Each year during our Grand Challenges in Parkinson’s Disease symposium, Van Andel Institute presents the Jay Van Andel Award for Outstanding Achievement in Parkinson’s Disease Research to a scientist or scientists whose work is transforming our understanding of Parkinson’s. This year, we’re pleased to honor Ted Dawson, M.D., Ph.D., a pioneer whose research has revealed critical insights into both the familial and sporadic types of Parkinson’s. Dr. Dawson is the director of the Institute for Cell Engineering and a professor of neurology at Johns Hopkins University.
Is there a specific area of Parkinson’s research that has yielded particular excitement and promise?
TD: I think the most exciting things and opportunities have really arisen from understanding the genetic causes of the disease. Studying the rare, familial causes of Parkinson’s have opened up our ability to really dig deep from a molecular standpoint to identify mechanism-based therapies. That is really exciting and there still is a lot of opportunity.
What have your studies into cell death revealed about Parkinson’s?
TD: We’ve been studying this particular cell death pathway for a number of years, which we named Parthanatos after the Greek god of death. We recently published a paper in Science that leveraged the alpha-synuclein preformed fibril model — also known as the pathologic synuclein model — which indicates that the major way dopamine neurons die is through the Parthanatos pathway. We showed evidence that suggests this probably also occurs in humans with Parkinson’s disease. It opens up the possibility that drugs that target this pathway could offer therapeutic benefit in Parkinson’s.
How has our understanding of genetics and Parkinson’s evolved in recent years?
TD: When I was in medical school, we were taught that Parkinson’s disease was not a genetic disorder. I think movement disorder clinicians kind of had a sense that it was related to genetics because they were seeing these family clusters of the disease. It really wasn’t until Robert Nussbaum, in collaboration with Roger Duvoisin and Lawrence I. Golbe, identified alpha-synuclein as the first cause of familial Parkinson’s disease that the field just exploded. There are now several autosomal dominant and recessive genes, and all these risk factor genes that have been identified. It’s really been a sea change since I started my career.
What is the most surprising thing you’ve found in your research?
TD: There are always unexpected things. For example, it’s really hard taking fundamental discoveries and turning them into therapies for people with Parkinson’s. When I was starting off, I didn’t realize how hard that was going to be. Looking back, I would say that was a surprise.
Are there specific types of experimental therapies or approaches that you think are particularly promising?
TD: Right now, there’s a lot of work in trying to lower alpha-synuclein, whether it be with antibodies, antisense oligonucleotides or drugs that are thought to break up alpha-synuclein aggregates. The community is very hopeful that one of those will work but if you look at drug development research for Alzheimer’s disease, it’s a reminder that this is a challenging endeavor.
Of those three, the one that’s probably the most promising could be antisense oligonucleotides because of the success in spinal muscular atrophy and preliminary success in Huntington’s disease — that, I think, we need to watch really closely. Then there are things that have arisen from an understanding of how the genes Parkin and PINK lead to loss of dopamine neurons, as well as avenues like the cell death pathway we’re investigating, the inflammatory pathways, the LRRK2 kinase inhibitors — all of those are moving through and we’re keeping our fingers crossed that at least one of them works.
Given the individualized nature of Parkinson’s, what role do you think personalized therapies will play in the future?
TD: Let’s say you’re a person with a LRRK2 mutation and we come up with a drug that works on LRRK2. We still don’t know whether it will work in garden-variety Parkinson’s. But if you had a LRRK2 mutation, it makes sense that you’d want to take a LRRK2 inhibitor. The same thing with other mutations and inhibitors. To that end, there will probably be custom-tailored therapies based on a person’s genetic profile but there also may be therapies that attack cell death and neuroinflammation that are common to all causes of Parkinson’s. If one of those therapies work, it could have very broad therapeutic use. It may be that as things move forward in the future, a person might be on two or three different drugs depending on their genetic profile.
What is the biggest unanswered question in Parkinson’s?
TD: I don’t know if it’s a question — it’s rather more a problem. The biggest problem we have right now is we lack a quantitative way to assess disease progression and to diagnose the disease, which will be critically important for advancing neuroprotective treatments. This is the “biomarker problem.” I think that’s our biggest issue right now.
Why do you think it’s so difficult to find a biomarker for tracking Parkinson’s progression? Do you think alpha-synuclein is an option?
TD: It’s twofold. One is the fact that alpha-synuclein is a protein that is found within a cell, which makes it very difficult to measure it via imaging. There are many groups working on that issue — fingers crossed that they find a way to make it work. If this type of marker comes forward, it will really revolutionize the assessment, treatment and evaluation of neuroprotective compounds.
The other thing is trying to come up with a blood-based test. In cancer, for example, mutations can be sequenced from the blood of patients. We’re not there yet in Parkinson’s disease. I think that’s because Parkinson’s is a brain disease and, as such, finding markers in the blood is extraordinarily difficult and challenging. It’s not that people haven’t been trying, it’s just that we haven’t had success yet. But if you look at Alzheimer’s disease, there have been three or four papers that have come out that suggest there may be a blood test. I can see that happening in Parkinson’s disease — the question is just “when?”
Where do you see research and treatment for Parkinson’s in five years? Ten years?
TD: There are number of promising agents in phase II trials right now. I’m really hopeful that at least one will be shown to be efficacious. I think five years from now, we’ll hopefully be at a point where we can offer people with Parkinson’s agents that have been shown to slow disease progression. From there, I think things will evolve and accelerate like they did for multiple sclerosis (MS). When I was in medical school, there were no treatment for MS — now we have around 25 or so. I think it’s going to be the same way for Parkinson’s. I believe we’ll be able to offer patients real medicine that slows progression.
I have a true sense of optimism that we’re at a crossroads. I think we’re close to having one of these agents that are in clinical trials right now work, which will be phenomenal.
This year’s Grand Challenges in Parkinson’s Disease scientific symposium and Rallying to the Challenge meeting for people with Parkinson’s advocates and care partners will be held Oct. 6–7. For more information, please visit grandchallengesinpd.org. To learn more about genetics and Parkinson’s, check out our explainer here.