acid, which is an antioxidant, and it's thought that oxidative stress may play a role in Parkinson's progression. There's a lot of data suggesting that low uric acid levels may play a role in progression — no proof in Parkinson's patients yet, but promising enough that this strategy was worth pursuing.

But rather than just testing inosine in all Parkinson's patients, for this trial we first measure uric acid level in a patient who volunteers to participate, and only if their level is low — below average — do we enroll them in the study. That serves two important purposes. One is they're most likely to benefit — they have low uric acid and the most to gain by increasing it. And two, it's safer, because you don't want to take somebody who already has a high uric acid level and raise it higher, as that would increase their risk of gout, kidney stones, or other problems.

So here's a way where using a biomarker allows us to identify patients at the greatest chance of benefiting and at the least risk from a given treatment. Unlike the genetic causes, this one — although it's only a subset of patients — is a big subset. About half of all patients would have the potential to benefit from this treatment if it works.

But I should strongly recommend against just going off on your own and trying inosine. It is actually available, but it would be highly risky for a patient to just go take it on their own from a health food store, because of the risks I mentioned — gout, kidney stones, and others. And even if you worked with your physician, who said, "I'll measure your uric acid level," I'd still recommend against that. We have really tight controls within the clinical study to do the best we can to ensure patient safety, but there are still risks — and that's in the face of no proven efficacy yet. Until we know, some people had recommended CoQ10 or creatine before we had results — fortunately, in those cases, it probably doesn't do much harm. But I think inosine carries a little more risk if used outside of a trial, and with still-uncertain efficacy, I think we need to wait for the phase three data before we know whether or not to recommend it for patients.

Dan Keller 13:46 So it sounds like there's some optimism looking ahead — but don't jump the gun.

Dr. David Simon 13:52 That's right, and jumping the gun is an important issue to raise, actually, because a lot of patients, when I tell them I have a lot of reason for hope and that we've got several studies underway and others in the pipeline — they say, "Well, I need something now," and they're willing to take risks. But this strong, motivating desire to do something now to slow progression can lead to risky decisions to use unproven therapies that may have risks — sometimes even unknown risks — in the face of unknown efficacy. I think that's a dangerous path to go down. Some people do go down that path, and I understand the motivation, but you have to be cautious. We don't have what we really want, which is a simple way to take a drug and know in just a few weeks if it slows progression. The only way to know is a slow process — but we're getting there. We are making progress. We're much closer than we were before.

Dan Keller 14:46 Very good. I appreciate it. Thank you.

Dan Keller 14:56 Research is the only way that new treatments may be found to slow the progression of Parkinson's, and clinical trials are part of that process. If you think you may want to participate in one, call our helpline at 1-800-4PD-INFO to find out about what research is going on in your area. Much of it is conducted at our Centers of Excellence around the country and internationally.

If you want to leave feedback or comments on this podcast or any other subject, you can do so 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.

In our next podcast, we'll hear about work testing a vaccine against alpha-synuclein. Until 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.

Advances in genetics have opened new windows on possible ways to look at the underlying causes of Parkinson’s (and other) diseases. But what is a gene, anyway? Genes are the basic units of heredity. They contain the instructions for making proteins, which do the work within our cells and bodies. There are several genes associated with Parkinson’s. The most common are LRRK2 and GBA. For more information on Parkinson’s genetics, and genetics in general, check out Genetics Home Reference.

Another concept mentioned in the episode that might be new to you is “biomarker.” Biomarkers, short for biological markers, are characteristics of the body that you can measure. They are important to medicine in general and to drug development in particular. Biomarkers tell us how the body is doing and can help identify disease risk or disease progression.

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, Parkinson's 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.