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Connecting ALS is a weekly podcast produced by The ALS Association in partnership with CitizenRacecar. We aim to discuss research and technology developments, highlight advocacy efforts, and share the personal stories woven through the community.
This transcript was exported on Feb 15, 2023 - view latest version here.
Larry Falivena:
I think a lot of it has to do with education. Let people know genetic testing is available, here's how it can help you, and then let them make the choice. There is a lot of genetic research happening. If something comes up and you happen to have a gene and there does happen to be a therapy, you want to know about that.
Jeremy Holden:
Hello everyone and welcome to Connecting ALS. I am your host Jeremy Holden. In recent weeks, lawmakers in Maryland have been debating a bill that would prohibit life insurance and disability insurance companies from using the results of genetic testing to deny coverage or affect pricing decision. Now to learn more about the fight to pass the Genetic Testing Protection Act in Maryland and in other states, check out our recent conversation here on Connecting ALS with Melanie Lendnal and Lindsey Gill from the ALS Association's public policy team. Or you can check out the links in this episode's show notes.
Genetic counseling and testing is an increasingly important part of healthcare. It can help diagnose the underlying causes of a disease or point the way toward clinical trails and potential treatments down the road. The decision to pursue genetic testing is a personal one, and genetic counselors can help you navigate all the considerations and make an informed decision whether genetic testing is right for you. But it is important that people with ALS and their family members do not face barriers to accessing genetic testing and counseling.
As many listeners are aware, ALS can be linked to a genetic mutation, an error in our DN instructions that can cause our cells to create too much protein, not enough protein or a toxic protein. These gene mutations can be inherited from our parents or developed during our lifetimes, perhaps randomly or perhaps due to some environmental exposure.
The scientists first discovered a gene mutation connected to ALS in 1993, it was a mutation in the SOD1 gene. Since then, researchers have uncovered more than 40 genetic mutations that have been linked to ALS including a mutation in the C9orf gene, the most common genetic mutation that has been tied to ALS. Because ALS can have a genetic component, that means it can be inherited. Listeners are probably well familiar with this data point, but somewhere between five and 10% of people living with ALS have family members who have also been affected by the disease. This is often referred to as family ALS.
I recently talked to Larry Falivena who was diagnosed with ALS in 2017 and who serves on the ALS's Association's board of trustees about his decision to pursue genetic testing and his experience living with a familial form of ALS. Larry, thanks as always for being with us on Connecting ALS.
Larry Falivena:
Happy to be here.
Jeremy Holden:
We've been talking about genetics and familial ALS recently. As I'm sure you're aware, the big legislative fight happening up in Maryland. We'll get to that in a little bit. And obviously the association has put together some resources for people to understand the benefits and the considerations around genetic counseling and testing. So I want to start there. What was your experience after your diagnosis, making a determination whether you wanted to pursue genetic testing and genetic counseling?
Larry Falivena:
Yeah, I was actually informed about it. It wasn't something that I'd ever talked about, but very soon after my diagnosis, Dr. Bedlack at the Duke Clinic said, "You should think about genetic testing because there is a lot of genetic research happening. If something comes up and you happen to have a gene and there does happen to be a therapy, you want to know about that." And that makes sense to me. Right? Let's find out. There's so much that we don't know about ALS. If we can find out something, that's only going to be helpful. And sure enough, not long after, a treatment came up for the genetic mutation I had, and that gave me the opportunity to get to a trial. So I think a lot of it has to do with education. Let people know genetic testing is available, here's how it can help you, and then let them make the choice.
Jeremy Holden:
You mentioned clinical trials, and I know that's one of the big reasons that we talk about genetic testing, genetic counseling. What's your experience been like in the clinical trial that you've been in?
Larry Falivena:
It's interesting. You're diagnosed with this terminal disease. There really aren't any treatments, so the first thing that you start thinking about is let me get into a trial. Because really experimental treatments are one of the few options available to you, and it's a daunting process. You have to put in the work, I guess you'd say, to find out what's out there, what might be a fit for you, and then try to get in. And I was actually disqualified the first time I applied for this trial. So finding a trial and then finding out you don't get in, that's just another slap in the face there on top of everything else.
Long story short, I did wind up getting in. I'm now a part of the open-label extension, which has been a tremendous blessing. I feel incredibly lucky. I think my experience and the data seems to show that there's a benefit. So every four weeks I have to travel two states away. I have to get a treatment, my wife has to go with me, friends have to cover the kids. I'm not complaining. Again, I feel very blessed, but there is a cost to it.
Jeremy Holden:
We had the opportunity to talk to Dr. [inaudible 00:05:45] a couple weeks ago on this show about efforts to expand access to clinical trials and try to reduce some of those burdens, make it easier for more people to participate in more trials.
So I mentioned at the top this legislation going on in Maryland, and we talked about it a couple weeks ago with the public policy team. Basically taking life insurance, long-term care providers and making sure that they can't utilize something that we learn through genetic testing to deny somebody long-term care or life insurance or to engage in some type of pricing discrimination. So really protecting patients what they learn through genetic testing and protecting the privacy of that information. Talk to me a little bit about the importance of making sure that people have access to genetic counseling and testing and the need to prevent discrimination based on the results of those tests.
Larry Falivena:
Sure. Genetic testing is important for many diseases, not just ALS. Certain types of cancer, cystic fibrosis, et cetera. So research continues to find genetic markers for all kinds of different diseases. And if we ever want to get to the point where we can detect these things early, apply treatments early, if we ever want to get to the point where we're actually going to prevent these diseases, genetic counseling and testing has to be an option. And I realize it comes down to money, but I think even for the insurers, if we get to the point where it's certainly we can prevent a disease or even just treat it earlier, that brings costs down because now you don't have lengthy treatments for diseases. We can prevent death. It could be a win-win situation. But to take that option away from people because they are afraid that they might lose life insurance or not get health insurance and not be able to take advantage of something that could save their life, just not fair.
Jeremy Holden:
We had an opportunity to talk on this show to a genetic counselor last year, and one of the things that really was brought home to of me that part conversation is the genetic counseling component of it. The genetic testing is important if you decide to pursue that, but the genetic counseling component can talk someone through the benefits and then the considerations that have to go into making that ultimate decision.
Larry Falivena:
Yeah, I agree. But I would also like to expand into the definition of genetic counseling. Because naively on my part, genetic counseling I think also needs to include the psychiatric side of things. Like I said, it's been a struggle for me and my wife. How do we deal with it? So again, when I first started genetic counseling, I pictured that like family counseling, psychiatric counseling. I would really like to see that part of the process because just dropping that in someone's lap, just like an ALS diagnosis, Hey, you have ALS, and then that's it. Having someone help you navigate that, especially with familial ALS, would be tremendously helpful.
Jeremy Holden:
Now, Larry, I'm sure many listeners are aware of the genetic connections to ALS, the genes and the gene mutations that are connected to the disease. But what have you learned since your diagnosis about familial ALS?
Larry Falivena:
With my particular genetic mutation, there's no history of it in my family, as I said before, but I do know several people who've had to deal with familial ALS and have lost numerous members of their family across generations. And what's really struck me is how devastating this is on a family. Just the other day of friend of mine who has ALS, familial ALS text me to say that her brother was just diagnosed. And on the one hand, he knew it was coming, but it's still a crushing diagnosis. And what we talked about is ALS is like having this giant boulder hanging over your head and you never know when or if it's just going to drop down and crush you. I can't imagine trying to deal with that on a daily basis. But that's the life of someone with a familial ALS. And that's why finding these treatments, hopefully finding preventions for this genetic side of ALS can make a huge difference to families who've already seen so much loss.
Jeremy Holden:
That's an important point and one that I definitely think should not get lost in the conversation. Larry, thanks as always for sharing your time and insight with us.
Larry Falivena:
I appreciate it. Thank you.
Jeremy Holden:
As Larry mentioned, knowledge of whether ALS is connected to a known genetic mutation, can point the way toward clinical trials that are testing therapies targeting specific genetic mutations. To learn more about the development of gene therapies, I recently connected with Dr. Michael Benatar, a professor of neurology, the Walter Bradley chair in ALS research executive director of the LS Center, Chief of Neuromuscular division, Vice-Chair for Clinical and Translational Research in the Department of Neurology at the University of Miami. Dr. Benatar is also a member of the ALS Association's Board of Trustees. Dr. Benatar, thanks so much for being with us this week on Connecting ALS.
Dr. Michael Benatar:
You're welcome. It's great to be here.
Jeremy Holden:
Yeah, really excited to talk to you a little bit about some of the research that's going on around the world and search for treatments and cures for ALS. But for starting points, what do you think are some of the biggest challenges that researchers face trying to develop effective treatments for ALS?
Dr. Michael Benatar:
Yeah, it's the million-dollar question, isn't it? I think a few things. I think one is fundamentally, and there are exceptions. But fundamentally, we don't understand the underlying causes of disease. And I said causes in plural, I can say more about that, but I don't think this is one disease. I think it's many diseases probably with many different causes. And even if we don't understand the cause, we don't understand what I'd call upstream biology. So I don't mean downstream consequences of that cause, but some early event in initiating the pathology of disease. We don't have good ways to study that in people and to understand that. And so we are often flailing about a little when we're trying to develop treatments because we don't know fundamentally what to target. Now, of course, the genetic forms of ALS are a little bit different and we'll talk more about those, but there, we understand the cause and we can target them. So I think that's the one central challenge.
But the other, and this has been the lingering worry in my head for a long time, is that fundamentally as a general rule, we treat too late. And this is intuitive in many ways. The analogy I often give patients is to say, if you go to the dermatologist with a cancerous skin lesion and it's restricted to the skin, you can cut it out and that'll be curative. But if it's metastasized to the brain and the bones and elsewhere, that simple surgical procedure is not going to do anything. So I guess I worry that we sometimes might be bringing what could be effective therapies, but too late to bear and so they're not having an effect. So I think those two things probably for me are some of the greatest challenges.
Jeremy Holden:
Yeah. We've talked a bit on this program about some of the efforts that are being done for earlier diagnosis, so potentially having some earlier interventions. But I want to go back to something else you mentioned Dr. Benatar, and that was the genetic components of ALS. Over the course of time, many genetic mutations have been found with a connection to ALS. So with that in mind, what progress is being made in developing treatments for those genetic forms of ALS?
Dr. Michael Benatar:
Yeah, so another important question, and very timely. So I think as the audience to this podcast probably know we can identify a mono genetic cause or a single gene as the cause of ALS insert 10 to 15% of people. And that's not restricted to people who have family history, that's people with a family history and people without. But there's a clearly identified genetic cause. The specific genetic cause, and there are many, depending on how you count them, 10, 20, 30 different gene that have been identified, which is most common depends to some extent on the population you're studying. But the two that are leading candidates or most common causes of the C9ORF72 repeat expansion expansion and the mutations in the SOD1 gene. We've known about SOD1 for the longest, since the early nineties. And really good progress has been made.
There's been advanced stage clinical trials of a form of a gene therapy using antisense oligonucleotides to knock down levels of the SOD1 protein that is thought to be toxic. And actually currently that data is before the FDA for consideration for accelerated approval. There've been other efforts in other forms of disease. So a similar ASL based approach has been looked at and is still being looked at in C9ORF72. There have been more fits and starts there. More challenges, more setbacks. Some of that early data has not yielded the results that we would've hoped for. Maybe harmful. Not seeing early promising signals. And maybe that reflects the more complex biology of C9ORF72 disease compared to SOD. And we need to understand that better even when we think we know the cause of disease. But there are other genetic approaches or gene therapy approaches that I think are coming down the pike. But I think being able to target that upstream cause of disease is really enabling us to make progress. And I guess I'm cautiously hopeful, optimistic that the first meaningful therapy, they're going to come to patients with some of these genetic forms of disease.
Jeremy Holden:
You talked about the percentages 10 to 15%, I think you said we can trace back to some type of genetic cause or genetic signal. So as we learn about ways to treat those underlying genetic causes potentially, so how can learnings from ways to treat genetic cause of ALS, how does that shine a light on other potential treatments for maybe non-genetic or sporadic cases of ALS?
Dr. Michael Benatar:
Yeah, so I think that's another really important question and I think there are a few ways to answer that. The first is, again, as this audience knows, we currently lack meaningfully effective therapies. If we can get one for any form of disease, I see that as a foot in the door, the thin edge of the wedge so to speak, that we can use to pry that door open. Because I think they're important lessons. And you're asking what some of those lessons are. So first I think one of the things we might learn is that if you can target the cause of disease, maybe you can have the biggest impact. So that'll further provide impetus for some of what we discussed earlier.
The second thing that I think we're learning is that even when you target the cause, depending on the nature of the therapy, this may not like be clicking a light switch. It may take time to exert the intended biological effect. So for example, to knock down that gene or the toxic protein that results from that genetic mutation. And it may take time after you've accomplished that biological effect to see a clinically meaningful effect in a way that matters to patients. Slowing disease, feeling better, living longer. And so I think there are several delays in that and that has important implications for how we design future clinical trials. So maybe a six-month trial isn't long enough even when you're targeting the cause of disease because over that timeframe you can impact the biology but not enough time to see the therapeutic benefit. So I think there may be learnings there in terms of the nature of the therapeutic and when and how we try to measure therapeutic response and for how long we need to treat.
The third learning I think relates to the importance of biomarkers. And I don't know how much you've spoken about these on this podcast, but biomarkers can be many different things and maybe we have to have a whole separate discussion about them.
Jeremy Holden:
We can't talk about biomarkers enough. I think it's a critical part of this conversation.
Dr. Michael Benatar:
Yeah, absolutely. So I think there are two important things that we should say about biomarkers relevant to this context. And I'm going to talk a little bit about some learnings from the SOD1 antisense oligonucleotide trials because I think we learned some important things about one of our most advanced and sophisticated biomarkers, the single neurofilament lights chain or NfL, not to be confused with Super Bowl NFL, but a different kind of NfL. Although Super Bowl raises your NfL too. But separate to that, we're talking about neurofilament light chain here. So this has two potential utilities here.
The one is we are learning that neurofilament light when measured in blood, it's also true in spinal fluid, but when measured in blood is a prognostic biomarker. So what that means when you measure it now or early, it tells you something about the future course of disease, how quickly disease, for example, is progressing or how long or short survival may be. And one of the things we know about ALS that it's enormously phenotypically heterogeneous. Some people progress slowly, some people progress quickly. And that's a challenge when we are trying to discern the therapeutic effect of the treatment. We have to know that that effect is due to the treatment and not just that natural variability of the disease.
So having a prognostic marker like NfL that we can stratify patients on. So when we randomize, we can make sure there's a good mix of fast and slow progresses on the active treatment, fast and slow progresses on the slow treatment, or we can only give a treatment to those with a neurofilament of a particular level or a particular range. There are various nuances in how we might use it. But having that as a prognostic marker can enable us to do more effective trials, meaning smaller numbers of patients measuring a therapeutic effect more quickly. And so that was one very important learning. Lots of literature built up to this, but I think an important learning from the recent SOD1 ASO trial.
But the other is not using neurofilament in that prognostic sense, but as what the FDA calls a response biomarker. So a response biomarker is a marker that changes, that tells us, there's being a biological response to a treatment. So what does NfL tell us? NfL is a marker of how quickly neurodegeneration is proceeding. The analogy I like to use is think about it as the the dial on the speedometer tells you how fast you're traveling. Going 80 miles per hour your disease is progressing more quickly than if you're going 40 miles per hour. The analogy there and the 80 miles per hour is a higher level of neurofilament. Going more slowly is a slower level of neurofilament. And what we saw in the SOD1 ASO trial was a lowering of neurofilament by about 60%. So we think intuitively, that's good. If we can slow the speed of which that car is progressing, slow the pace with which disease is progressing, surely that must have a clinical benefit. We don't know that for sure, but there's a reasonable expectation that that's the case.
So some of these learnings, once we have an effective therapy, will tell us how we can use biomarkers like neurofilament to help us in future trials and in future drug development efforts. So again, it's that foot in the door, that thin edge of the wedge. If we can get a treatment that works, now we've got to proof of principle as to how that biomarker can be expected to respond. And we can use that to tell us, for example, when we test new treatments, do we see a change in this biomarker? Is this a promising therapy? Should we move that from a phase two trial into a phase three trial? So I think, again, it's not that this is genetic learnings to non-genetic, it's maybe first success to future successes. And if the first success happens to come in the genetic realm, then that will be a lesson that will be relevant hopefully to developing therapies for all forms of ALS.
Jeremy Holden:
As listeners are well aware, one of the hallmarks of genetic ALS is the potential to pass it on, for it to be inherited. And that's why we've been talking in recent weeks a lot about genetic testing, genetic counseling. What is some of the potential for prevention of genetically caused ALS?
Dr. Michael Benatar:
Great. So now we're talking about what I'm really interested in. So we've been interested in this question for the better part of the last 15, 20 years. I think this comes back to where we started, which is at some level it feels intuitive that the earlier you can treat, the better. And if you can prevent, how much more so is that even better and more likely to be effective if you can get in super early? But in order to prevent, we need to know who's at risk. You need to know when they're likely to develop disease and you need to have a window of opportunity where you can intervene. So we started studying this problem and this potential, I guess in the genetic realm because the genetic risk factors are the best known risk factors for developing disease. If you have, for example, an SOD1 mutation, there's a very high lifetime risk depending on the specific mutation, but for the most part, a very high lifetime risk that you will develop ANS at some stage.
But it's very variable the age of onset. Could be in your twenties, could be in your seventies or eighties. If you've ever seen an ORF72 mutation, the risk is high, but it's not complete. The penetrance there is incomplete. Not everyone will develop disease. So how much more so is it difficult to know in whom should we think about intervening early to prevent disease? But again, the principle is that if we know that you have a factor that puts you at greatly elevated risk, then there's the potential to intervene early. So we've started in this realm. But now what are we going to use to intervene early to prevent? And what's the risk of that? So if I've got a high risk treatment, I'm going to give it to you when you're 20, but you might not develop disease until you're 70, maybe I'm going to cause more harm than good. And so I need to know when you're going to develop disease.
Now, this brings us back to our biomarker neurofilament light. And we found several years ago that [inaudible 00:25:02] genetic mutation that puts them at very high risk of developing aggressive forms of disease, neurofilament levels go up six to 12 months before people ever show clinical signs of disease. So maybe that can tell us the when. Could we use that if we are monitoring that in blood, not spinal fluid, in blood, to tell us in whom we should give a gene therapy super early? And in fact, we are now doing that in the ATLAS trial, a study that I designed together with colleagues at Biogen and which is now ongoing.
But maybe there are opportunities to go beyond that as we discover more biomarkers of presymptomatic disease to give us opportunities to intervene in other genetic populations and maybe even in other non-genetic populations. Because if we want to get into prevention outside of the genetic realm of disease, we've got to identify those risk factors. We've got to know who's at risk, when are they at risk, and how can we intervene upon that? And we can talk more about that if we'd like to go there.
Jeremy Holden:
Yeah, I would. I wanted to go back to your wedge in the door, foot in the door. What was it? The thin edge of the wedge in the door. Does that apply here to prevention as well? That as we learn preventative efforts for genetic forms of ALS, it shines a light toward how we can apply that to non-genetic forms of sporadic ALS?
Dr. Michael Benatar:
I think it absolutely does. So let me give you another example of a learning from the genetic population that I think will be at risk for the non-genetic. So the first was the example I already cited that neurofilament levels seem to go up pre-symptomatically. So that's non-specific, there are other things that can do that like head injury, but that may be one early marker.
But one of the other important things we've learned from studying people at genetic risk for ALS is for the most part, people don't flip over from being what we call clinically silent to having ALS. In between those two stages, there's a prodromal period that we have called mild motor impairment or MMI. We're thinking some people because there's a close relationship between ALS and NTD, some people may have mild cognitive impairment, some have mild behavioral impairment. So these prodromal syndromes could be MMI, MCI or MBI.
Now, I don't know this, this is a hypothesis, but I strongly, strongly suspect that even people without genetic risk for disease, the people with other risk factors also go through these prodromal states. So if we could recognize these and study these, maybe that's the foot in the door, the edge of the wedge to begin to think about studying early disease in people with sporadic forms of ALS. Maybe studying prodromal disease will lead to earlier diagnosis, earlier therapeutic intervention, maybe one day even prevention.
But it's not just people with these prodromal syndromes. I think there are other categories of people or other risk factors. These are challenges, but we are beginning to get a sense of this. Veterans have twice the risk. Family members of people with non-genetic ALS have eight times the risk. People with some environmental exposures have elevated risks in perhaps one and a half to two, to threefold increases. People with family history of other neurodegenerative diseases, FDA, AM... Not FDA, FTD. Other neuropsychiatric diseases. Family members of these sorts of people also may have an elevated risk. Now, the challenge is that their risk is still relatively low. So that's still a challenge. But I think studying those people who are at elevated risk, trying to identify other factors may be putting some of these together identifies people at even greater risk. And I think that's the opportunity and one of the pressing means for what we need to be doing in the coming years.
Jeremy Holden:
You talked about challenges and opportunities. Before I let you go, Dr. Benatar, what gives you hope that we're on the right path and that that progress could be on the not too distant horizon?
Dr. Michael Benatar:
Yeah, I think there's always a challenge. We want to be a need to be hopeful and optimistic, but I'm also always very cautious not to give false hope and false optimism. So I'm concerned that we don't have meaningful therapies on the immediate horizon for people with non-genetic forms of disease. But I do think we have made very meaningful strides in developing approaches to developing therapies that are going to be more efficient and more effective. I think we're developing better tools. I think we are beginning to get that foot in the door, and I think we're increasingly as a field, I think asking the right questions and focusing our efforts in the places where they need to be. Coming back to where we started. Really understanding the biology of disease, the upstream causes of disease, and thinking about how do we intervene early. We have no hope when we are asking the wrong questions. When we're asking the right questions, and focusing our efforts where I think we're beginning to get traction, I think is a real reason for hope and optimism, hopefully in the not too distant future for meaningful therapies.
Jeremy Holden:
Well, with that, we will let you get back to the important work of understanding those upstream causes and looking for treatments and cures. Dr. Benatar, thanks so much for your time.
Dr. Michael Benatar:
Thank you. Great to be with you.
Jeremy Holden:
I want to thank my guests this week, Larry Falivena and Dr. Michael Benatar. If you like this episode, share with a friend. And while you're at it, please rate and review Connecting ALS wherever you listen to podcasts. It's a great way for us to connect with more listeners. Our production partner for this series is Citizen Race Car. Post-Production by Alex Brower. Production Management by Gabriela Montequin. Supervised by David Hoffman. That's going to do it for this week. Thanks for tuning in. We'll connect with you again soon.
ConnectingALS_021623_Ready2 (Completed 02/14/23)
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