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Dr. James Beck, Chief Scientific Officer at the Parkinson’s Foundation, talks with Daniel about the role genetics can play with Parkinson’s, a progressive neurologic disorder with no known cause, and which affects nearly one million people in America.
Healthy Conversations brings together leaders and innovators in health care to talk about the biggest issues facing patients and providers today. Every month, we explore new topics to help uncover the clinical insights and emerging technologies transforming health care in real time.
Dr. James Beck:
Ultimately, what we'd like to do is have genetic testing become the standard of care for a person with Parkinson's. So as a clinician is breaking the bad news, "I think you have Parkinson's disease," the next part of that conversation is, "and my nurse is waiting for you to take a blood sample so we can do genetic testing to learn more about it and what treatments might be available."
Dr. Daniel Kraft:
Welcome to Healthy Conversations. I'm Dr. Daniel Kraft and today we're in Healthy Conversations with Dr. James Beck, the Chief Scientific Officer at the Parkinson's Foundation. Welcome, James.
I thought before we dive in, maybe we just ask you to tell us a bit about yourself and what you think mostly our listeners who are healthcare professionals should really know about Parkinson's disease and your foundation.
Dr. James Beck:
As Chief Scientific Officer at the Parkinson's Foundation, I oversee the scientific focus of the foundation. For those who don't know, Parkinson's disease is a progressive neurologic disorder that has no known cause, that we don't really have a adequate way of tracking its progression or much less understanding why it progresses moving forward.
What I think is unique about the Parkinson's Foundation is that we have this combined mission of trying to help people live better lives with Parkinson's disease. So we work very closely with the clinician community through our Centers of Excellence to ensure that they're getting top care today, as well as funding a significant amount of research to better understand what is really the ultimate cause and potentially treatment for Parkinson's disease.
We have tremendous hurdles in front of us, but the Foundation and others in the community are doing the best we can to really tackle this disease and improve the lives of the nearly 1 million people in the United States who live with Parkinson's disease every day.
Dr. Daniel Kraft:
Of course, we're now in this digital and pandemic era where we've done a lot of things virtually. How's that shifted how the Parkinson's Foundation has operated, how you interact with clinicians, researchers, patients?
Dr. James Beck:
I think it's meant a greater opportunity to really meet people virtually face to face, and I think that's been very helpful for potential collaborations.
For our patient community, it's meant a big shift for them. We have an elderly population who really is certainly vulnerable to COVID and the concerns about exposure were tremendous. One of the unique things about Parkinson's disease is that by and large, it can be assessed relatively easily via telemedicine. Rarely does a neurologist or clinician have to actually lay hands on a person with Parkinson's to understand their status, and that has meant the world for our community.
People with Parkinson's have a movement disorder and typically they're coming in from someplace that is in the suburbs of maybe a large metropolitan area. They're elderly, often with an elderly caregiver, have a lot of anxiety, and just getting into the hospital can be really difficult, and our hope is that these lessons we've learned from the COVID pandemic will persist after the pandemic maybe reaches a pandemic state.
Dr. Daniel Kraft:
You mentioned on a telemedicine visit, you can help assess a patient. I've seen in the past some early versions of wearables and apps, even from Apple, that can help track a tremor and give you some quantification. Is that something you've seen come into clinical practice or research and become a tool for assessment?
Dr. James Beck:
I think the idea of wearables is really exciting. The interpretation of what they mean is something that's still missing, not only for the patient but also for the clinician. There's certainly the desire to have it. I think it'll come, we're just not there yet.
Dr. Daniel Kraft:
And it's a continuum, right? At some point, a wearable might help you track and optimize medication, but so other digital biomarkers, voice as a biomarker, I imagine can be plugged in in some very compelling ways.
Dr. James Beck:
They certainly can, but I think by and large, for the majority of people living with Parkinson's disease, PD is a very time-demanding disease. Medications need to be taken in a very tiny window, usually within a 20-minute window throughout the day in order to optimize quality of life and minimize symptoms. And then that's balanced against whatever meals they may be taking because protein can interfere with some of the medications that people with Parkinson's are taking.
Adding on anything else on top of it for those people who generally are an older population, may be less technically savvy on a whole, needs to be as easy as a telephone in order to use and as rewarding as one.
Dr. Daniel Kraft:
It's really all about the experience and workflow for the patient, their caregivers and their clinicians.
One component that's getting super interesting and has for a while in Parkinson's has been the realm of genetic predispositions, genetic testing. Can you talk a bit to clinicians and other health care professionals about the role of genetic testing, both in predicting who might be at risk and as well as managing and treating?
Dr. James Beck:
Yeah, absolutely.
So Daniel, I think most clinicians can appreciate that genetics and Parkinson's has been an academic pursuit. It's something you read about, but it's not something you actually would bring into your practice necessarily because patients are treated based upon their symptoms, not upon their genetics. But that's going to be changing. There are at least a half-a-dozen drug companies that are looking to take advantage of a person's genetic status to bring precision medicine to Parkinson's disease. We're on the cusp of that. We don't really know who has a genetic form of Parkinson's disease or not. We're, as a community, not ready. Everyone's in the dark.
So what the Foundation is doing is looking ahead to where the field is going to prepare the community as a whole for what we think is going to be a sea change in the care of people living with Parkinson's disease. Through our large genetic testing and screening effort we call PD GENEration is offering free full-length gene sequencing of seven common Parkinson's disease-related genes and genetic counseling as part of this process. This isn't direct-to-consumer testing and we really depend a lot on physicians referring their patients with Parkinson's to the Foundation, and then as a result, we return report back to those referring physicians so they too know the status of their patients.
This is incredibly important in order to not only identify who might be able to benefit from these treatments as they come, but also recognizing that we'll need to identify people with genetic forms of Parkinson's disease in order for those drugs to move farther along in the clinical trial process and hopefully to approval.
Another component is looking at expert neurologists in Parkinson's disease. We've surveyed the group and really tried to understand what is their comfort level when talking with patients about returning results of genetic tests. And we found that many clinicians, even expert clinicians, are not really comfortable doing that quite yet. So what we've also been doing is working with other groups to provide CME for clinicians around Parkinson's disease genetics, counseling and PD Genetics 101, a one-hour course for those who have a busy clinic schedule, and then we have more in depth three to five-hour courses. There's a lot of reliance on genetic counselors within this space, but there's just not enough genetic counselors to go around, and so the more we can empower clinicians to be able to take this on themselves, that is something that we really hope to see change.
Ultimately, what we'd like to do is have genetic testing become the standard of care for a person with Parkinson's. So as a clinician is breaking the bad news, "I think you have Parkinson's disease," the next part of that conversation is, "and my nurse is waiting for you to take a blood sample so we can do genetic testing to learn more about it and what treatments might be available."
Dr. Daniel Kraft:
Famously, the Co-Founder of Google, Sergey Brin, as you know, his mother has Parkinson's. He helped fund fund the consumer side of that with 23andMe, and I believe they did some sort of crowdsourcing elements using genetics to understand who are the folks who are at risk. Do you see a role for that consumer side?
Dr. James Beck:
The 23andMe, the direct-to-consumer tests, have really kind of energized the community about it. But one of the problems we've seen is that too often, genetic counseling isn't a mandatory component of that, and as a result, even individuals who have had some medical training have had trouble interpreting those test results.
My postdoc advisor, his wife has Parkinson's. They're both neuroscientists by training. In fact, she focused on Parkinson's disease, genetics and molecular biology is part of her research. They participated in the 23andMe test in the early days and those results were very complicated and confusing for them. It's changed and I think the return results are a little better for participants. Nevertheless, these are chip-based tests, meaning they look at hotspots, a single spot on a gene, to see if there's a mutation and not the entire length of the gene if we're looking for all relevant mutations. And too often, people with Parkinson's don't know what's been tested and what hasn't been tested.
And so as we have looked to recruit people into our trial who've gone through direct-to-consumer testing, they say, "Oh, I've been tested and I don't have a PD gene," and they don't realize that those direct-to-consumer tests typically only looked at maybe one gene or two genes and only one mutation in either one of those genes.
By comparison, one of the genes that is probably one of the most difficult ones to sequence is the GBA gene, and it's certainly amenable to hotspot sequencing, but there are hundreds of mutations in that gene that could be relevant to disease, and certainly dozens relevant to Parkinson's. Half the participants in our PD GENEration study who have a genetic form of Parkinson's disease, and that's of the about 3,000 we've tested, there's a little over 400 who have a genetic form of Parkinson's disease, they have a mutation in the GBA gene, and of those in that GBA gene, there's 30 different mutations we've identified. And so a lot of these individuals would get perhaps left behind by using the chip analysis. It's inexpensive but it's incomplete when it comes to a disease as complicated as Parkinson's.
Dr. Daniel Kraft:
Folks who have relatives with known Parkinson's may have certain genetic elements. Is there any evidence yet on what can be preventative upfront when you have someone at risk and diagnosing folks at stage zero and preventing them from progressing in the first place?
Dr. James Beck:
The idea of some type of prophylactic approach to Parkinson's would be revolutionary. Unfortunately, we're not fully there yet, so if a person does have a family member with Parkinson's, the risk certainly increases and potentially even higher if there's a genetic risk. Certainly, "clean living" in air quotes would be a way. Potentially even going organic because there's certainly a known indication that exposure to pesticides, industrial solvents can be the problematic. Head injuries also put people at risk, and maybe combined with genetics, can really add to that.
Another thing to keep in mind about the complexity of Parkinson's genetics is that just because someone has a known mutation that could lead to Parkinson's disease doesn't necessarily mean they'll actually develop Parkinson's disease. Going back to your Sergey Brin example, his mother Eugenia has a LRRK2 mutation that's causing her Parkinson's disease. He has identified that he has the same mutation but he has only about a 30% chance of developing Parkinson's disease. It's not guaranteed. And so why people have what's called incomplete penetrance of a genetic mutation still needs to be determined and there's a lot of research really trying to understand what could be there to trigger and cause this mutation to really become, for lack of a better word, a malignant.
Dr. Daniel Kraft:
And it seems like it's so multifactorial. Is anything in the Foundation trying to crowdsource some of those elements so you can get a picture of those at risk, as well as response to therapy?
Dr. James Beck:
We certainly are looking to compile, in essence, a registry of individuals with Parkinson's and we're working on a next generation registry which will really depend upon patient-reported outcomes, less clinician-reported so that we can do this crowdsourcing as you suggest. And we certainly are funding research to better understand the microbiome in particular and how that may impact inflammation in the body and then potentially trigger Parkinson's disease as a whole.
What we recognize is that the pathway to better understanding Parkinson's disease still remains unknown, and so we have to put out feelers in many different directions and hopefully, one of those will reach a deep vein that can allow us to get to where we need to go.
Dr. Daniel Kraft:
There's some new platforms, one's founded by one of the Co-Founders of Waze called StuffThatWorks.Health where folks can, with almost any disease, share what's worked, what hasn't worked, and as you get hundreds of thousands of members, really gleam some interesting insights that could be provided back to the individual as well as their clinicians. It might be worth connecting on that one.
Dr. James Beck:
That's a great idea.
Dr. Daniel Kraft:
Back to the PD GENEration project, maybe give us a little bit of where it stands right now, some of the initial findings, and maybe a bit of Parkinson's Genetics 101.
Dr. James Beck:
Our PD GENEration study is looking to identify individuals with genetic forms of Parkinson's disease. We only look at seven of the top PD genes. GBA is one of them. I mentioned LRRK2, DJ-1 or also called PARK7, PINK1, Parkin, SNTA, which the scientific consensus was we'd find about 10% of individuals with a genetic form of PD and we're finding closer to 15%. So it's a larger number than we've anticipated, but there's still rare forms. We only have, for instance, two individuals who have a VPS35 mutation, so increasingly rare the further on you go.
We've explored the landscape of genetic testing and some that offer a panel for Parkinson's disease have as few as five to as many as 62 different genes, and as you add more genes to your panel, it really kind of blurs the lines and provides unnecessary complications, particularly with genetic counseling and interpretation of those results. So we focus exclusively on well-known, well-characterized Parkinson's genes and try to steer clear of genes which are less relevant to an individual with Parkinson's disease.
COVID came and then we quickly pivoted to doing a virtual approach to our genetic testing program and it's worked incredibly well. So whereas we had six physical sites throughout the United States from East Coast to West Coast, in essence six states, now we're able to reach all 50 states through a virtual approach. We are over 3,000 individuals in a little more than two years. I wasn't expecting that we'd find so many people with a GBA mutation, but we find a fair number. And the next most common is LRRK2 mutation. A lot of individuals will have PINK or Parkin mutations, but most of those individuals are a carrier of just one allele, so they're not homozygous or young-onset. And so it's very interesting to try to understand whether carrying one mutation in one of these genes associated typically with the Young-onset Parkinson's disease puts someone at risk.
Another interesting thing we're finding is that some people carry multiple mutations, so we find people with GBA and LRRK2 mutations for instance, or they'll have a GBA, a LRRK2, and a Parkin mutation. We found one individual who has nine different mutations in their GBA gene. Right now, it's not influencing care, but the more we can understand about genetic forms of Parkinson's disease, I think the better overall. We'll get to a point where we can use that so that physicians would be able to advise their patients not only about what medications to take perhaps, but also what it might mean for their prognosis.
Dr. Daniel Kraft:
Depending on what mutation, might you then affect a different course of care or a targeted therapeutic?
Dr. James Beck:
Yeah, absolutely. So there certainly are drugs which you're targeting LRRK2 gene as well as the GBA gene. Those, I think, are the ones that hold the most promise and we'll start seeing whether those will be successful soon. And so a range of approaches, some are using oligonucleotides, some are using small molecules as potential therapeutics.
Another less precision medicine approach are those which are targeting the protein alpha-synuclein. Those are probably going to be less amenable to genetic intervention simply because they're incredibly rare forms of Parkinson's disease. That said, too much alpha-synuclein and misfolded alpha-synuclein seems to be a problem for everybody with Parkinson's disease, and those are also in early stage clinical trials as well, so hopefully they will be successful. That's really where the excitement's coming.
And then there's also, I think, a recognition about the non-motor symptoms, really perhaps the most debilitating is what we hear from our community, whether they be issues around psychosis or dementia to even issues with gastric dysfunction, particularly constipation. Something as simple as that can be incredibly debilitating and lead to a much decreased quality of life. So therapies which can tackle these non-motor symptoms, and many of which are in development, will be really most welcome for the community as a whole.
Dr. Daniel Kraft:
PD kind of overlaps with multiple chronic diseases or are they combine. I've seen and many may have seen some examples of pretty dramatic therapies using neuromodulation, deep brain stimulation. Where does that exist right now on the curve?
Dr. James Beck:
The idea of deep brain stimulation is really quite remarkable, almost can provide a Lazarus effect for some individuals in how dramatic the change can be. But it kind of remained stagnant, if you will, for almost two decades.
Recently though, we've seen some real interesting advances primarily around having electrodes or leads which have multiple contacts that have been split contacts which allow something called beam steering. Before, the electrode from a deep brain stimulation lead would provide even electrical stimulation in a concentric circle around the electrode. It's much like having a light in your room without a shade. And now with beam steering, it's like adding a shade to help guide some of that electrical energy to particular parts of the brain.
The subthalamic nucleus in the human brain is tiny. It's about the size of your pinky nail and neurosurgeons are very good, but to be able to take a watermelon, in essence, and from the outside, not really being able to see very well, aim it at a particular watermelon seed exactly in the center of it, is a mean feat. The brain is moving around. It's not a rigid structure that allows that to happen easily. So anything to improve outcomes will be really helpful.
And then the next phase where I think it'll be really exciting is this idea of using what's called closed-loop stimulation for deep brain stimulation. So right now, you kind of set the parameters and forget it, but closed-loop will allow the real-time monitoring of a person's physiological processes. They could be looking at brain waves, they could be looking at motion, but using those will allow the pattern of stimulation to change based upon the needs of a person with Parkinson's. So if the person is recognized to be sleeping, maybe the DPS stimulation uses less intensity, or if a person has particular activity that they need to do, can be adjusted so that they can perform at an optimal level.
That's the kind of thing that would be really interesting to see, and it's certainly in the works at some academic centers, like UCSF for instance.
Dr. Daniel Kraft:
Some major medical device players are now kind of building the ability to do remote manipulation, at least for DBS, mostly related for pain, but I imagine it could roll into the Parkinson's realm with a telemedicine visit and the clinician somewhere across the world can literally tune your algorithms.
Dr. James Beck:
The idea of relying on the patient to play a key role is important, and so giving a patient the ability to set some of the parameters could allow them to help fine tune what's going on in real time because too often, the programming can take weeks or months. Having everything linked together via smartphone or whatnot, you can get that information in order to make those conclusions.
Dr. Daniel Kraft:
One other example of convergent technologies I think is trying to meet the motion disorder space is MR-Guided Focused Ultrasound. Is that something that the Foundation is looking at?
Dr. James Beck:
It certainly plays a role for people who have intractable tremor where medications can't seem to resolve it and DBS may be able to help.
Within the PD space, I'm less excited about it in its current state because it's basically a 21st Century approach to something that happened, in essence, in the 1950s: lesioning of the brain. It's something that's irreversible, not very modifiable, and it's not something you can do bilaterally. But one of the things I hear from clinicians is that their Focus Ultrasound machine is probably the best referral device they have for deep brain stimulation surgery because once a person with Parkinson's, a patient, learns about the advantages and the disadvantages, they often tend to select deep brain stimulation.
I think it's important for clinicians to always have this broad armamentarium of choices that they can deploy for the right patient at the right time.
Dr. Daniel Kraft:
Have you seen the ability now to open up who you access and to sort of add better health equity to the data sets on genetics and beyond that drive the rest of your work?
Dr. James Beck:
Everybody with Parkinson's needs to benefit from where the future is taking PD therapy. We've been funding, particularly genetics, in underserved communities since 2009.
I remember our funding, our researcher Dr. Ignacio Mata, who is at the Cleveland Clinic and has a particular focus amongst Latin America and Central America for Parkinson's genetics, giving him an early start and working with him continuously since then. Our entire informed consent, the ICF, all the way to genetic counseling has been translated into Spanish and can be accomplished by native Spanish speakers. When we had brought on advisors from the Hispanic community to really help us guide our patient pacing literature and our approach, we were able to double our recruitment of individuals with an Hispanic background. Approximately 11% of our study are those with Hispanic background.
We're also reaching out to these targeted groups to bring precision medicine to them as well, particularly the Dominican Republic and Puerto Rico. One of the great things about virtual clinical trial participation is that you can reach people who would not be able to participate in clinical trials in general. So the Foundation's really made a concerted effort, for instance, to reach individuals who are underserved. To the extent that we can break down those barriers, we're certainly doing our best that we can.
Dr. Daniel Kraft:
And if we could zoom out and forward, let's say the next decade, what do you think the biggest levers might be for sort of eliminating or really shifting the game in Parkinson's? And also, who are you finding are new collaborators?
Dr. James Beck:
So the Parkinson's Foundation has 47 Centers of Excellence, not only within the US but throughout the world. We've worked with a number of outside groups. Again, we mentioned Sergey Brin. He has been a big proponent of research in the PD space and has been a big funder of that through his Aligning Science Across Parkinson's Program. We work certainly across the Atlantic with Parkinson's UK, particularly amongst those that try to raise the patient voice within the realm of clinical research.
Dr. Daniel Kraft:
I have a friend in the UK with advanced Parkinson's who's very involved in sort of #PatientIncluded, whether it's how you're designing your trials, the social supports, and how you connect the dots between other patients, caregivers, and the wider community.
As we sort of close up here, we've got a lot of clinicians listening, some who may see PD rarely. Any sort of key takeaways or elements you'd want clinicians to be aware of?
Dr. James Beck:
I think one of the most important things that's perhaps come out of recent research as a whole is how important it is for people with Parkinson's to get on a dopamine replacement therapy as soon as it's identified they have a need for it. Not waiting, I think, is really important. Not only does a person's quality of life improve, but their longevity is there too because they are able to avoid potential issues like falls and other problems that can be encountered.
Number two, the standby Sinemet, levodopa/carbidopa, really does as well as monoamine, MAO-P inhibitors, or other medications that can be brought to bear. It's inexpensive, it's readily available, and it's something that many people can take advantage of.
Another thing is that people with Parkinson's, one of the biggest causes of mortality and morbidity is falls, and that can be directly from a blow to the head to a fracture, particularly a hip fracture. And so we've partnered with a group out of UCSF and as part of a study called TOPAZ, it's a trial of Parkinson's and zoledronic acid, which goes by the brand name Reclast, to see if we can improve bone strength and minimize fractures in a large population of individuals with Parkinson's disease. So that's something that we're very hopeful on because being able to minimize fractures would not only improve the lives of people with Parkinson's, but mitigate costs for insurers and help society as a whole.
Dr. Daniel Kraft:
My background is stem cell biology, regenerative medicine. There was some work in the past doing transplants of dopaminergic cells in into patients, whether it's field-derived or other sources. Anything happening in the sort of full-on curative cell therapy side that that's of interest?
Dr. James Beck:
There's a lot of interesting things that are going on when it comes to cell replacement therapy for Parkinson's disease. They are working on different types of allogenic grafts, either from IPS-derived cells or human embryonic stem cells, which are going through extensive testing. They are going to be the best mitigators of symptoms of Parkinson's disease, but they won't be a cure.
And the reason I don't think it's going to be a cure for a person with Parkinson's, but really provide endogenous supply of dopamine, a good relief to symptoms for a period of time, is that this doesn't seem to stop the progression of Parkinson's disease unfortunately. There have been some case reports of individuals who had fetal cell transplants and those individuals have lived for decades with full-blown dementia, developed typical hallmark problems with Parkinson's, inability to swallow, speak properly, and so PD progressed. It doesn't stop with just replacing the dopamine or the dopamine-producing cells.
And so I think it's a combination in the future of stem cells and medication, which will bring a halt to Parkinson's disease as we know it, at least for this generation of individuals living with PD.
Dr. Daniel Kraft:
Anything that we might have missed or you want to go into more detail?
Dr. James Beck:
One thing I also want to offer is that our foundation has a 800-number that can answer questions not only for patients, but for clinicians who have trouble, some basic understanding of what's going on.
Dr. Daniel Kraft:
Well, thanks so much for joining us today on Healthy Conversations and for all the work you and your colleagues at the Parkinson's Foundation are doing in research and prevention and diagnostics and therapeutics to really help move the needle on this really challenging disease.