The Genetics Podcast - 069
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[00:00:00] Patrick Short: Welcome everyone to the genetics podcast. I'm really excited to be here today with not one but two fantastic guests, Dr. James Beck and Dr. Ignacio Mata to discuss the genetics of Parkinson's disease. And in particular, we're going to dive into the different prevalence of Parkinson's disease between people of different ancestries and in particular, the role that genetics play.

So first off Dr. Mata he's at the learner research Institute at the Cleveland clinic and his research goals are really focused on understanding the genetic component of neurological disorders. More generally, including Parkinson's disease, but also migraine, uh, Parkinson's disease, dementia, and dementia with Lewy bodies.

In particular have been focused on performing genetic studies in non-European populations, primarily those of minority ethnic backgrounds, such as Latinos. And now Dr. Beck is the chief scientific officer of the Parkinson's foundation, where he oversees a portfolio, which has guided more than 360 million in research funding to explore the causes of Parkinson's disease and also how to improve treatments and really the Parkinson's foundation's mission is working towards a world without Parkinson's disease. In particular, Dr. Beck relatively recently in the last couple of years has helped to launch the PD generation program, which is a national study started by the Parkinson's foundation that offers no-cost genetic testing for a number of different Parkinson's related genes and genetic counselling as well to people with the confirmed Parkinson's diagnosis.

So I'm really excited to have both Dr Beck and Dr Mata on the program. Thank you both so much for taking the time. 

[00:01:31] Jim Beck: Glad to be here. Thanks for the invitation. 

[00:01:33] Ignacio Mata: Thank you. 

[00:01:34] Patrick Short: Dr. Mata, I wonder if I could start with you. You've been at the forefront of neuro genomics in Parkinson's disease for some time. I'd love to just cover a few different aspects of this first what was the understanding of the role that genetics plays in Parkinson's when you first started in the field and how has that changed through today? And maybe you can just talk a little bit about your background and how you came to research this and the first place. 

[00:01:55] Ignacio Mata: Yeah. So I studied biology and under my bachelor's degree, I got really interested in, in genetics and I also loved the brain. So, uh, when I was looking to opportunities to do my PhD at my local university in Spain, I was . Lucky enough that there were two main research lines that they had and one of them was neurogenic diseases. So they were doing a lot of work in Alzheimer's at the time. And they also wanted to start programming parkinson's disease. And, uh, as always happens, funding wasn't really there. Uh, so with the help of a Parkinson's support group in my local city, uh, we actually got a little grant to be able to start doing some genetics and by then there was only really two genes that we know of that were involved in Parkinson's disease before the Parkinson's was thought to be all environmental.

So genetics really wasn't a playing a role. I mean, Uh, it was an exclusive criteria for diagnosis of Parkinson's disease to have a genetic medical history of Parkinson's in your family. But the problem, I think when we started is that those two genes or say nuclear Parkin really affect, uh, not your typical presentation, they were a little bit on the early onset side.

I know you're your normal 60 to 70 year old. And then they, they had some, some features that didn't seem very typical. So we thought, okay, maybe these genes are important, but maybe only for a small subset. So we knew that they were probably other genes and that's kind of how we got started. And then I was lucky to move to the Mayo clinic when the LRRK2 gene was discovered, and then all my efforts shifts to that gene that looked like support and more of the typical presentation of Parkinson's disease. The field move really fast in those two, three years where I started my PhD. And I think the role of genetics became really important with her too.

And it is very, I think it's one of the genes that is . Driving all the research that we're doing. 

[00:03:40] Patrick Short: And this has maybe a little bit of a leading question and probably an impossible one to answer, but how many genes are there involved in Parkinson's today? If you had to answer that question and put a number on it. 

[00:03:50] Ignacio Mata: Well, I mean, we know for more than 20 in the familiar forms and then there's at least 78 risk factors.

So, you know, genes where variants that are common in the population increase your risk by a little bit, I would say a hundred plus. And hopefully we'll be able to have that answer soon. But yeah, there's a lot and a lot of them are in like one or two families, especially their familial forms. There's, you know, there's maybe seven, eight genes that are common amongst the families, but there's a lot of them where it is maybe one or two variants in various specific families. 

[00:04:22] Patrick Short: Great. And Jim, maybe this is a good segue to you and to PD generation in particular. So as I mentioned in the intro, you have a very large research portfolio from the early stage, fundamental understanding the disease through to clinical trials and helping patients to get access to these medicines.

I'd love to hear more about the PD generation problem. Clearly genetics has become a big priority for you all in the last five to 10 years. I'd love for you to just talk through your background and also how the program started and how it works today in the context of those a hundred odd genes that Dr. Mona mentioned, 

[00:04:55] Jim Beck: I think if I can just step back even a little bit further, cause you know, you know, Ignacio Mata and I met a number of years ago, too, too long ago to really talk about the years. But, uh, you know, that's kind of, I think where we got really interested in genetics or funding, I mean, 97 was when the first gene was identified, you know, it was a 2003 or four, for LRRK2 and so when Ignacio Mata and I met, he was really interested in genetics and had had a discussion around reaching out to non-European populations.

We were funding his work early on and recognizing the importance here. And then, so likewise with PDG generation, it came from a conversation. So one of our scientific advisory board members, Roy Alcalay at Columbia, deeply involved in genetics of Parkinson's as well from a clinical standpoint and recognize that we're at a tipping point within the field of Parkinson's disease.

Just like in cancer, precision medicine has come to the forefront where identifying a specific gene mutation can lead to a specific therapy. We're getting there for Parkinson's, which is, which is fantastic. It's not there yet, but the field wasn't ready. I mean, so if you want to recruit people for trials to test a specific medication that targets a specific gene, people have to know what gene they have.. And so basically we recognized that there was this real need in the community and put PD generation together to offer an essence, a genetic testing and counseling to just about anybody with Parkinson's. Um, it's US-based right now, but we're working to expand that as not to, with his help, uh, to reach other populations in our, in our hemisphere.

[00:06:31] Patrick Short: Wonderful. That's great. And, and Ignacio Mata it's been known for some time that genetic forms of Parkinson's are. Of different frequency and different populations. Maybe you can talk a little bit about, what's known today about populations, where genetic PD is, is more frequent and what types, and then also what you all are working on because I understand in Latino populations, there's still a lot of work to be done, to understand which variants may be more prevelant. 

[00:06:56] Ignacio Mata: Yeah. I don't know if we can answer the question of if their genetic forms are more common, but we know that certain genes that are very well studied like LRRK2 for example, variants have very, very different frequencies depending on, you know, where you're coming from.

And we just started doing work in LRRK2 most of the families that we were identifying were in the Northern Europe, a lot of families in Norway, Ireland. So we thought that this could be a population specific mutation. Then one more status came from other regions of the world. We realized that this vairant it's actually very common elsewhere as well. Uh, but there's different. The difference in the frequency from going to zero or very low in populations in Asia, for example, or in some populations in Latin America, where native American ancestry is very high. And then he goes as high as 50% in Berbers in north Africa.

So one of every two patients have, uh, one of the various alert to, so I think it's understood in the, in the field that there are differences in the proportions. Then there's also variants in the LRRK2 gene that are also only present in Asia, for example, their risk variants, but there are only present in Asia.

So I think this is very interesting. Again, from one gene perspective, we look at all the genes. The problem is. The research that we have right now. And the data that we have right now is very Eurocentric. So the genes that we're all testing are the ones that have been identified in Europe. So we, we know a little bit of those, but we believe, at least I believe that there are other genes that still can be identified if we include a more diverse populations. And we see this in Latin America where we have a panel that we've been screening our families through that has all the known genes, all those 20 some that I was talking about. And we see that in Latin America, there's very few families that have, uh, pathogenic variants. But there are still families with like 5, 6, 7 affected individuals that look like there's something going on there.

I mean, Dalian a form of the disease, but none of the genes are hits any of these families. So I, I, we're now using whole genome sequencing to try to identify new genes. So there's definitely things to understand, especially are coming from the more diverse underrepresented populations. 

[00:09:12] Patrick Short: Interesting. So, Jim, I guess in, in PDG duration, the main things that you'll see are patients who have either a Lark two or one of the GBA, one of the mini GBA variants.

So not sure is it right that those which are tend to be the heavy hitters in U S population or particularly Ashkenazi Jewish ancestry or, or Moroccan Berber. Those actually aren't necessarily the most common ones in Latin America. 

[00:09:37] Ignacio Mata: Yeah, actually, GB GBA is different than alert too. So why alerts? We see differences in Latin America where the more, uh, native American countries like approved for example, have very low frequency.

GBA frequency is very common improved. For example, is the frequency is very similar to see in the U S or in Europe. However, in Latin America, we see the opposite effect. Actually, we identified in Colombia, a new population, specific mutation in GBA that accounts for 50% of all the GBA carriers and basically.

By a fold the frequencies instead of being 5%, which is what we see in the U S in Columbia is about 10% of the patients will have a GBA mutation because it is population specific variants. In the case of GBA, we identify a cohort. For example, if we think about clinical trials, Like Jim was mentioning.

It could be ideal because there's quite a few patients and they all carry this one or half of them carry is one single variant. So yeah, I think it goes both ways. So it's not only that some of them are underrepresented, but some of them are actually more frequent probably because there's not a lot of coming people coming from outside of Columbia, for example, and maybe one of the founders, uh, one of the European individuals that moved there had this variant or originally in Columbia and only spread out there. 

[00:10:53] Patrick Short: Right. So, yeah, Jim, I'd love to hear your, your learnings from the PD generation work so far. I've doing some background research as preparing for the podcast. I think you all are planning to test at least 3000 people this year, or maybe cumulatively through this year.

I'd love to hear more about what the larger vision is for the program. And you mentioned before looking at expanding outside the U S. Talk about it a little bit. What it's been like to get it set up the challenges, the things you've learned and what you see it looking like in the future. 

[00:11:21] Jim Beck: I mean, that's a really great question. And I just want to put in context here for listeners who may not be super familiar with Parkinson's and genetics. We talked about 20, some odd, different genes and a bunch of risk factors. But by and large, only about 10 to 15% of people with Parkinson's will have a genetic link, clear genetic link that we know of to link them to their PDA.

So just if, if this isn't like, um, Huntington's or some other diseases or CF where there's like almost always a genetic link in them. I think when we started this process, I think the scientific consensus was there's going to be 10% of the individuals we would identify would have a genetic link.

What's interesting from this study, and this is not a true epidemiological study where we're just randomly finding people with Parkinson's, you know, people come into a study and recruit, but nevertheless, we're still seeing something on the order of 15 to 17% of people have a genetic form of Parkinson's.

Of the seven genes we're looking at. So we're only looking at the top seven, what are relatively rare forms of Parkinson's disease? So we're covering GBA, recovering lurk two. We've got the alpha-synuclein gene, we've got pink and Parkin, which often are associated with the young onset Parkinson's disease, as well as DJ one and DPS 35.

So these are be rare genes as they come through yet. We're still seeing someone who has a carrier for each of those genes. We're talking about GBA. We have like 170 people who've been identified with GBA mutations, which we think are pathogenic. We have a whole bunch who have GBA mutations, which we don't think are pathogenic.

And that's an interesting thing to talk about too. And getting us up to this point was no mean feat because we started in September of 2019, and we're really hit our stride by January of 2020 and then, you know, the world kind of shifted, you could say with COVID. And we were really based upon doing in-person genetic testing, where people come in and we do a blood draw.

Cause get a lot of DNA. One of our goals, our PD generation studies to share that DNA with researchers like Ignacio Mata. So we're doing just using CLIA approved testing to just take a look at these seven genes, but then Ignacio Mata and his, and his colleagues and researchers can take a look at whole genome sequencing.

They can look at a whole bunch of other methylation of DNA, perhaps to better understand what's going on. So we wanted to make certain, we had that. So we had a pivots and moved to using telemedicine. So we added a telemedicine arm, um, my colleague and Anna Nito, who's the scientific lead for this study. She's done tremendous work with our team and been able to implement a telemedicine component to PD generation.

So where our recruitment, you know, the number of people come into the study basically dropped to zero. Over the summer of 2020. Once we really had gotten telemed up and going, we really hit our stride again and have been consistently recruiting over 200 people a month since the spring and in 2021. And really seen it take off.

There's a lot of interest within the PD community to understand their genetics. You know, Parkinson's is one of these diseases for many people, which has comes out of the blue. Um, so trying to understand why they develop this disease, uh, is something that a lot of people are interested in knowing and genetics for some may provide an answer to that.

And not having a gene, uh, at least one of the genes we're testing may have an answer to. So, you know, it provides, uh, something for the participants as well, in addition to collecting the DNA and some of the clinical data to share with researchers. 

[00:14:43] Patrick Short: Did you all have to do a lot of work to bring neurologists on board.

I mean, there's probably people on all different ends of the spectrum, but from, you know, from, from one side of things, there's not currently a, an approved therapy for any of that genetic forms , Parkinson's as far as I'm aware, but there is this big chicken egg problem where without, as you mentioned earlier, without testing, you're unable to run trials, but without trials, there are no approved drugs.

How much did it take to kind of bring the clinical community in and how much help did you have from your other collaborators? Like Roy to evangelize that message. 

[00:15:16] Jim Beck: Yeah. So that's a really great question. One of the fundamental issues of why there isn't a lot of genetic testing in Parkinson's disease is as you pointed out, there's nothing understanding that you have a genetic form of PD currently doesn't alter your treatment plan for most people moving sort of urologists treat to control symptoms.

And whether you have a lurk, two mutation or GBA mutation, you know, people still have dyskinesia and bradykinesia. And so they're given medications to control that. So one of our key things I think was, you know, enlisting the help of a neuro ethicist to really make certain that what we were doing was something that would be responsible for the community.

And so we did that, uh, just because of, of issues in the past, when it comes to neurological space around Huntington's disease, how do you. And talk to participants patients about their genetic status. So these were all people who had Parkinson's disease. And that was a lot of buy-in because our steering committees comprised of a lot of really experienced neurologist who really, I could say cut their teeth on the Huntington's days.

And so they had some of that muscle memory about that experience, which didn't initially go well. But I think now has reached a good steady state and how the, how to talk to patients about genetics. Parkinson's is different. It's not a death sentence. People live with Parkinson's for a long time, and there's a potential for treatment.

So this isn't just for edification, but even though we've known for genetic forms of Parkinson's for quite some time. And, and these two common ones looked to and GBA have a pretty good foundation of research around it and discussion. We did some surveys of sort of urologists who are people who have really trained to take care of Parkinson's.

And particularly this is a group called the Parkinson's study group who were really involved in research and clinical studies. And we would have thought would have been really experts in this and what we saw from a paper we published based upon the survey. They're not that confident, you know, on a scale of like one to 10, they put themselves at a five on, on their level of confidence and talking and returning results to people with Parkinson's.

So what we realized then is that the job was bigger than we had anticipated. So not only are we trying to educate people with Parkinson's about their disease, we have to educate clinicians about how to talk to. With Parkinson's about their genetic forms. And so what we've done is had a kind of a two-pronged effort, you know, educating patients, but also educating clinicians.

Uh, so we partnered again with the Parkinson's study group and just this past Friday had a bootcamp as an opportunity, you know, Ignacio Mata was a presenter at that to provide training on how to return results and what those results might mean to patients. So clinicians who have that grounding. And then at the foundation, we're also building a training platform for CME that would allow clinicians to come in, who may not have that time to sit through a three hour session, but maybe have an hour or can break that up into some segments to get that experience, to do it because it's really critical.

I mean, that's what, as you probably were. From, you know, running a genetics company, getting people to talk about the results to participants is really important. It can't just come through like a piece of paper in an email. They need to have a live person to explain it to them. But especially the Parkinson's community when their sixties and seventies it's been a long time since they took Biology.

So Watson Crick was probably, you know, the result around by then when they were taking biology, but still the it's not something people think about on an everyday basis and getting that to where it's become people more literate about it. 

[00:18:29] Ignacio Mata: We also need to remember that direct to consumer testing, sometimes they will report variants for Parkinson's disease. So it is very common that patients will come to the clinic and said, Hey, I have this result. So we, as Jim said, it's very important that the movement disorder specialist. Uh, you know, uh, provide care to these individuals with Parkinson's. Know, what that means so they can explain it to them or at least pointing to the right person.

So having institutions like the Parkinson's foundation, where they have the expertise, or they are connected with the people that have the expertise also helps this individuals to find, but we had one case where there was somebody that believed that had a alert to mutation for almost. Until they go got enrolled in degeneration and volunteer proper counseling, and then realize that yes, she has to LRRK2, because everybody has the LRRK2 gene.

She didn't have the variant that caused Parkinson's. So it is extremely important to not only get the data, but also being able to report it and make sure that the patient understands what that means. 

[00:19:27] Jim Beck: And that's the only time that's happened. I mean, I've heard that from a number of different clinicians whose, uh, someone did direct to consumer testing and say, I've got the gene.

Yes, but you don't have the mutation. And so it's that misunderstanding. That's part of it. So in addition to training conditions, we are lucky we partner with Indiana university, which has a really dedicated team of genetic counselors who specialize in Parkinson's. And so they're really providing the backbone to help support this effort so that we can empower people with Parkinson's to know more about their disease.

[00:19:56] Patrick Short: Yeah, absolutely. And, and maybe this is a opportunity to talk about how it's probably going to get more complex still in the future, because Ignacio Mata alluded to the 78 risk factors, which will probably the next paper that comes out, it'll turn into 200 risk factors. How do you guys think . About this? It's already Difficult to communicate the nuanced risk of LARC two and GBA, which have a pretty large effect. How do you think about this transition into the murky water? Poly genic scores and maybe not show you could actually just give us a little bit of a primer on the biology of PD in general, or Jim, Jim, or Ignacio Mata.

Maybe you guys can, can combo this, but what role does genetics play in people who don't have one of the mendelian or mendelian like genes and, and how does, how did these two sides of the coin, the common low-risk variance or small incremental risk and, and the relatively rare, but high risk variance how does that all kind of play together into the bigger. 

[00:20:49] Ignacio Mata: I, yeah, I can, I can start. So Parkinson's is very complex, but we see that from the clinical aspects, we're not to Parkinson's, uh, individuals with Parkinson's have the same symptoms. They don't have the same onset even within the same family. So we know that theirs is very complex.

There are many different things that could influence this starting from is that happened when you're a kid probably. Really the majority of the individuals with Parkinson's, there is a combination between genetics, some kind of a genetic component, and then also has the environmental lifestyle and all the other things that happen to you.

You know, you play soccer, you do you know, or have you been in a car accident? All those things kind of start adding up. Right. So I think that majority of the individuals we'll, we'll see that it's a combination and obviously that's really hard to predict, right. So even if you have. There's at least 50, 60% of the component that in most of them, they're not going to be, it's not going to be determined just by your genetics.

It's just a predisposition, but there are other things that need to happen in order for somebody to develop. And even if they develop it, you won't be able to. Is it going to be in the fifties or sixties or seventies, or maybe you'll pass away from something else before you even start showing any other symptoms.

So I think we put this in context of regeneration. I think we'll generate scores and those things are going to be very hard to apply right now. The utility of this is that if we can identify certain individuals that are in really high risk, those are great cohorts to apply neuroprotective therapies, right?

So we can identify those and then find some good biomarkers to see if our therapies are really help us low in are stopping the disease. That's where those things are going to really play an important role. I don't know how important it's going to be in the individual case-by-case in terms of being able to predict, but we can certainly identify individuals that would benefit a lot from this kind of therapist.

So something that people don't really realize is that a Parkinson's disease really starts maybe 20 or 30 years, even before you started seeing some of the motor symptoms. And a lot of people believe that the treatments that we're putting up front right now to try to treat these individuals, maybe they are affected.

It's just, we're treating them too late in the disease. So I think that's where maybe the polygenic risk scores are going to play an important role. 

[00:23:05] Jim Beck: Yeah, I think what's also interesting that not as alluded to is this idea of incomplete penetrance. So there's this common mutation. We talk about the LRRK2 genes, the G 2019 S mutation.

And so we're in PDG ration. We're just testing people with Parkinson's disease. So the cat's out of the bag, they already have Parkinson's. And so we're just looking for trying to see what clues may have led to this, but for other people like the children of these individuals who might have mutations.

You know, other people in general, who are curious if they have a G 2019 S mutation, they're wondering whether they might develop Parkinson's. And the answer is, you know, as, as natural too, we don't know. I think the best we can say is they've got a 30% chance of developing it as we try to really understand what's influencing the penetrance of this mutation.

Why some people develop PD. But it's complicated. And then what makes it even more complicated is to think about, well, there's at least six different mutations in the LRRK2 gene that are considered pathogenic. And what I think Ignacio Mata's work is really important is identifying other populations that may have mutations, which are pathogenic.

Because you look at a Eurocentric approach may just not be anything. They'd be like, ah, this is just a, we call it a variant of unknown . Significance, these VUS's. And so, you know, the PD generation approach to reporting results to participants is if it's a VUS, we don't report it to the participants because we just don't know.

So it, it wouldn't really add any benefit to it, but what we're also doing. On the, in parallel, we've created a gene creation expert panel. This is a part of a critical domain working groups, Klingon through the NIH, the idea of a gene creation panels that identify which genes are relevant to Parkinson's. And I think it's, you know, there are seven genes that we have are probably not really up for discussion.

I think people pretty much will, will agree to that. The real interesting part comes in. We talk about variant curation and this is where I think, you know, Roll up the sleeves and take off their gloves and they kind of want to duke it out to discuss what individual point mutation in a gene is relevant to Parkinson's.

So I think the example is with the GBA mutation, there were some trials. So GBA, if you have two mutations in that gene leads to disease, but one gives you a really high risk of developing Parkinson's. And so some maybe, you know, again, this idea of penetrance and risk is something that I think Ignacio Mata can talk about much better than me being the geneticist, but you know, one mutation in particular is, N370S mutation

So it's not considered a risk factor or causative for gal chaise, but it is considered relevant for Parkinson's. And so identifying what mutations are relevant, which disease is going to be really important too, because this is where the education, the training comes into play because a general genetic counselor will do their due diligence and look up . And say, oh this isn't, Really important, but in fact, it hasn't been called, a committee hasn't come together to say, well, this is really is important for Parkinson's and allows that person to give the proper feedback on it. I know Ignacio Matas found some unique mutations for glare to GVA two, I guess, is that correct for Ignacio Mata that are, wouldn't get picked up again for this. And so, you know, having his help and helping recruiting, uh, these underrepresented populations is gonna be important.

Not only to make the call about, well, this is important or not, but I think the end result of our work will be to influence drug companies in ultimate FDA. So when a company says, well, here's got a drug will for people with GBA mutations, I bet FDA will say, well, which mutations? And so making certain that precision medicine is available for everybody by getting these underrepresented populations in their mutations, being recognized as.

It could mean the difference between someone not getting the treatment because insurance won't pay for it or insurance paid for. I mean, that's kind of really puts it in, you know, squarely why these types of efforts, you know, combination with a large group of people important for the Parkinson's community. 

[00:26:41] Patrick Short: So natural, where are you at with that effort?

I think it's large PD, right? Is that the Latin American consortium that you're helping to lead in part of. I'd love to hear more about that. What stage are you all at and what have you learned about the LRRK2 and GBA variants that might be missed? I mean, I think Jim, you just made an excellent point about, we need to shine the light there to know about these things.

Otherwise you don't know what you're, you're missing notch. I'd love to hear more about that. 

[00:27:03] Ignacio Mata: Yeah, so, so large. It is really a collaboration effort from many different neurologists, uh, in Latin America and the Caribbean. So this is a private starting 2006, really from high motivation from this clinicians, to be able to give an answer to the patients about it.

This. Was when LRRK2 was really hot. And they really wanted to know is I do any of my patients carry any of these variants, right? There's a high, uh, European ancestry in all the countries. So they're like, if it's in Europe, it's probably going to be here too. But a lot of them didn't really have the resources to be able to test, especially for a gene, that huge because LRRK2 has 51 exons. So he's a very large gene. So really this started as me trying to provide help to try to identify LRRK2 mutations, and then we'll also start looking at parkins again, we're common in early onset individuals. And then it kind of grew organically. We started with only two sides, one in Argentina and one in Peru and then when people found out what we were doing this today, we want our patients and their stuff's in the DNA. So if you fast forward, 15 years now, we have 36 centers in 13 different kinds. We have over almost 5,000 individuals. And our goal is to get up to 9,000 in the next two years, as Jim said, Covid kind of threw a wrench on, on our plans and is making things really hard, especially because COVID is getting really hard at some of those regions where we were high expectations of recruiting, lots of individuals.

But yeah, we're getting to the point now also with, again, with another grant from the Parkinson's foundation. Really the first 4,000 individuals we recruited in the small two year grant from their foundation. And then once we created this school where we apply again, not to do some science, right? So first we needed the cohort and now we apply for, to do some science.

So we were able to do the first, you know, studies to try to identify or try to really correct her as the genomic. Parkinson's in this individual. So we have money to genotype of our 1500 individuals, about 800 patients on 700 controls. And we just got that published in annals of neurology where we saw first the synuclein very important.

It's probably the most important gene, also in Latinos, as we have seen previously in Europeans and Asians. But using very, smart techniques by some of people that we collaborate with, we were all also able to dissect the ancestry, especially the native American and the African ancestry, which also is very frequent in some countries like Brazil, Columbia uh, even in the coast of Peru, we see a lot of African ancestry and then use the studying those ancestry on their own, identify some areas of the genome that might be important in those a specific population. So obviously, you know, 1500 on a GUS level is very small. So that's what we're trying to grow the cohort.

And we now have an ROI that will allow us to genotype all 9,000 individuals to be able to do, uh, you know, a much larger cohort and try to replicate some of this. A new claim hits was replicated by 23 and me, they have a large cohort of Latinos and they were able to replicate our new claims. So I think we're in a really good spot right now to be able to do more interesting things than our ideal is to grow the research locally. So there's a lot of efforts to try to do a lot of genotype phenotype correlation. So, you know, we've identified LRRK2 of patients, GBA patients. Now, can we correct rise those uncompetitive to the people in the United States and Europe, you know, and see if they have any differences, because we need to understand that genetics also play a role of modifying the Spanish trans that gene was talking about.

So there's other variants in other genes that might be making are very likely to to penetrant or less penetrant depending on where you're coming from. And we we've seen that with Alzheimer's. For example, if you have a boy in a African background is actually less effective than if you have it in a European background.

So this adds a level of complexity in populations like the Latinos, where there's such a huge mixture, right? So when we do local ancestry and we'll look at their haplotypes, You know, lots of their genome comes from Africa, native Americans, European, and those are all barriers that are interacting with each other.

I'm making this story even more complicated. So yeah, to me is, as a researcher is mesmerizing. I'm very excited about, you know, the things that we can do, but, you know, to be able to bring this to personalized medicine is a huge, huge thing that we need to understand and kind of jump over. Uh, if we want to be able to apply this to individual risk.

[00:31:33] Patrick Short: Yeah, Jim, I, I mentioned at the start of the show that you, you look after a 260 million or so dollar budget to fund research and, and just hearing Ignacio Mata talk, you can just hear the new ideas spinning in his head, and I'm just interested in learning more about your process. You can't just focus on genetics.

You've got to look at the entire spectrum of potential research that you all can support from the Parkinson's foundation, from the early fundamental biology all the way through to I'm sure there are people asking you to fund trials and things like that. How, how do you think, and maybe you could talk us through your, your architecture thought process for how you as a foundation, think about where you put what sounds like a lot of money, but really it doesn't probably last very long when you start to do some of these really large scale projects.

[00:32:17] Jim Beck: Yeah, that's a really good question. And we're not quite that large. It'd be great if we were on as funders, but I think even if you were to combine all the funders in the PD space, it's just a drop in the bucket compared to what's, you know, the billions that are necessary to, to really make a difference.

But you, our approach, uh, as you said, is really to think about how do we generate a pipeline of ideas that can really impact people Parkinson. And look to make differences along that way. And so, you know, what it comes down to is a lot of times it's conversations to understand and to encourage people, to put their ideas together, pen to paper, and gives us a chance to review them.

You know, this is something I want to make clear. It's not based upon Ignacio Mata didn't get funded because he and I had a good conversation and it really supports. We through a peer review process, as you would expect, bring in some outside experts who can help evaluate whether the idea makes sense in the context of where we are.

But you know, one of the things I think we've recognized it's important not to have a narrow focus on, you know, uh, what's the, the mode du jour of, of what causes Parkinson's, but to just keep an open mind to track where research is going so that we don't go down dead ends with our funding, but just make certain that the people who really know where the science is going, are the scientists themselves.

So, you know, Uh, rely on them to help give us that guidance. And so by having an open call for many of our grants programs and our funding mechanisms, we can see where the science is going and then be able to really evaluate, you know, where are we today and what might make the biggest impact within the PD space and helping people with Parkinson's.

What's also unique in what we do with our evaluation is that we include people with Parkinson's as part of the review panel. So, not only do we have scientific experts who are there to really ensure that we're only going to fund good science, but we have people with Parkinson's in there to ensure that what we fund is as relevant to a person with Parkinson's, you know, the NIH funds a lot does important work, but they have a different mandate in the sense, our goal is to really help people with Parkinson's.

Pure academic research, things that are too far a field for what will impact people with Parkinson's or not things we fund and having person with PD speak up during the discussion, say, you know, I don't see what merits it has, how is this going to help me or my family deal with Parkinson's? So those are the kinds of things we consider as we put together our phase, as well as what we want to fund in the long-term. 

[00:34:34] Patrick Short: Absolutely. I, I, we're running up against time here. So I did want to ask you both one question to close out, which is really a general one. And I'll give you a moment to think about it, but I'd love to hear. And really this is for the audience as much as it is for me. What one area of either Parkinson's research. Precision neurology, more widely or precision medicine, more widely you're really excited about. Um, and in particular things that maybe people aren't talking as much about as they can, it could be a new technology, new initiative or something else.

I'll give you a moment, both a moment. It looks like maybe you guys have some ideas in mind, but I'd love to hear about anything you'd like to share as something that you think in 10 years, time, five years time, we'll all be really excited about it, but it's emerging right now. 

[00:35:15] Jim Beck: So I think what we have seen that could be really exciting in the cusp of it is this idea of gene delivery in an unconventional way.

So our COVID vaccine is a nanoparticle, you know, drop it a fat, uh, wrapped around, uh, an MRN a that gets expressed in largely muscle cells. Um, but if we could develop a way for. Those nanoparticles to be injected and go right to the brain to treat neurodegenerative disease. I think that would be fantastic.

We had funded some research in the past, you know, to, to help start exploring that. But I think, you know, that would be a place we could go with precision medicine that could also. Move from, you know, treatments, which are, you know, uh, taking care of maybe stopping the disease, but, or, you know, ongoing to something that becomes maybe not a one and done, but certainly would minimize how often someone has to go get a therapy to control their disease.

And Parkinson's people are taking upwards of 10 to 12 pills a day managing their disease. And the timing of that has to be very exquisite. So it's not just like, oh, it takes some in the morning takesome in the evening it's, you know, setting the timer, the timer on your watch and trying to take those during the day to maintain optimal function, to be able to relieve people of that burden would be liberating for our community, uh, to be able to cure the disease clearly is our goal.

Yeah. I think the idea of precision medicine of targeting individual genes to provide that correction aside from having to do with essences brain surgery, where currently the idea of delivering gene therapies, drill a hole in someone's head and, and inject a virus, uh, to act as a carrier, to take the gene to the cell, but to be able to do it with an injection or infusion would be amazing.

[00:36:53] Patrick Short: Completely agreed, not sure. What, what do you have in mind? I'm curious to hear.

[00:36:56] Ignacio Mata: I'm very biased. I'm always thinking about how we can use genetics to help individuals with Parkinson's disease. And I think Jim alluded to this that ultimately that's the goal, you know, it's great to find a gene, but you know, if he's going to take 20 years to develop a therapy, you know, it's too, it's too long.

I want to have, I want to have, uh, you know, shorter, uh, goals in mind. So we're always trying to find. To apply, you know, well, it could be precision medicine or personalized medicine using genetics. So I already mentioned, you know, being able to identify patients with high risk, uh, that we can treat, but I think we can do more with genetics.

The more testing we do both with the degeneration, but also the more GUS we might be able to use this genetic information to predict outcomes, both clinical outcomes. So can we tell a patient that is diagnosed. Well, this is what your package looks like. That's something that the patients really are afraid.

And they go to Parkinson's support groups and they see other patients, or some of them look like they don't have Parkinson's. Some of them look, you know, they're in wheelchairs. There's a huge, huge range of how your Parkinson's might develop. So being able to tell them from the beginning, well, this is what you should expect.

I think that will be a major thing. And also to do the same thing with treatment outcomes. Identify individuals that are going to respond really well to a level up, or maybe they don't need anything else. People that will respond really well to DVS are people that won't respond. Right. So they don't go through this whole thing.

I think that could be very important. And also try to come up with a more specific treatments and maybe a combination of different treatments for certain patients, depending on what kind of biologically, what their cost is. Right. Um, so I think that I'm very excited about that. And I'm part of a very global initiative that is funded by the aligning science of, uh, across Parkinson's the ASAP, uh, is, uh, is the GP2 project where our ideas to genotype 150,000 individuals, 50,000, at least 50,000 of those being from underrepresented populations to really map out exactly what all the variants, all the genes that are associated to Parkinson's disesase.

As we able to create this map that will guide us to, to answer some of these questions that I was talking about. So I think those two things I'm very excited about. And again, I really hope that we can, uh, achieve them. I can give a better answer to patients when they said, okay, so how does what you do? How does that help you? It happens very often. 

[00:39:22] Jim Beck: I think we've got the, the mashup of these would be Ignacio Mata being able to identify people at risk and then providing the therapy before they get the disease. So that you can knock it out. That would be that's the holy grail. So people never have Parkinson's 

[00:39:36] Patrick Short: You hit the nail on the head.

I think, I always think about the promise of genetics. Is there sort of a barbell for some people you've got the star Trek level therapies that you're talking about? Jim, can we deliver. Uh, gene therapy to the brain and some amazing way. And then there's a whole other end of the spectrum, which is, can we use data in a way that means we never get there in the first place.

And ultimately we're probably going to need both, but if we can push as much to one side or the other of that spectrum, I think we'll be in good shape where we only need to intervene when absolutely necessary. And otherwise we, we act early. Well, thank you both. I really appreciate it. This has been an amazing conversation.

Thank you so much for taking the time. I'm looking forward to catching up with you guys in a couple of years to hear on how these things are going. And I know just everybody who's in the Parkinson's community really appreciates all the work you do. So thanks so much. 

[00:40:22] Jim Beck: Thanks for the opportunity to chat with you.

[00:40:23] Ignacio Mata: Thank you. 

[00:40:24] Patrick Short: Thank you all for listening and a see you next time.