Episode 61: The Launch of the PD GENEration Genetics Initiative

Dan Keller 0:08

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. No two cases of Parkinson's disease are exactly alike. Throughout this podcast series, we've talked about biomarkers—those identifiable and measurable traits that a person carries or exhibits. One of those is a person's genetics. People with PD may experience different symptoms at different times and may vary in how the disease progresses. These are the outward signs that they experience. But beneath the surface, are there genetic makeups which contribute to a person's risk for PD, how the disease presents, and the course that it may follow? To explore these genetic factors, the Parkinson's Foundation has initiated the largest and most comprehensive genetic study in PD, aiming to assess these factors in 15,000 people with the disease. I spoke with Dr. Jim Beck, the Chief Scientific Officer of the foundation, about this initiative called PD GENEration: Mapping the Future of Parkinson's Disease. He says that while only a minority of people will have identifiable genetic risks for their disease, the study should shed light on mechanisms of the disease that may be applicable to the entire PD population and may lead to better treatments. We spoke about the three main goals of the PD GENEration study.

Dr. Jim Beck 2:10

One of them is a very pragmatic goal, and that is to accelerate clinical trials which are coming. The other is to be able to bring precision medicine to Parkinson's disease, meaning being able to utilize genetic information to make informed decisions about the care of people with Parkinson's disease. And the third one is to really empower people with PD to know more about their disease, to be able to make informed decisions about what it means to have Parkinson's disease, and so that they can take control of their lives. What's it looking at, and how it's [a] genetics initiative? So we're going to be looking at genes. And for your listeners who may or may not [know] what genes are—genes are recipes for making proteins in the body, much like a recipe you'd have to make cake. And these recipes sometimes have errors in them. And it's much like... I like to make pound cake; it was my mother's dessert she'd always make for me, and so I still make it. And sometimes I try different things, and I bought a fancy flour I saw at a grocery store, and my cake was awful. One time I didn't put enough vanilla into it, and it was fine, but, you know, it was okay. So one was a deleterious mutation, which led to something bad. The other was a risk factor or slight change or variants in the recipe that could have been bad or could have been good. And so you see that same thing with genes for people. And so what we want to do is look at genes which affect Parkinson's disease. Some of these genes, when they're mutated, cause Parkinson's disease—we have lots of confidence. Other ones are like these variants in the recipe, and they are associated with a greater risk for Parkinson's disease—not always getting Parkinson's disease, mind you, but a greater risk. And the two we're going to be looking at are LRRK2, which stands for leucine-rich repeat kinase 2, and GBA1, which is a gene which makes a protein that's involved in Gaucher's disease. Where you have two copies of GBA mutation, a person gets Gaucher's disease; one copy, they have an increased risk of developing Parkinson's disease. And we want to be able to test people for these genes and be able to provide that information back to them.

Dan Keller 4:13

Where does it stand now? How far along is it? When do you see it producing useful results?

Dr. Jim Beck 4:17

We just announced this initiative, and we're collaborating with the community—both the scientific and the PD community—to ensure that what we're doing is going to have impact in their lives. So what we want to do is not just simply offer genetic testing to people with Parkinson's disease. That's something that people can do to a certain extent already. What we want to do is offer it within a clinical setting, because we think what has been a missing part of the equation is including a person's physician as well as a genetic counselor to be able to provide that interpretation to what the results mean. Used to be, you could go get over-the-counter testing; you spit into a tube, and you get your report back, and it would say whether you had a PD gene. But what people didn't realize, because they didn't have a counselor there with which to guide them, is that they only looked at one variant of one gene when there are over two dozen genes which could be impacting for Parkinson's disease. And as a result, they would say, "Oh, I don't have this variance in this one gene. I don't have a genetic form of Parkinson's disease." It's like going to the mechanic and having them, you know, take a look at your car because it's not running right. And they just look at the gas cap. "Yeah, gas cap's working fine, problem solved," when, in fact, that there's some other issue which might be causing their PD. The other thing is that because we want to look at these two different genes—LRRK2 and GBA—genetic testing for them, if you wanted to do that on your own privately, is not easily accomplished. The LRRK2 gene—you can go to some places, direct-to-consumer, or even get it ordered; they can provide some limited testing. GBA is much more difficult, because we need to get the full gene sequence. It's kind of like with LRRK2, you can kind of go by the CliffNotes and just look at a couple bullet points to find out whether you're affected, but with the GBA, you have to go through page after page, line by line, in order to really understand whether there's a variation in that gene which could lead to Parkinson's disease. And so you could do that, but you'd have to go to two different providers, two different genetic testing places to do that. And we want to consolidate that into one place to be able to offer it for free for people with Parkinson's disease, and then be able to incorporate that as part of a larger study that we have, our Parkinson's Outcomes Project, which has the largest natural history study of people with Parkinson's disease. What we want to do, ultimately, is to link someone's genetic status with their clinical status. It's the scientific way you say genotype and phenotype. And so we want to understand how someone's genes influence their course for Parkinson's disease. How can we utilize that information to improve their care?

Dan Keller 6:41

You named two genes out of this multitude of them. For example, these two genes—do they lead down the same Parkinson's disease road, or is there some difference? What would it matter to a patient whether they have Parkinson's disease because of this or because of that?

Dr. Jim Beck 6:55

Yeah, that's a really good question. And I think the first thing to keep in mind is that most people won't have a genetic form that we can easily identify at this point for their Parkinson's disease. We're only talking about genes which affect probably 10% of people with PD. And in fact, most people—it's only maybe 15 to 20% of all cases of PD have a genetic form of PD. So within this limited range, people with LRRK2 PD or GBA PD—and this goes back to something just even a couple years ago—if you were to get genetically tested, trying to understand a genetic cause to your PD, and you went to your physician and you said, "Hey, I've got LRRK2 mutation, I've got LRRK2 PD," or "I've got GBA variants and GBA PD, how's that going to affect my treatment?" They kind of shrug their shoulders and say, "Not really. It's not going to affect your treatment at all," because their doctor, like most movement disorder specialists or neurologists, are treating for symptoms. And so knowing the genetic status didn't affect the treatment of symptoms. But fast-forward a couple years now, we now have an understanding that someone who has LRRK2 PD, on average, has a slower time course to their Parkinson's disease. And we also understand that someone with GBA version of PD has a slightly more aggressive form of Parkinson's disease, and it progresses more quickly than LRRK2 PD—more quickly than the average case of PD. And so what's the impact of that? The impact of that is that, you know, as part of this initiative—you know, how we want to improve care—is that if someone were to go through our genetic testing initiative and find out they had LRRK2 PD and were experiencing motor complications to their Parkinson's disease, their neurologist would probably say, "Hey, you know what? The likelihood is you're not going to have any cognitive involvement. Your PD is going to progress slowly. Maybe we should be more aggressive and consider something like deep brain stimulation as a potential therapy for your complications." Whereas someone [who] had GBA PD, which has a faster progression, typically with some cognitive involvement—so people with GBA PD often have some cognitive impairment as a result of their disease—their neurologist might say, "You know what? Let's hold on a second. Let's really carefully evaluate the situation here, because we know that deep brain stimulation can cause cognitive impairment on its own. We don't need to make a bad case worse. So let's see about what our options are and how we can improve your situation before we go to deep brain stimulation." So that's one very practical way with which we could see how understanding someone's disease status could be useful for their care.

Dan Keller 9:25

Given the variety of different genes that may be involved, do you think that 5 to 10% number you gave today will hold, or is it just that you haven't discovered all the genes that are affecting it and many more—a higher percentage—could be genetically related?

Dr. Jim Beck 9:44

Yeah, that's a really good point. So by and large, most people who come through our genetic initiative are going to come up empty-handed if they're looking for a gene to cause their PD, simply because we may not know what that gene is as of yet. So that leads to two questions: you know, what do we [want] to do with that DNA, and then how is that going to impact the broader range of people who have idiopathic PD? You know, the PD we don't know why they developed it. So what we plan to do is bank all the DNA that people contribute because they've given their time and their efforts. And this is a valuable collection. We want to make it available to researchers—researchers who don't look at just a handful of genes that are actionable right now, but they look at 30, 50, 150 genes to try to get a better sense of what might be causing Parkinson's disease. The example, Dan, that I give to many people is that we understand there's a clear genetic correlation to something as simple as height. You look at a family—the parents are really tall; you're not going to be surprised to learn that the children are going to be tall. And the vice versa happens, too—the flip side where a family of short stature are probably going to have children which are short as well. But I ask people, "How many genes are involved with height?" And, "Is there one height gene? Is there two height genes?" I show up five fingers, 10 fingers, and I say, "Is there 30 genes involved in height?" And people are flabbergasted to recognize that there's over 100 genes involved in determining someone's final height. And each gene contributes about a third of an inch to that overall height. And so these 100 genes play a role in determining someone's height. So there might be 100 or more genes to determine someone's risk for developing Parkinson's disease. One thing that I think would be really cool, it could happen—and this is, you know, we're not there yet, but that's why we want to make this DNA available for research—is that scientists might figure out a genetic risk score for someone with Parkinson's based upon this dataset that we have. And so that means when someone is in their 40s and they go in as part of a physical or even earlier, when this type of precision medicine becomes kind of the standard part of medical care, they run the genetic tests on someone and determine that this person has a higher risk for developing Parkinson's disease. And as a result of this initiative, we hope to be able to facilitate and accelerate the development of drugs which might halt Parkinson's disease. And so those drugs might then, in turn, be utilized for these people who have a higher risk score for developing Parkinson's, or at the very least, the clinician's going to say, "You know, we need to keep an eye on you so we can intervene when you show that first sign of symptoms." So that's something that's really interesting. Have we missed anything interesting or important? Yeah, yeah, yeah. One question that I often hear from people is, why are we focusing a lot of resources on, in essence, 10% of the people with Parkinson's disease? What about these other 90%? Wouldn't you be better served trying to understand what's going wrong with these other 90%? And so I often like to tell a story about two people who many folks know, and that is Winston Churchill and Jim Fixx. Winston Churchill was a man of short stature who drank a lot, smoked a lot, who ate a lot, who had some stress in his life, and yet he lived to be 90 years of age. Jim Fixx, on the other hand, was a man who wasn't particularly healthy early in life but really turned it around, became a big believer in exercise, and in fact, converted many people in the United States to become really into running, and started Runner's World magazine. He died at the age of 52, I believe, of a massive coronary while running in Vermont. What's the difference between these two men? Well, genes. Genes is the difference. And so in Jim Fixx's case, he was likely a person with a mutation in a gene that led to high levels of cholesterol called familial hypercholesterolemia. And scientists understanding mutations in that gene led to better understanding of how cholesterol is regulated in the body, and then could develop a drug called statins. And so I ask people, "How many people here know," and your listeners, "how many people know anyone who actually has a mutation that leads to familial hypercholesterolemia?" Most people say they don't know anyone. But when I ask them, "How many people do you know are taking a drug, statins?" And most people know somebody who's taken a statin. And so I think that's where we're going with Parkinson's disease, I hope, is to be able to identify certain individuals who are rare and have a risk for developing Parkinson's disease, utilizing that knowledge, being able to potentially impact their Parkinson's disease, and then hopefully be able to go broader, broader, and be able to help a larger population of people with PD. Because people with LRRK2 mutation—LRRK2 is an enzyme that gets overactive when they have that mutated gene. But there are people who don't have a mutation in LRRK2 yet still make too much of that enzyme, and they have Parkinson's disease. And there are people who don't have a variant in their GBA gene and still have low levels of the enzyme, that glucocerebrosidase, that gets made by the GBA gene. Much like someone who might have a mutation in that gene would have low levels of that enzyme—not as low, but they also have Parkinson's disease. So therapies which can be utilized to either rein in LRRK2 or boost the levels of GBA might affect a broader range of people with Parkinson's disease. And what's really interesting, too, is that—and this goes beyond the 10%, the 90% story—but it goes on to the fact that there's a whole host of people who have yet to be diagnosed with Parkinson's disease, yet are at risk. And so identifying those who might have a genetic mutation that could be causative to develop their PD, we might, hopefully again, accelerate clinical research to the point where we have a drug which could be used prophylactically, which basically means that, again, when someone turns 50, they go in for their colonoscopy, they may get the genetic test to understand that they're at risk for PD. And then their physician says, "You know what? You might be worried about PD one day. I'm going to prescribe this medication which we hope will prevent you from ever experiencing the symptoms." Our goal as a foundation is a world without Parkinson's disease, and that is one way with which we hope to achieve it.

Dan Keller 15:50

I hope you succeed. Very good. Thank you. For more information on PD GENEration, go to our website at parkinson.org/PDGENEration, where you'll find more information about the initiative. Learn about the power of genetic testing in achieving precision medicine for individual patients, why you might consider participating, and how you can. Be sure to search our PD Library at parkinson.org/library to find more resources on genetics, including fact sheets and an archived Expert Briefing by Dr. Roger Barker that looks ahead at what's in the PD pipeline, focusing on gene and cell therapies. And be sure to go back and listen to Podcast Number 7, where I talked with Dr. David Simon about how modern genetics can help guide the development of new drugs to preserve nerve cells with a goal of keeping Parkinson's from progressing. If you want to find out how you may be able to participate in the PD GENEration genetic study, you can also call our toll-free helpline. Our PD information specialists can answer questions and provide information about this topic or anything else having to do with Parkinson's. You can reach them at 1-800-4PD-INFO. For 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. 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 every other week. 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.

James Beck, PhD, has led the scientific affairs of the Parkinson's Foundation since 2008. Dr. Beck oversees the foundation’s research strategy and programs, including management of grants that support research centers, individual investigators, fellows and collaborative projects. In his role, he has changed the parameters of investigator-initiated grants programs to provide additional funding and multi-year support to Parkinson’s-focused scientists; expanded funding for early-career Parkinson’s researchers, established Conference Awards and instituted the inclusion of Parkinson's Foundation’s Research Advocates in the foundation's own programs. Dr. Beck is a member of the Forum on Regenerative Medicine of the National Academies of Sciences and the Udall Center Coordinating Committee.

Dr. Beck is currently an Adjunct Associate Professor in the Department of Neuroscience and Physiology at the New York University School of Medicine. Previously, he taught at Long Island University as Assistant Professor in the Biology Department. Additionally, Dr. Beck was a recipient of National Institutes of Health (NIH) funding and has been published in journals, such as the Journal of Neuroscience, Journal of Neurophysiology and Journal of Comparative Neurology. His research focused on the neural control of vertebrate motor systems and behavior.

Dr. Beck holds a BS from Duke University and a PhD from the University of Washington, Seattle. He completed his postdoctoral training at the New York University School of Medicine. Dr. Beck frequently comments in the media about the implications of the latest Parkinson's science headlines.