|
Lyle Ostrow, MD, PhD, is a neurologist at the MDA/ALS Center of Hope at Temple University who sees ALS patients, conducts research, serves on steering committees and review panels, and gives talks about ALS. Dr. Ostrow directs the Temple University ALS Postmortem Core, a collaboration with the CDC National ALS Biorepository that makes autopsy tissues and data available to researchers around the world. He is also Chair of the Programmatic Panel for the Department of Defense ALS Research Program (ALSRP), which is presently the largest dedicated annual funder of ALS therapeutic discovery and validation.
|
|
Tell us about your work in the ALS community.
I'm an ALS clinician and researcher in the Department of Neurology and the MDA/ALS Center of Hope at Temple University. I have a research lab, see patients, do muscle and nerve biopsies, and play several different roles in the ALS community.
I'm the Chair of the Programmatic Panel for the Department of Defense ALS Research Program. I also direct the ALS Postmortem Core. When people with ALS pass away, many choose to donate their brain, spinal cord, and other tissues. We dissect them, curate the information, and share the tissue samples and all of that data with researchers around the world to help accelerate ALS research. And I am a Scientific Advisor for Everything ALS, where I help design, lead, and interpret several large ongoing digital biomarker programs.
I'm the Chair of the Programmatic Panel for the Department of Defense ALS Research Program. I also direct the ALS Postmortem Core. When people with ALS pass away, many choose to donate their brain, spinal cord, and other tissues. We dissect them, curate the information, and share the tissue samples and all of that data with researchers around the world to help accelerate ALS research. And I am a Scientific Advisor for Everything ALS, where I help design, lead, and interpret several large ongoing digital biomarker programs.
What is the impact of the DOD ALS Research Program?
The Department of Defense ALS Research Program is the largest dedicated funder of ALS early therapeutic development. When I first joined the Programmatic Panel, our budget was around $7 million a year, but thanks to the efforts of ALS advocates, we now have a budget of $40 million a year. Because of the budget increase, we've been able to expand the kinds of research we fund to include clinical trials we never could have before because clinical trials are very expensive.
People living with ALS and their caregivers are involved in every aspect of this program, from vision setting to deciding priorities to making final funding recommendations to the government. We're all volunteers and we're all doing this because we think it's important. It's really invigorating and it really matters.
Now that our budget is what it is, we fund early phase biomarker-driven clinical trials to get the kind of data that's needed to have successful later phase trials. These clinical trial mechanisms are designed to get the kind of information that can de-risk the next big trial.
People living with ALS and their caregivers are involved in every aspect of this program, from vision setting to deciding priorities to making final funding recommendations to the government. We're all volunteers and we're all doing this because we think it's important. It's really invigorating and it really matters.
Now that our budget is what it is, we fund early phase biomarker-driven clinical trials to get the kind of data that's needed to have successful later phase trials. These clinical trial mechanisms are designed to get the kind of information that can de-risk the next big trial.
Can you elaborate on de-risking clinical trials?
ALS trials are very expensive. If you were a pharma company, you wouldn't want to invest a lot of money in a trial that fails. A big deal right now is finding ways to de-risk investment by industry and venture capital to get clinical trials funded so that we can fund the best science and the best trials in a way that helps answer questions.
That's why there are a lot of trials right now looking at genetic forms of ALS. It's because those are the ones where there seems to be less risk because you have a test that predicts whether it's the right patient. If a clinical therapy is targeting a specific gene mutation, the predictive biomarker to predict whether someone should be in that trial is the test for that mutation. If you don't have the mutation, you're probably not going to benefit from that therapy.
We don't have those things for the different therapies that are not genetic. You'd like to have a way to measure something that would predict which people with the disease are likely to benefit from a given therapy because maybe the reason many ALS trials fail is that we're not figuring out the right people for the right therapies.
A lot of times these trials get done and we think that there's some subset of people in a trial that seem to respond and some that clearly didn't. So what we need is a way to predict which therapies should be given to which people, and we're finally making some progress in that area. And then we need to detect whether the drug had the biological effect it's supposed to have when we give it to people.
That's why there are a lot of trials right now looking at genetic forms of ALS. It's because those are the ones where there seems to be less risk because you have a test that predicts whether it's the right patient. If a clinical therapy is targeting a specific gene mutation, the predictive biomarker to predict whether someone should be in that trial is the test for that mutation. If you don't have the mutation, you're probably not going to benefit from that therapy.
We don't have those things for the different therapies that are not genetic. You'd like to have a way to measure something that would predict which people with the disease are likely to benefit from a given therapy because maybe the reason many ALS trials fail is that we're not figuring out the right people for the right therapies.
A lot of times these trials get done and we think that there's some subset of people in a trial that seem to respond and some that clearly didn't. So what we need is a way to predict which therapies should be given to which people, and we're finally making some progress in that area. And then we need to detect whether the drug had the biological effect it's supposed to have when we give it to people.
What are biomarkers and why are they so important?
|
In the simplest sense, a biomarker is something that tracks something about a disease—a biological marker—something that we can measure in blood or in spinal fluid, or maybe a finding on an MRI scan that tells us something about disease in a person who has a disease. We've been talking about them for well over a decade in ALS.
|
|
There are different kinds of biomarkers, and we've become much more savvy about this recently. One kind of biomarker is a diagnostic biomarker. This would be the equivalent of a blood test for diabetes. This would be something that helps us diagnose somebody with ALS and maybe diagnose them earlier.
Now, the fact is that we're not bad at making the diagnosis. We'd like to diagnose it earlier. We'd certainly like to know when somebody's changing earlier, but that type of biomarker is not actually our biggest need.
Another type of biomarker is a predictive biomarker. A predictive biomarker is something that predicts whether a given patient is likely to respond to a certain therapy. So if a therapy is directed at a particular gene mutation, the predictive biomarker is, do you have the gene mutation? If a therapy is directed at a particular pathway in cells in your body, like let's say oxidative stress, a predictive biomarker might be some measure of oxidative stress that says you have that problem.
We need another kind of biomarker, really importantly, called prognostic biomarkers. A prognostic biomarker is something I'm measuring, say in your blood, an imaging study, or something in any biological substance that helps me tell something about your prognosis. So I measure it one time and it tells me, let's say, are you a fast progressor or a slow progressor?
And so not only do we need those to better understand what's happening in an individual patient, we need those for clinical trials because you'd like to make sure that in a clinical trial where you have a group that's treated and a group that's not treated, that those groups match—that you don't have slow progressors in one and fast progressors in another. So prognostic biomarkers are very important.
We also need yet another important kind of biomarker called a pharmacodynamic biomarker. If I give you a therapy that's designed to target a particular kind of biology in your body, I want to know if that change is happening when I give you the medicine.
So we'd like to have ways for specific targeted mechanisms to have biomarkers that tell us, yes, we hit the target. Those are critical. We need all of these. We're getting much better at this, and these are tools that are going to make us better at doing clinical trials.
Now, the fact is that we're not bad at making the diagnosis. We'd like to diagnose it earlier. We'd certainly like to know when somebody's changing earlier, but that type of biomarker is not actually our biggest need.
Another type of biomarker is a predictive biomarker. A predictive biomarker is something that predicts whether a given patient is likely to respond to a certain therapy. So if a therapy is directed at a particular gene mutation, the predictive biomarker is, do you have the gene mutation? If a therapy is directed at a particular pathway in cells in your body, like let's say oxidative stress, a predictive biomarker might be some measure of oxidative stress that says you have that problem.
We need another kind of biomarker, really importantly, called prognostic biomarkers. A prognostic biomarker is something I'm measuring, say in your blood, an imaging study, or something in any biological substance that helps me tell something about your prognosis. So I measure it one time and it tells me, let's say, are you a fast progressor or a slow progressor?
And so not only do we need those to better understand what's happening in an individual patient, we need those for clinical trials because you'd like to make sure that in a clinical trial where you have a group that's treated and a group that's not treated, that those groups match—that you don't have slow progressors in one and fast progressors in another. So prognostic biomarkers are very important.
We also need yet another important kind of biomarker called a pharmacodynamic biomarker. If I give you a therapy that's designed to target a particular kind of biology in your body, I want to know if that change is happening when I give you the medicine.
So we'd like to have ways for specific targeted mechanisms to have biomarkers that tell us, yes, we hit the target. Those are critical. We need all of these. We're getting much better at this, and these are tools that are going to make us better at doing clinical trials.
What do you say to patients who are interested in clinical trials?
|
Clinical trials are really important for all of us, and I'm grateful to any people with ALS who want to participate. Every clinical trial has inclusion criteria and exclusion criteria. Only a certain number of people can be in it. It's only for a certain time.
If you want to be in a clinical trial, if it's something that interests you, take one that's offered to you. Don't pick and choose. It's like going to a movie, but there's only one showing and you only can get in once. You only might qualify for a trial at a particular time of your disease. |
|
So if you're interested in clinical trials and one is offered to you, take it. Don't sit there and try to research on the internet to see if this therapy is more promising than this one. Nobody knows that. We need to do the trials and see if they work. If you're interested in being in a trial, take whatever is offered.
Why is tissue donation important for ALS research?
|
I direct the postmortem ALS tissue bank. People with ALS pass away and donate their autopsy tissues for research, and we provide them to researchers around the world. This is a truly critical resource and truly an unmet need because we use these tissues to make sure that something that is studied in the lab in a mouse or in cells is also happening in people with ALS.
|
|
This is a very much an unmet resource and we are finding ways to do this more collaboratively and share this resource amongst different centers.
How can people become tissue donors?
If somebody is interested in donating, there are some large multi-centered efforts that are doing this. I would say, go to any of them. Talk to your neurologist because we're all working together. We're all sharing. There's the VA Brain Bank. There's our program here at Temple that collaborates with the CDC ALS registry. Target ALS is a foundation that has a multi-centered postmortem tissue core effort that is at many centers.
We're actively working on ways to be able to collect autopsy tissues from someone wherever they might live, and have it done the same way, in the same data collection and the same analysis. The websites of the Northeast ALS Consortium, Department of Defense ALS Research Program, and the CDC ALS Registry have lists of these types of efforts.
Certainly anyone that is interested—wherever you may live—I'm happy to talk anytime and happy to hook you up with whomever might be in your geographic location that can help make those arrangements. It's something that is unbelievably important. It is the most valuable donation.
So please reach out. I'm happy to talk with any person or their family who has questions about the process or how to do it. It's not something you can arrange after somebody dies because certain things have to be done quickly and certain data has to be collected during life to make the tissues valuable to researchers.
We're actively working on ways to be able to collect autopsy tissues from someone wherever they might live, and have it done the same way, in the same data collection and the same analysis. The websites of the Northeast ALS Consortium, Department of Defense ALS Research Program, and the CDC ALS Registry have lists of these types of efforts.
Certainly anyone that is interested—wherever you may live—I'm happy to talk anytime and happy to hook you up with whomever might be in your geographic location that can help make those arrangements. It's something that is unbelievably important. It is the most valuable donation.
So please reach out. I'm happy to talk with any person or their family who has questions about the process or how to do it. It's not something you can arrange after somebody dies because certain things have to be done quickly and certain data has to be collected during life to make the tissues valuable to researchers.
If you are interested in becoming a tissue donor, there are links to many ALS tissue banks in the Research Resources PDF on the ALS Research Program (ALSRP) website. You can also email Dr. Ostrow at [email protected] to learn more.
What are some of the biggest challenges in ALS research?
One thing we truly don't understand is what we call selective vulnerability. What is it that makes the motor nerve cells in a person with ALS specifically be impacted? If we can answer that, maybe we would be able to design therapies differently.
But because we don't have a diagnostic test for most people with ALS, and because we know there are so many different kinds of ALS, trials are so hard. How do you know that your treatment is the right treatment for everyone that you are enrolling in a trial? Different people in a trial might have different things that are wrong.
The other thing about ALS that's challenging is that I can see someone in my clinic who's got just a little weakness in one hand and they have ALS, and a few months later they've succumbed to their disease. I can see somebody else in my clinic who also has just some weakness in their hand, and several years later, they're still coming back to my clinic and they don't look that different from when I met them. And they also have ALS.
And ALS can start anywhere. It's progressive weakness. It can start in your limb, it can start in your breathing muscles, it can start in your speaking muscles, and then it spreads. It's fatal because eventually it's going to involve the muscles that are used for breathing and for swallowing. All of this variability is why it's so hard to tell if our therapies are working. This is why defining the disease is so hard and why trials are so hard and why we need biomarkers.
But because we don't have a diagnostic test for most people with ALS, and because we know there are so many different kinds of ALS, trials are so hard. How do you know that your treatment is the right treatment for everyone that you are enrolling in a trial? Different people in a trial might have different things that are wrong.
The other thing about ALS that's challenging is that I can see someone in my clinic who's got just a little weakness in one hand and they have ALS, and a few months later they've succumbed to their disease. I can see somebody else in my clinic who also has just some weakness in their hand, and several years later, they're still coming back to my clinic and they don't look that different from when I met them. And they also have ALS.
And ALS can start anywhere. It's progressive weakness. It can start in your limb, it can start in your breathing muscles, it can start in your speaking muscles, and then it spreads. It's fatal because eventually it's going to involve the muscles that are used for breathing and for swallowing. All of this variability is why it's so hard to tell if our therapies are working. This is why defining the disease is so hard and why trials are so hard and why we need biomarkers.
What gives you hope on the research front?
If you look back through the history of research and ALS, different things come in and out of style. We've all been wrong. The reason that I am excited about research right now is I think we're doing a better job of validating potential new therapies and new targets using relevant tools from people with ALS.
If something happens in a mouse or in a dish, it doesn’t matter if it doesn't happen in a human brain or spinal cord. We're figuring out better how to look for changes, whether it's in autopsy tissues after somebody dies from the disease or during life with imaging studies and ways we can measure different things in nerves and muscles. Again, I think biomarkers are the most exciting thing about research right now. Those are ways that we can see changes that we can measure.
I think we're getting better at understanding the different subtypes of ALS and perhaps targeting the right medicines to the right people at the right times. Certainly the most progress right now is in these genetic types of ALS. Those are the ones where it’s easy to make sure you're giving it to the right person—and from pharma's standpoint, that's the risk. So how can you de-risk clinical trials for ALS? Make sure you're giving the right therapies to the right people.
If something happens in a mouse or in a dish, it doesn’t matter if it doesn't happen in a human brain or spinal cord. We're figuring out better how to look for changes, whether it's in autopsy tissues after somebody dies from the disease or during life with imaging studies and ways we can measure different things in nerves and muscles. Again, I think biomarkers are the most exciting thing about research right now. Those are ways that we can see changes that we can measure.
I think we're getting better at understanding the different subtypes of ALS and perhaps targeting the right medicines to the right people at the right times. Certainly the most progress right now is in these genetic types of ALS. Those are the ones where it’s easy to make sure you're giving it to the right person—and from pharma's standpoint, that's the risk. So how can you de-risk clinical trials for ALS? Make sure you're giving the right therapies to the right people.
Is there anything else you would like to add?
Supposedly, I'm an expert in ALS. I think about that a lot. What does that mean? What am I actually an expert in? The truth is, I'm not sure I am. I'm an expert in telling my patients about the biology of the disease, understanding how we do the science, and telling them things that improve their quality of life. But I don't want to be an expert in that. I want to be an expert in treating this disease.
My patients are the most inspiring people. It's not just their dignity and their sense of humor and how they deal with such a horrible thing. It's that they're all doing 400 things to help improve our understanding of this disease and accelerate therapy development. And that's the big change. Fifteen years ago, patients were involved in medical research by donating money. Now, the entire community is involved. It's the reason why I am optimistic that soon I'm going to be able to truly treat this disease.
I don't know what it means to be an expert in ALS if I can't treat my own patients the way I want to. So I don't think of myself as an expert in this disease until I can do that.
My patients are the most inspiring people. It's not just their dignity and their sense of humor and how they deal with such a horrible thing. It's that they're all doing 400 things to help improve our understanding of this disease and accelerate therapy development. And that's the big change. Fifteen years ago, patients were involved in medical research by donating money. Now, the entire community is involved. It's the reason why I am optimistic that soon I'm going to be able to truly treat this disease.
I don't know what it means to be an expert in ALS if I can't treat my own patients the way I want to. So I don't think of myself as an expert in this disease until I can do that.
