Dan Keller 0:08
Welcome to this episode of Substantial Matters: Life and Science of Parkinson’s. I’m your host, Dan Keller. At the Parkinson’s Foundation, we want all people with Parkinson’s and their families to get the care and support they need. Better care starts with better research and leads to better lives. In this podcast series, we highlight the fruits of that research—the treatments and techniques that can help you live a better life now, as well as research that can bring a better tomorrow.
The most efficient development of therapies depends to a large extent on identifying a specific problem in the body and then designing a way to correct or mitigate it. In the case of drugs for Parkinson’s disease, knowing the underlying molecular, physiological, or genetic defects that lead to the disease and its symptoms significantly helps to design or discover treatments.
I spoke with Michael Okun, National Medical Director of the Parkinson’s Foundation, at the World Parkinson Congress, where he described how knowledge of disease mechanisms is facilitating the hunt for better treatments. Let’s first talk about new mechanisms in Parkinson’s disease, and possibly as targets for drugs and drugs in development—what’s coming along?
Michael Okun 1:34
So there’s a whole host of interesting new approaches to how we might attack Parkinson’s. We, in general as scientists, look for targets, and the targets can be drug targets, they can be device targets, or they can be targets by modification using other techniques, such as behavioral techniques. So even exercise affects targets in the brain. And so it’s important to keep in perspective the wider picture.
Right now, there are a couple things that are hot that people are really keying in on. Now, the idea that could we take away the abnormal accumulations in the brain—some of these plaques—and use drugs or vaccines or other approaches to clear away these abnormal deposits. And if we clear them away, will that lead to an improvement?
And so I think that there are a group of companies that are working on different vaccination approaches. There are several safety studies that have been completed there. There are a few people that are working on it from the drug angle, and a few of our colleagues in Alzheimer’s have some interesting drugs who are trying to do the same thing.
And the lesson from Alzheimer’s in the past was that when they cleared the plaque away, it didn’t necessarily improve the symptoms, and there may have been some side effects. We have more optimism in Parkinson’s, and there are multiple different approaches of how we can do it.
There’s also a class of drugs called c-Abl inhibitors, and c-Abl is part of the degenerative cascade. And it turns out that there’s an approved chemotherapy drug called nilotinib. And this is a drug that is of interest because, again, it works on that pathway that may clear plaque or these abnormal deposits out of the brain.
And people are interested to see how this is going to pan out. There was a very small study that was published by our colleagues at the Parkinson’s Center of Excellence at Georgetown, but only 10 or 12 patients have been done. And there are a couple of trials now that are being planned, and there are other groups that are working on c-Abl drugs, and they think if they can go after this particular enzyme in the brain, that’s going to be a viable therapeutic approach.
And so there are a couple of really interesting scientific avenues that are being pursued by a lot of people all over the world.
Dan Keller 3:42
What about the time frame here? I mean, they’ve identified targets, some drugs exist for other uses which could be imported, but in a realistic sense, when do you think these things might actually help a patient—not in a trial?
Michael Okun 3:56
So your point about repurposing drugs—drugs that are already on the market that have a known mechanism of action, and then once we identify a target we think, “Oh, well, let’s take this drug because it’s already been through the FDA or has some sort of stamp on it”—that’s a great notion, and I’m glad that you brought that up. That speeds the drug development and getting it to market and to trial quite a bit, by a number of years.
The disappointing thing for Parkinson’s patients and for patients with other neurodegenerative disorders, and for that matter cancers, liver issues, kidney issues, heart issues, is this long latency that can be anywhere from five to 15 years to get a drug through development, several billion dollars in terms of trying to move it to market.
So there’s been a big push from the foundations, from the patient advocacy groups, to work with the Food and Drug Administration and to try to decrease that latency so we can get things to market quicker. People are anxious—they want to get on with different therapies.
There’s a famous picture by McGlynn of a man standing on top of the world looking at his watch, and I think that’s probably what every Parkinson’s patient is thinking about: “Can we get this done faster?”
So it’s a problem. I think it’s getting better. I think that the repurposed drugs, like the cancer chemotherapy drug, will get into a larger trial here within the next year. I think we are going faster. I think the FDA is responding faster, and we are starting to see things move through there. And so there are a number of symptomatic drugs that we’ve seen move through a little faster than we’re used to. So we’re liking the trend—we’re hoping it’s going to speed up.
Dan Keller 5:27
What about vaccines? There’s passive immunization, there’s active immunization. If you give a vaccine that’s active, it’ll keep working in your body. Passive would be antibodies you keep administering. In the Alzheimer’s area, the monoclonal antibodies you administer haven’t really done much—there have been a lot of trials. Do they think that in Parkinson’s there would be something different?
Michael Okun 5:49
Yeah, so it’s an interesting question. And just to back up and talk a little bit about how this may work—the idea is that you could utilize your own immune system, which is designed to fight disease, to try to fight off some of these abnormal depositions in the brain and perhaps attack inflammation and some of these other potential underlying causes of Parkinson’s disease.
And so you can do this a number of ways. You can inject the antibodies into a vein and then have them travel around, hopefully get across the blood-brain barrier, which is obviously one of the things we worry about the most.
So the brain is a privileged area—it’s protected, as it should be—but that makes it harder for us to get treatments there. And so the first idea is when you do treatments like monoclonal antibodies, they’ve got to get across the blood-brain barrier, they’ve got to get to the target, and they’ve got to do their job. And that’s a lot of “what ifs,” so we have to take them to trial to see.
And so when we see a failure, I like to tell people we shouldn’t look at this as yes or no—we should look at it as process refinement. How can we refine it to make it better?
The other type of therapy is injecting something that then raises your immunity, kind of like a flu shot would do. And so then it can fight off these abnormal issues going on in your brain by raising your own immunity.
So there are two different approaches, and actually there’s a whole host of different ways this can be done. Another thing people don’t realize about vaccines are off-target effects. Sometimes you’ll have something designed to do one thing that actually has a beneficial effect you didn’t anticipate—but it’s a good effect.
And we’ve seen this in other areas like small nucleotide RNA therapy and eye diseases and other areas of medicine. An off-target effect isn’t necessarily a bad thing. We see this in deep brain stimulation surgery too—sometimes you see something you didn’t expect, but it can be a good thing.
Dan Keller 7:44
I suppose if you do active immunization—giving someone a protein like alpha-synuclein and have them make their own antibodies—there’s evidence recently that lymphocytes do end up in the brain. So I guess that would overcome this idea of antibodies having to cross the blood-brain barrier to get in.
Michael Okun 8:01
Yeah, there’s some evidence that there are ways to permeate the blood-brain barrier, that some things get across that we don’t expect. And then there are clever things like using ultrasound to temporarily open the blood-brain barrier and break it down. So there are really clever ways scientists have come up with to try to combat that problem.
Dan Keller 8:22
Are you encouraged at this point that there are new mechanisms, new pathways, and new targets that have come up recently? Because the field has depended essentially on levodopa for so many years and its brethren.
Michael Okun 8:35
Sometimes when you’re out there fighting the battle day by day, it’s hard to interpret: has the needle moved? Have we done something that’s helped people and helped the field?
I think I can say without a doubt—between this World Parkinson Congress and the last two, which occur every three years, and this year we’re in Portland—the needle is moving on a lot of things, particularly symptomatic therapies and symptomatic drugs.
We think of these therapies in three buckets: symptomatic therapies, disease-modifying therapies (trying to slow progression), and then the cure bucket. We are certainly furthest away from the cure bucket, but some of these single-gene defects and DNA problems might one day be amenable to gene silencing or other new technologies.
Disease modification—we’re still fighting that battle. But in the symptomatic, meaningful symptomatic therapy bucket, we’re doing pretty well. And if you look across other neurodegenerative diseases, frankly, they’re fairly jealous of the Parkinson’s community because we are moving the needle on a lot of things.
Dan Keller 9:48
To learn more about what’s coming along in drug development and research, visit parkinson.org and search “drug development.” You can also call our toll-free helpline at 1-800-4PD-INFO to speak with PD information specialists.
If you have questions about the topics discussed today or want to leave feedback, you can do it at parkinson.org/feedback.
At the Parkinson’s Foundation, our mission is to help every person diagnosed with Parkinson’s live the best possible life today. We’ll be bringing you a new episode every other week.
For more information, visit parkinson.org or call 1-800-473-4636.
Thank you for listening.
