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International Parkinson and Movement Disorder Society
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The Basic Science Perspective on Future Therapeutic Targets | Congress 2023

September 18, 2023
Series:MDS Congress 2023
Basic science research for movement disorder therapies is booming. Prof. Tiago Outeiro asks Dr. Lorraine Kalia what therapeutic targets she thinks are stealing the stage at this year's MDS Congress. 2023 Congress virtual access

2023 Congress virtual access

[00:00:00] Dr. Tiago Outeiro: Hello and welcome to the MDS Podcast, the podcast channel of the International Parkinson and Movement Disorder Society. I'm Tiago Outeiro, professor at University Medical Center Goettingen in Germany. And today I have the pleasure of interviewing Professor Lorraine Kalia from the University of Toronto.

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Hi Lorraine. How are you enjoying the Congress so far? 

[00:00:26] Dr. Lorraine Kalia: Hi Tiago. Thanks for inviting me to this podcast. I'm enjoying the Congress. It's just day two , but there's a huge degree of energy I find this year.

And maybe it's partly 'cause it's our second in person congress since the pandemic. But a lot of interesting clinical practical. Advice being given and I have to say, I'm enjoying the content of basic science, too. 

[00:00:48] Dr. Tiago Outeiro: Great. No, I think it's very exciting to be back and see the, the full size of the Congress with so many people.

So yesterday you presented in the plenary session on therapeutic strategies for the future. I'm [00:01:00] always an optimistic and I think we are living exciting times when we are getting and expecting additional results from ongoing clinical trials. And I think a key point is that basic science is really opening novel perspectives for future trials, and that's what we tried to cover in the session yesterday.

So can you first briefly summarize the major overall highlights from the session yesterday? 

[00:01:21] Dr. Lorraine Kalia: Yeah, and I guess first I'd wanna just commend you on putting together such a great session yesterday. I think it was really forward looking and allows us to not just look at what we're doing currently, but have our eye on the future.

And so yesterday there were three talks for the session. The first one really focused on viral therapies, or using viruses to deliver genes, which is a really active area of investigation. And I think we were reminded, importantly, that there are many viral-based therapies already being used clinically for other diseases.

And so this is not something brand new, but something quite [00:02:00] well developed. And we got some good examples as to how this is being applied in movement disorders with some examples such as the AADC gene replacement therapy that is having significant impacts for young children who have really debilitating disease.

The second talk was focused on immune related mechanisms, but also immunotherapies, which is always a hot topic for discussion, as we're entering the age of immunotherapies for neurodegenerative diseases with some promising results in some trials and some negative results in other trials. And that always brings up a lot of discussion and opinion, which I think is healthy in our field.

And then I talked about emerging targets and different strategies that are being used. I tried to cover the spectrum of movement disorders to kind of give something to everybody in the audience, since not everybody just entirely focuses on Parkinson's disease or Huntington's disease. And I think that my own exercise in putting together that talk was, was valuable too for, for me to see the breadth of what's going on in our field. [00:03:00] And similar, too, I'm an optimist in seeing what's going on and, and really feel that we're at a place where there's lots of exciting developments happening.

[00:03:08] Dr. Tiago Outeiro: I think it was good that you all tried to touch on what's happening on multiple movement disorders to make it attractive for the broad audience. So that was great. 

And regarding your presentation in particular, are there any particular targets you are excited about that you think, well, there's big hope here, so let's see what happens?

[00:03:28] Dr. Lorraine Kalia: Yeah, so I am excited about alpha-synuclein, as I think most of us are in the field. I think we've had decades now of really solid research that tells us that it's associated with the disease. Of course there's a huge number of unanswered questions, as there will be for the next decades to come. But I do think we're at the place now where there are a variety of different strategies, not just the immunotherapies that are being used to target alpha-synuclein, and I am excited to see what they teach us.[00:04:00] 

I think there are a number of other targets that have come out of the repurposing work that a lot of researchers across the field have done. And so I talked yesterday about GLP1 receptor agonists. It's a incredibly active area. I was familiar, obviously, with the Exenatide story and the trials going on, but to see all of the kind of offshoots that have come from that, I think that's an exciting place to look.

And I think from the point of view of Huntington's Disease, I just am so — it's not an area that I focus on in my research. I know you're probably far more up to date on what's happening in Huntington's disease and even clinically, it is not a a disease that I see in a clinic myself.

But it's just so amazing all of the different technologies that are being applied for that disease. And I'm optimistic that we're gonna learn a lot for sure from them. But with all of the different kinds of strategies, I think when you don't have all of your eggs in one basket, I think your chances of success are clearly gonna be greater.

[00:04:57] Dr. Tiago Outeiro: Regarding alpha-synuclein, I want to get [00:05:00] your opinion about this idea that is also going around in the field. And some colleagues are very active in pushing this, this idea that perhaps we are wrong, and perhaps we need to think that this protein aggregation is just something happening, but there is not causal. And maybe what you need to do is to increase alpha-synuclein levels. 

So, How do you look at this? And you know, realistically there's data that makes us question what, what has been happening and the negative trials also raise flags and, and suggest maybe we need to think about this, but how do you integrate this and, and what do you think is the position we should take on, on this at this point? 

[00:05:42] Dr. Lorraine Kalia: Yeah. And so that can take a multi-hour podcast, I think. But I think the first important point when we talk about hypothesis, for instance, for me and maybe for others, it's not the same a clinical trial is a complicated [00:06:00] entity. And when I think about what hypothesis is being tested in a clinical trial, to me, for example, the immunotherapy clinical trials for alpha-synuclein, they're testing the hypothesis that this specific antibody, given in this specific way, to this specific population, at this specific time point, for this specific length of time, will change this primary outcome.

That's what I think the hypothesis is being tested. And based on that, the two initial immunotherapy trials refuted that hypothesis. But I don't think that refutes the hypothesis or provides us with sufficient data to say that the biological hypothesis that alpha-synuclein is an important driver in the pathogenesis Parkinson's disease can be refuted from these clinical trials.

I think there's a huge amount of basic science evidence to point in the direction that alpha-synuclein in some ways leads to neurodegeneration. And both you and I know that if you overexpress alpha-synuclein in a variety of different [00:07:00] systems, bad things happen to neurons. 

But that being said, I think that we all have to always keep an open mind. And if there are other hypotheses to be tested, then they should be tested. And so I think healthy skepticism in what we do is always important. I don't view my own hypotheses in a religious way, as is sometimes implied for some of us. But I think we don't know everything.. But at the same time, I also think we can't stop progress because we don't know everything. And so there's certain leaps of faith that we're gonna have to take and certain clinical trials that we're going to have to do without having all of the answers.

[00:07:37] Dr. Tiago Outeiro: I really appreciate this balanced response because I totally agree. I think we need to be open-minded. I think we should not be religious about our beliefs and scientists tend to be a bit in love of their own models and hypothesis. So I think it's, it's important to acknowledge that there are weaknesses in the theories and in some of the [00:08:00] data being generated, and it's important to test the alternative hypothesis as well. So it's great if colleagues come up with ideas and ways for testing this possibility that maybe instead of lowering synuclein to increase synuclein. And then we'll let the data speak for itself and tell us what's best. So what we all want is that something works irrespectively of whether it involves reducing or increasing synuclein. 

So now more generally, since you are a clinician, but also a basic scientist, which is fantastic. What do you consider to be major recent advances in basic science? Of course, this is a huge question, but if you can just give us one or two ideas of what you consider exciting that is happening in the field, not just here at the meeting, but in general. 

[00:08:45] Dr. Lorraine Kalia: Yeah. So that is a huge question. Probably my answer's not gonna be uncommon to many people's. I think big data at subcellular levels is an exciting area. I think this notion of being able to understand and phenotype cells [00:09:00] at their individual level are going to tell us a lot. You know, the standard way that we usually study things is taking a brain and mushing it up and running it on a gel and trying to get an answer from that. But clearly that's a mixed population of cells. Not every cell, has the same function. And I think being able to understand cells at the actual cellular and subcellular level is gonna give us a lot of information.

I must admit, it's not an area of science that I've delved into in my own research and the cost of doing that kind of science is hopefully gonna change over time. But I think for those who are able to invest in that, I think we're gonna learn a lot. 

And then I guess in partner and hand in hand with that, with that amount of data, I, and again, it might seem like a bit of a cliche answer, but I, I think it's true, I think that artificial intelligence and machine learning algorithms. To be able to take that data and make some sense of it. But even beyond that, understanding fingerprints of [00:10:00] transcriptomics and proteomics and modeling proteins and predicting what small molecules will fit into what binding targets. I think all of these are, are remarkable advances. 

I can talk about just a recent experience last week. I trying to figure out if we can make a small molecule that fits into a certain binding region , and the first step that the medicinal chemist is using is, his modeler who's using software to say, is this even feasible?

And it's an important step because it kind of guides which way you're gonna go and where you're gonna invest and both time and resource. And, you know, the answer from the modeler was like, Hmm, that's not the approach to take. We've gotta take a different approach. And that's actually hugely advantageous, I think, for a researcher.

[00:10:47] Dr. Tiago Outeiro: Yeah. It sounds like that's the right way to go, for sure. Okay, great. We're reaching the end. So are there any other thoughts you'd like to share from the meeting? Any highlights you would like to...? 

[00:10:58] Dr. Lorraine Kalia: I'm looking forward to [00:11:00] the rest of the meeting. I'll be going through posters. I thought there were a lot of exciting abstracts that were submitted. A huge number. And I think that's just a demonstration of how much enthusiasm there is from case reports to clinical trials to basic science posters. 

I hope our congresses will continue to really marry the clinical research with the basic science research 'cause as you mentioned at the beginning, I think this is where we're going to see real advances in the future. The basic science is there to kind of push everything forward and this is where I hope that we'll continue to all work together. 

[00:11:36] Dr. Tiago Outeiro: Wonderful. So thank you so much.

It was wonderful having you on the podcast. We just interviewed Professor Lorraine Kalia and discussed her participation at the MDS Congress 2023. So thank you all for listening and join us in our upcoming podcasts. [00:12:00] 

Special thank you to:

Dr. Lorraine Kalia
Associate Professor
University of Toronto
Toronto, Canada

Tiago Outeiro, PhD 

Director of the Department of Experimental Neurodegeneration 

University Medical Center Goettingen, Germany

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