In order to advance the science of ALS risk factors and preventing ALS, we recently launched a new grant program funding research on disease prevention.
On a recent Connecting ALS podcast episode, we discussed the incredible strides being made in the science of preventing ALS with Dr. Stephen Goutman, Director of the Pranger ALS Clinic and Associate Professor of Neurology at the University of Michigan.
The transcript below has been lightly edited for brevity.
How long have researchers been talking about the concept of trying to prevent cases of ALS?
Let's take a step back first and let's just talk about this idea of prevention. I think prevention may have a different idea in people's heads. So, some people may think about preventing the spread of disease, preventing the accumulation of disability with disease, or even preventing the onset of disease. And so, here in this podcast, what we're focusing on is really preventing the disease from manifesting in the first place.
If one looks back in the literature, really from descriptions in the mid-1800s and even into the early 1900s, there were physicians and other scientists really trying to think about: What are the potential ALS risk factors? It's not really until more recently when we're really trying to understand how to operationalize these prevention efforts, whether they be based off genetic factors, environmental factors, or other factors, I think this idea of taking risk factors and then translating it to something that we can use to really prevent disease, is maybe coming into its infancy right now. And I know that those of us who study these risk factors are really hoping to accelerate this process so that we can really get to this goal of preventing disease very, very soon.
Talk to us a little bit about what these risk factors are and where we go from figuring out what they are to this idea of prevention.
Yeah, they all really have interesting data to show us some linkages or connections to ALS. And I think it's important for us to also recognize that these risk factors may differ from person to person and even from region to region. And so, obviously, not everyone that I see and take care of has this long history of chronic traumatic encephalopathy or a large number of head injuries. And not everyone that I take care of has served in the military.
So, we do need to be thinking that these risk factors, including others like pesticides or certain occupational exposures or certain exposures to metals, may differ across the spectrum of individuals who get ALS and across the regions of the country and even the regions of the globe. But I think what's critical is that these risk factors, whatever they may be, could really help us identify some of these modifiable risks and could help us really link what these particular exposures are doing to the mechanisms that are leading to, say, neuronal cell death and the mechanisms of ALS. And that gives us a therapeutic target.
I think we have to have an open mind as to what we consider a risk factor, and we have to follow the scientific evidence wherever it goes. So we need to explore whatever the risk people are trying to see in a certain population. So if it's the military population, let's dig deep, let's try to understand those risks. If it's chronic traumatic encephalopathy, I mean, certainly, there's a lot of building evidence in certain professional athletes that ALS may be higher risk in certain sports. And we need to chase that down, but we need to understand these things scientifically because then, we can translate that into what changes can we make, whether they be lifestyle changes or other changes or other druggable targets that can be used to eventually prevent people from getting ALS.
What role can genetic testing play as we start to think about prevention?
So genetic testing is certainly one of the ways that we can think about ALS prevention. It's almost in a way easier to think about operationalizing the prevention of ALS through genetics, as it is through these really nonspecific environmental risk factors. And so, we haven't really talked about this yet, but there are a whole host of risks that may lead one to get ALS. One may be a certain gene that is highly associated with one's risk of developing ALS. It may be a sole genetic cause, it may be a genetic cause plus other exposures or on the flip side, it may be entirely driven by some environmental risk factor or what we think more commonly is really a combination of someone's underlying genetic risk spread across the genome, combined with exposures over time that really push somebody over some threshold to go on and get disease.
What is unique about genetic testing, is to some degree, we actually understand the problem. We understand to a certain degree how many genes are testable and the risk that one may have if they carry a gene, we have some idea that they may go on to get disease. We understand that more for somebody that say carries the C9orf72 mutation versus some of the other less common mutations. And so, I think that genetic testing plays an important role. Certainly over the last 10 years, there have been many more genes connected to ALS than there have been in the past. It seems to almost be exploding, the number of genes that people are associating with ALS risk. And so, when I first started caring for people with ALS, genetic testing, we really limited it to people who had a family history. And that was for a few reasons.
One, tests were costly. They were difficult to get approved or insurance wouldn't cover it. And now we have this opportunity to really order genetic tests on everybody, even at no cost to people, there's some sponsored testing programs. And so, I think genetic testing is becoming more available and through some programs, there have been barriers broken down against the cost of genetic testing. So, genetic testing really is going to play a role in identifying individuals who could benefit I think, from targeted therapeutics. And I think this is what the real potential that we see with genetic testing.
So our hope in the future is that there's going to be some therapy that's really targeted towards a certain genetic form of ALS. And then expanding on that, our hope is that, in somebody who carries that gene, if there's an effective therapy, that therapy could eventually then be used to prevent them from getting disease.
We don't know all the genes that are implicated in ALS. We can send a panel of genes and it has 30 genes. And there are people who are going to argue that maybe only a handful of those are strongly connected to somebody's risk of going on to get ALS. And some of those are less connected to that risk. So, this is information that we need to continue to discover. I think we're going to learn more as we start more wider testing of individuals living with ALS. We're going to really understand what is the frequency of some of these mutations? Who seems to be affected? What are some of the clinical characteristics and over time, understand what is the rate of ALS in families with some of these mutations?
So, genetic testing is not necessarily in its infancy, but it's definitely being used, I think more commonly in ALS. And I think as these therapies are hopefully coming to the clinic that we can use to target people or target people that have certain genetic forms of disease, that we're really going to be testing more widely and understanding the different distribution of genes in our patients.
The ALS Association recently launched its first ever research funding program for prevention research. What are your thoughts on grant programs like that, that have the potential maybe, or do they have the potential to push this from its infancy and move it forward?
The ALS Association can definitely move the needle on an issue like this. There are a few critical pieces that we need to solve here. So one is the risk factor identification, right? So we need to find the factors that are involved and implicated in ALS. We also need to really understand how to take these risk factors and translate them into some clinical action, right? What clinical change can I suggest that makes somebody less likely to go on and get ALS? And I think that's a harder concept. It's a harder grant to write because we may not necessarily be walking in right now with all of the things like preliminary data that we need to support a grant opportunity. So the fact that The ALS Association is really coming in saying, "We want to put an emphasis on this need for prevention, and we want to put an emphasis on some ability to translate what we know now to actual better clinical outcomes in the future," I think is really important.
We want to keep our eye on the fact that we do need to continue to spend our time identifying risk factors in doing the scientifically rigorous types of studies that we do to make sure that the risk factors we're identifying are indeed linked to ALS. But I think in parallel, we do want to say, do we know enough now to make changes to the way we care for people, advise people and counsel people? And I think that's really what this proposal will let us start thinking about or enable us to think about with the funding, backing of the association. So I'm excited for it. I'm excited to see what ideas come in front of the review committee and see how this funding opportunity is going to help move the needle as we work towards preventing ALS.
Where do you see this research going in the next, say five to 10 years? I know that you are co-authoring or working on a white paper that's going to help set the agenda here, but what are the next steps? And what does this look like in the future?
So my crystal ball broke today and I can't really tell you what all the ideas are, they're going to come out to change this scope of prevention in the next five years. I would say that we do have this white paper, and this really came out of a workshop that The ALS Association hosted back in October of 2020. And we're working on getting the scope of this workshop out into the community. And Michael Benatar is leading the publication along with Ammar Al-Chalabi, Evelyn Talbott, Marc Weisskopf, and Eva Feldman and really additional support from Kim Staats and The ALS Association team. And so, the idea behind this workshop is: What do we know now about risk factors? What do we need to know? And what do we need to do to be thinking about prevention and for operationalizing prevention?
So I think we have some idea now about what are some of the critical risk factors involved in ALS. You had noted previously, I mean, we know there are certain families that have genetic mutations, certainly those individuals are going to be at higher risk of developing ALS. We know that veterans of the military are certainly at higher risk of developing ALS. We've seen literature say in former NFL football players that seem to be developing ALS at higher rates. There's the literature surrounding Italian soccer players that have higher rates of ALS. We're concerned about individuals that have higher exposures to things like pesticides to metals. We've published recently about certain occupational risk factors. And we've seen that those working in production occupations have a higher risk of ALS and those that self-report occupational exposures to things like metals and to combustion and diesel exhaust seem to have a higher rate of ALS.
So one of the things that we need to do is keep working to understand who's at risk. How to identify who's at risk? How do we target populations at risk for modification? I think that there are potential risks that we've not yet thought about. And so my hope over the next five years is, how do we continue to identify risk factors? How do we continue to strengthen the evidence that certain risks are highly correlated with ALS? And then how do we use this information to do a number of things? So I think one, is generate the continued funding so that we can dive deeper. I think when we start thinking about risk factors that are say present in the environment, this requires some action or change, right? Because we are not necessarily always able to control the things that we are exposed to.
So if we're worried about pesticide exposure, we can choose say, to buy organic foods or change the types of foods that we're buying, but we can't control necessarily who's spraying our community with pesticides. We don't have the ability say, to control all the air pollution around us, although we maybe have the ability to move, but that's not the case for everybody. But we also know that some of these exposures that we're thinking about are not necessarily confined to a particular area. So I do think there's going to be some advocacy behind some of the findings that we see over the next five years. Are we going to need to be making some changes in policy that's going to overall reduce the risk of ALS?
I do think that there's going to be some overlap with other neurodegenerative diseases. And so, what we learn for ALS is not necessarily going to be living in a vacuum. Hopefully the changes that we make to reduce the risk of ALS is also going to help reduce the risk of frontotemporal dementia or Alzheimer's disease or other neurodegenerative diseases. And I would hope the reverse is true, right? If there's some policy changes that are reducing the risk of somebody going on to get Alzheimer's disease, it's going to help reduce the risk of say, somebody getting ALS.
As we think about ways that we could prevent the disease, how important is speeding up time to diagnosis?
At the beginning, we talked about the different ways that we can be thinking about prevention. And one of the ways I talked about was really preventing the progression of disease and preventing the progression of disability. So, it's critical that we diagnose this disease earlier. Essentially, the time it takes from somebody to first start developing symptoms to the time that they get diagnosed, has not changed in decades. It's still around this one year mark. And there was a really nice article actually published this month in the journal Neurology by Dr. Mitsumoto and Dr. Kasarskis and Dr. Simmons talking about this and talking about this journey for someone to get ALS. And as you know, The ALS Association has this Think ALS tool.
I know it's been discussed on a prior podcast, and this is a tool to really make clinicians think about the person sitting in front of them. And are they presenting with these unique features that should make them think, "Hey, this could be ALS. I don't need to make the diagnosis, but I need to get them to somebody who can and do this on an urgent basis." And the reason is this. Early diagnosis means an earlier opportunity for us to start treating people with therapeutics and other devices that may slow disease. And I think what we've started to see is that there's building evidence to say that the earlier we can get somebody treated, the bigger effect it's going to have on slowing disease and the bigger treatment effect. So if we can really collapse that window from the onset of symptoms to the diagnosis, I think we're going to be able to improve outcomes.
Now, when we link this back to the idea of prevention, I think we can take this a step further and say, "Well, if we know individuals who are at risk," and Michael Benatar, at Miami has done a really nice job with his family studies. So if we know who's at risk, can we even move that window earlier? In other words, can we diagnose people before they have symptoms? Because if we can do that, then we can start treatments before they even develop symptoms. And maybe that gives us an even better treatment outcome. So moving the diagnosis forward in terms of someone's symptom onset is critical. And I think as we're thinking about prevention, really trying to identify people before they get disease, before they get symptoms, which seems like an impossible task, but nothing's impossible if we put our minds to it. If we can identify who's at risk of disease and monitor them, if we can treat before the symptoms start, I think we're going to have a better opportunity to make a more meaningful impact on someone's treatment and thus prevent the progression of the disability and prevent the progression and symptoms.