A Test to Identify People Likely to Develop ALS

Siblings and children of people with the rare, neurodegenerative disease amyotrophic lateral sclerosis are being offered a test in the United Kingdom at no-cost to see if they carry mutations to one of more than 40 genes that would make it likely for them to develop the condition. Sano Genetics developed the test under a grant from Innovate UK. The hope is the effort will expand the understanding of the condition while allowing people who are likely to develop the disease to make informed decisions about their lives. We spoke to Paul Wicks, vice president of neuroscience for Sano, about its test for ALS-related gene mutations, how it works, and why some healthy people might want to take advantage of it.

Daniel Levine: Paul, thanks for joining us.

Paul Wicks: Thanks. It’s a pleasure to be here.

Daniel Levine: We’re going to talk about ALS, Sano Genetics, and its offerings of a test in the United Kingdom for more than 40 genes associated with the neurodegenerative condition for siblings and children of people diagnosed with the disease to see if they might be at risk of getting it as well. Let’s start with ALS itself though. For people not familiar with the condition, what is it?

Paul Wicks: Sure. So, ALS goes by a couple of different names. It’s also known as Lou Gehrig’s disease. In the UK and other former commonwealth countries, it’s also known as motor neuron disease, but it’s all the same thing. ALS is a rare neurodegenerative and, sadly, terminal disease that tends to affect people between the ages of about 50 and 65, although it can affect people when they’re younger, and some of your listeners may remember it from the ALS Ice Bucket Challenge 10 years ago. It’s actually the anniversary this summer. So there’s sort of a revival, if you like, of people dumping buckets of ice water over their head. But yeah, it’s a relatively rare condition only because the prognosis is so poor. So, people, very sadly, only live between two and five years with the condition on average. So it’s one of these that in terms of how many new people get it each year, it’s about as common as something like multiple sclerosis. But because it’s so rapidly fatal, there aren’t that many people living with it at any one time.

Daniel Levine: How does the condition manifest itself and progress?

Paul Wicks: For most people it starts off with weakness in their muscles. So, their voluntary muscles are the ones that are affected in ALS. So things that control movement. You might see that someone’s had a problem with their foot, so their foot might be dragging along the floor, or they might be experiencing weakness in their arms. That means they have difficulty just with everyday tasks, for example, with lifting a kettle once it’s full of water, they might just notice that that’s something they’ve always been able to do, particularly with their dominant hand perhaps—that sort of change. They might notice changes in their handwriting, in their grip, in their ability to turn a key in a lock, for example. And in some cases they can also have problems with their speech. So, there’s basically different forms of disease depending on the site of onset, but it does progress over time. Somebody who started off with symptoms in their legs is likely to eventually get symptoms in their arms, symptoms in their mouth and throat, and eventually it’s actually problems with breathing. That is the reason why it’s a fatal condition. So unfortunately, as people progress with their condition, more and more regions are affected. More and more regions get weak, and so as a result, the muscle atrophies, they lose quite a lot of weight, they get weaker, and unfortunately towards the end they become dependent on things like BiPAP machines or even ventilators to help them with breathing. So yeah, it’s a really devastating condition and the rate of progress can vary. So some people can be like Stephen Hawking, he’s actually the most well-known example, but in some ways he’s not a very typical example. But like I said, most people it’s a prognosis between two and five years after that onset.

Daniel Levine: And what treatment options exist today?

Paul Wicks: Yeah, so still we don’t have as many treatments as we would like. There are other neurodegenerative conditions with more treatment options available. Since the mid-1990s, we’ve had a drug called Riluzole, and that drug slows the disease somewhat, we think. We hope it keeps people in earlier stages of the disease for longer. But on average, when you look at a whole bunch of studies added together in a meta-analysis, we’re really only looking at extending life by a matter of months. So we’re still pretty far off. Now, there have been some other drugs approved recently, at least in the United States. They’re not all available all around the world. There’s been some controversy of some treatments that were given accelerated approval, but then withdrawn from the market. But if people are interested, they can go and look into those. So, we’ve got this drug Riluzole that’s been around for over 20 years that makes a very modest impact. We do have a treatment that can help people with their emotional expressions, emotional lability that can happen with this condition. There is a pill that slows the condition in some people, again, we think by a few months, but you can kind of get the sense from what I’m saying, that they’re very marginal benefits. There has been one more significant treatment that’s come online recently that’s actually a gene therapy, and that’s really opened up a lot of interest in genetic testing and really stratifying the disease. So that’s for a subset of people who have a genetic course of the disease and the gene that they have is called SOD1, and that makes extra protein that you don’t want to have hanging around in your motor neurons. And this gene therapy that’s come along actually helps to tamp that down. It’s called the gene silencing technology. But of course, if you don’t know what gene you have, you don’t know if you’re eligible for that treatment. And like I say, it was just approved in the U.S. last year. It’s currently undergoing review in other countries around the world.

Daniel Levine: I think if you look at neurodegenerative diseases more broadly beyond ALS, there seems to have been a lot of difficulties in developing effective therapies to treat them. What makes these conditions so challenging to develop therapies for them? Why haven’t we seen greater success to date?

Paul Wicks: That’s a great question and one that I know thousands of my colleagues are working around the clock and have been for many years working on. I mean, look, the basics are we don’t understand what causes the disease. And when we look over at adjacent serious illnesses like cancer, you can see a tumor growing and you can build a model where you see a tumor in a dish and you see how it responds. We’re a lot further behind other conditions like that. But in neurodegeneration, we have a couple of other challenges. So number one, there’s this thing called the blood brain barrier. So if you take a pill, it’s not necessarily going to get to your nervous system, and there’s good evolutionary reasons why the body would evolve to keep a good filter between what you ingest and what goes into your brain. But that’s a challenge for delivering medicines. So some of the medicines that we see coming online now or that are in experimental trials are not a pill. So right now, the gene therapy that I mentioned, you actually have to have that as an injection, as an infusion into your spine. Some of the other forms of treatment that people are experimenting with actually require you to have brain surgery, to have a shunt put into your head to actually inject this medicine into the spaces in your brain where it can have an effect. So partially it’s that, and then the neurons, they don’t grow back. They’re very vulnerable. The motor neurons, if you are six foot two like me, the motor neuron that goes to my brain down to the base of my spine is nearly a meter long. And then the connecting lower motor neuron that goes from my spine down to my pinky toe, it’s almost another meter long as well.

And if that gets severed, it doesn’t grow back. So there is a lot about that system that is just tougher to work in. There’s no neuron transplants, there’s no brain transplants, and we also just don’t have enough good measurements. My training is as a neuropsychologist, so I have expertise in assessing people’s cognitive function, but there are still not great tests for that. Doctors can tell you all sorts of things about your heart and your lungs and your cardiovascular system and how well you process insulin, all this kind of stuff. You can even get, even as a consumer, you could probably go to a supermarket right now, buy a whole bunch of gadgets if you’re wearing an Apple watch, probably pulls a whole bunch of numbers off of your hand. We don’t have good measures for cognition. We don’t have great measures for movement, and so we’re really lacking outcome measures. So I think it’s a combination of those things. We don’t understand that etiology, the nervous system is hard, it’s brain surgery. And then this third aspect of the outcome measures. Those three things combine to make it a really challenging space to work in.

Daniel Levine: You mentioned a treatment for this SOD1 form of ALS. There are small percentage of cases known to be genetically driven. What do we know about the causes of ALS today and to what extent is it a genetic disease?

Paul Wicks: Yeah, so we’re really increasing our understanding of that driven in part by funding from the Ice Bucket challenge that raised a lot of money in a short space of time and allowed us to do more basic research and really strengthen the base of researchers that we had studying the disease. So historically, I believe motor neuron disease, ALS, was thought of as a sporadic disease, an idiopathic disease. It just comes out of nowhere. It’s just an unfortunate thing that can happen in life. Over time though, some patents started emerging where it could run in families and in particular this gene that has a treatment. Now, SOD1 was the first gene to be identified, and that was identified in the early 1990s, but it was still clear there were other families where say a patient could present a clinic and their mom had died of ALS. And then as you go further back in the family history, maybe a grandparent, maybe they weren’t diagnosed with ALS, but maybe they ended up in a care home pretty early, or they had challenging behavior or they had things in their notes like senile dementia or creeping paralysis or polio or something like that. And one of the challenges is when you start going back in time, there weren’t many neurologists at all and there wasn’t a good way of diagnosing ALS. So the family histories were a little murky. So, what’s been happening over the past 30 years, especially, is as we’ve got better at diagnosing patients and developing relationships between families and specialist ALS centers, we’ve been able to do more genetic discovery. And so that has led to the discovery now of over 40 genes, some of which have got many, many variants. So, we now know there are over 200 different forms of the SOD1 genetic variant, for example. And we’ve been discovering that there is a relationship between some of these genotypes and the phenotypes that are expressed. We actually found that there’s a more common genetic variant that can cause ALS in families called C9ORF72, and that can be a driver of both ALS and also another neurodegenerative disease, frontotemporal dementia, FTD. And what’s incredibly challenging for these families is when that gene expresses itself, and it doesn’t necessarily express itself in everyone that carries the expansion, but that person could get ALS, they could get FTD, or even more devastating, they could get both. And so, everything that I’ve just told you about the physical manifestations of that disease, now think on top of that having something like FTD, which again listeners may be familiar with now a little bit more because of people like Bruce Willis, Wendy Williams, but with FTD, you’re really talking about personality changes, difficulties with language, disinhibited behavior, apathy. And so yeah, it’s kind of both the motor system and the cognitive system being affected. But really that’s one of the areas where we’ve been able to pull on a thread and go, okay, now we understand that these diseases come in kind of a cluster. What do they have in common? How might we reevaluate what we know about these diseases? So it’s been a really rich seam to explore. And so, when I started training 25 years ago, we thought only 2 percent of ALS was genetic. These days, we think it’s more like 20 percent. So a much, much better defined genetic component.

Daniel Levine: How does the fact that there are mutations in different genes that can cause the disease complicate getting a diagnosis or developing an effective therapy?

Paul Wicks: So now that we know that diagnosed patients are quite likely to have a genetic cause for their condition, you might think that everyone who works in the space would say, well, let’s test everybody then. But actually it’s a bit more complicated than that. So historically we used to see what we call the sporadic form, which just seemed to pop out of nowhere. And then if you had a family history, we’d call that familial ALS. We now know though that for various reasons like adoption and things potentially skipping a generation or people having a gene but not actually expressing the disease, this concept of incomplete penetrance, that there are many people who have got a genetic course, the ALS for whom you can’t find a family history. And so, there’s still controversy in the field about how to approach this because obviously if you start talking about genetic counseling, genetic testing, you are opening up a lot of conversations within a family. You are potentially causing some anxiety within that person for something that may or may not be addressable with treatment. But yeah, we do know that in the long term, we will probably move towards testing everybody so that we can help with that. Now what that might mean is, if you have someone who doesn’t have a clear-cut diagnosis, that it might be that having that genetic information could be helpful, but right now it’s a clinical diagnosis and it’s a diagnosis of exclusion. So I’ve mentioned a few symptoms to you. If anyone’s run a marathon recently and they’ve got a bit of a sore foot, don’t worry, that doesn’t mean you have this serious neurodegenerative disorder. Sometimes people can get very worried when they hear about ALS if I have a twitch or something, or a spasm, is that a sign of it? And the answer is generally no. But yeah, I think what we need to move towards is more comfort with acknowledging that it can have a genetic component and offering up genetic testing to everybody. And if we do that, I think we’ll do a much better job of preparing families for what they can do next. And the reason that’ll be really key is like I said, there are these forms of the disease that affect the phenotype, so affect how the disease is expressed. So unfortunately, there are mutations which mean that people will have an even more aggressive form of the disease. Now, if people with that more aggressive form of the disease are invited to participate in clinical trials not targeted towards their gene, they’re unlikely to work. I mean, in general, clinical trials are there to evaluate whether or not something works, not to offer treatment to people. But what it might mean is that it obscures the effect of a treatment. If someone’s got a really aggressive gene, that means that they’re only going to have nine to 12 months of survival versus other people in the trial who’ve got two to five years, then perhaps we could be missing out on a potential effect that might benefit more people. So that’s a challenge. The other challenge would be that those people could be better served by being in a gene targeted therapy appropriate for the reason why they have the disease. So it’s still early days. We’re still in the middle of a gap period. I would say in five to 10 years, it’s probably going to be pretty common that everybody, at least in the United States, the UK, richer health infrastructures are likely to have genetic testing become routine as we see in something like Huntington’s or what have you. But it’s important to note there are many neurological diseases where we know there’s a genetic aspect from a research component, but we don’t necessarily offer clinical testing to everyone that comes through the door. So most people with Parkinson’s disease, most people with Alzheimer’s disease may not be routinely offered a genetic test, even though there may be a genetic component just because it doesn’t necessarily affect how you would treat that person.

Daniel Levine: Sano Genetics has developed a test for a number of genes associated with ALS. This is being made available at no charge to siblings and children of people with ALS in the United Kingdom through a $500,000 grant by the government funded research and innovation agency, Innovate UK. Why are they doing this?

Paul Wicks: Sano Genetics is offering this program called Light the Way, and really it consists of several different components all developed in response to the need from the community. So it starts with education. As you can imagine, we’ve just been talking about it for a few minutes now, but you can pretty quickly grasp how complex this is. And if you think when people first become symptomatic or they’re first talking about getting diagnosed, they’re emotionally overwhelmed, there’s an awful lot of information to process, and they might be dealing with onset of disability. So they often don’t have the time to learn about the genetic aspects and particularly the more up-to-date information because there’s new papers coming out every week. So our first of offering is around genetic education to ensure that people understand concepts like, how do I inherit genes? How do I pass them on potentially to my children? What are concepts like penetrance where just because you carry a gene doesn’t necessarily mean it will be expressed? And then what are the sort of options? So we’ve talked a little about medical treatment, but there’s also life choices that people might make. They might decide to make certain decisions around family planning. So some people I speak to have decided not to have children so that the inherited component of disease ends with them, if you like. Other people have gone through IVF and actually in certain circumstances it may be possible for people who are thinking about starting a family who are gene positive to actually have a form of IVF where they don’t pass on the genes to the offspring. So education’s really the core of it. And then if people want to go further, we can actually offer them up what’s called pre-test genetic counseling. Using a video connection, kind of a zoom, Skype type thing, we can put people in touch with a genetic counselor. Now, a genetic counselor is someone who’s specially trained in supporting people in a non-judgmental, non-directive way to inform them further about their risks and their options and, if they want to, try and advance them to access testing. So the testing pathways, they look different depending on who you are and where you are. So in the UK, as you may know, we have a national health service. It is free at the point of use, and so many services are available for free. There can be a waiting list though. So, what our genetic council will be doing in these cases is helping people to understand their options, their risks, if appropriate. They certainly may suggest they go and seek out genetic testing through the NHS. If they’re diagnosed with a condition already and they’ve not been able to access that testing, we are prioritizing access to genetic tests that we have that we can deliver in an at-home spit kit, a saliva-based kit to help support that in order to help them find out might they be eligible for research studies. So yeah, it’s really about driving awareness, hopefully helping to relieve a little bit of pressure that’s in the system and hopefully helping to clear down some of the backlogs that exist in this country at least.

Daniel Levine: And is the test being offered elsewhere outside of the United Kingdom?

Paul Wicks: Yes, absolutely. So perhaps unusually for a UK government grant, we actually made the case that what you really want to do with an online digital platform like this is build it to be multinational and multiple countries from the get-go. And in the long term, that could mean that particularly the educational components of this could scale to many other countries, many other languages to fill that education need that really exists all over the world. And many of our partners have identified a relatively low rate and low quality of genetic education and genetic counseling in countries that are not speaking English by their default. And all low and middle income countries struggle to get this kind of information. The argument we made was that we should go to the U.S. as well. So, we’ve had a lot of interest in the U.S. where we have deployed since December of 2023 in English, but also in US Spanish. And really the intent of this was to look at some of the health disparities that exist. Right now, access to education counseling and testing is uneven. It is inequitable. And so, we’ve been developing the services in US Spanish to try and see if we can bridge that gap. So adjusting language is only one of many things that need to be done in order to address this. But you may have seen recently that the FDA has called for diversity and inclusion plans for clinical trials. And if it’s only the case that relatively wealthy, educated white individuals that live near cities, if they’re the only people that take part in clinical trials, it really limits the generalizability of the evidence that we generate as a field. So yeah, we wanted to be able to go to multiple countries and really integrate with the systems they have there. In the United States, for example, there’s a different profile of risks and benefits to getting tested. Some people have been asked in the past to pay out of pocket for genetic tests because their insurance company would refuse to cover them. There are other ways of getting testing in the U.S. now. There’s these sponsored genetic testing programs that some of the drug companies are using to help recruit for clinical trials. But yeah, there still may be reasons why people in the U.S. don’t want to have a genetic test on their medical record, for example. And there are some protections against say, insurance discrimination, but they’re not fully comprehensive. So that’s been one of our learnings that although the knowledge about the disease, the knowledge about the genes is quite universal, the implications differ depending on where you are and who you are, unfortunately.

Daniel Levine: Well, how does the test work? Walk me through going from the patient to a result.

Paul Wicks: Sure. So, let’s take the hypothetical situation then that you’ve been diagnosed with ALS. You’ve been experiencing symptoms for a few months. You’ve probably seen your doctor, you’ve had a referral to a neurologist. You may have had a referral to an ALS specialist, and there are networks of these around the world, specialist medical clinics. So they may have offered you genetic testing at the time, or they may say, go away and think about it. If you were to access the Way program, and you might have found out about it from your doctor, you might have found out about it from a support group, then the first thing is just education, just making sure that people understand the implications of genetics and ALS. So, they would complete a series of blogs, which is supported by videos, supported by quizzes, so that we can sort of check people’s understandings before they go to each step.  And then for some people, that’ll be all they want at this time. There’s a lot to take in. Some people don’t want to know any more, to open Pandora’s box if you like, but for those people that want to go further, they can book at no cost themselves an appointment with a genetic counselor who, now that the person understands the basics, can address that person’s individual needs. And obviously that’s very different if they’re say a 25-year-old versus a 55-year-old, maybe one lives in a rural area, one lives in a city, one is interested in accessing this gene therapy that might be available, someone else might be interested in accessing a clinical trial, and they might have different fears, might have fears about employment, might have fears, maybe they have a twin or something like that. So that personalized counseling is really key. And obviously this is a trained licensed professional who just really knows how to give people calm and nonjudgmental environment in which to share their fears. If they do turn out to be eligible for the testing part of the program, then the genetic counselor can action that. And so we would send out a spit kit, a saliva gathering kit to that person’s home. It arrives in the post and then they provide a sample, they pop it in an envelope and return it back to us. We send it off to our lab where it goes through genetic sequencing, and then we work with a team of professionals to ensure that the way that those findings are interpreted is done in a way that is compliant with all the appropriate regulations. So, the laboratory is something called a clear CAP certified laboratory, and that means you can rely upon its results. And the report is something called an LDT test, which means that it’s not just a research grade finding or the sorts of ancestry.com stuff that people sometimes can do, which is not really medical grade, if you see what I mean. So, really putting it through very stringent testing and then the results should be returned within about six to 10 weeks. We’re looking at the moment, and that return of results is going to be done by your genetic counselor, so trying to avoid the situation where someone gets say an email saying, something’s changed in your electronic record, come and read this document, and then being very surprised or shocked or not prepared for it. We want to avoid that. So the return of the results is a conversation. And actually the first thing that post-test genetic counseling session is going to tackle is do you want to know your results? And they don’t have to decide right there on that, there’s no pressure. They can bring other people, they can bring care partners or professionals with them into that call. So yeah, then they will have the conversation with the genetic counselor and basically one of three things could happen. You could be positive for the gene. You could have a gene that actually is linked to causing ALS., You could be negative, in which case, that doesn’t mean that it’s impossible that there’s a genetic cause. It just means that we haven’t found one from what we know so far. And then there’s a third category called a variant of uncertain significance. And these are a little bit more complicated, but it means that it’s an area where researchers are still trying to figure out, does this cause disease? Or maybe it just increases risk a little bit, but we’ll keep an eye on those. We’ll review the scientific literature about once a year with our science team to know what’s going on. So yeah, clearly in terms of the implications, if someone’s positive, if they’re positive for SOD1 that could mean they’re eligible for the new treatment. That could be potentially—obviously having ALS at all is bad news—but good news in this case. They could have one of the other variants that might make them eligible for a research study and that research study, that clinical trial could potentially benefit other people could get them access to more information and support. And if they’re negative—so I have a family member with ALS, they tested negative for this genetic result and we breathed a huge sigh of relief because the alternative would’ve been worrying if his descendants and my children and things like this would be at a potentially much elevated risk of ALS at some time in their lifetime. But yeah, I think those negative cases, they should hopefully feel a sense of relief, but many of them are still caregivers. Many of them will still be deeply involved in the fight against ALS. And so in all cases, what these people will get access to, they’ll get a copy of their report that they can share with their doctor, and then they go into our virtual waiting room. And the virtual waiting room is a place where they can access peer support so they can meet other people like them. They can engage in advocacy activities. There’s an emotional support group about once a month that really helps talk through some of the family issues, especially they’ll be able to be informed about upcoming clinical trials and be signposted to sources of information about things like family planning. So if someone really wants to learn more about say, this IVF route, then we’ve got very high quality resources that have been developed with professionals, but also checked by people with lived experience to make sure they’re explained in a way that people can understand. So hopefully it’s really wraparound support for these individuals. And I think crucially, it’s happening in between the clinic visits. It’s not happening when you’re a rushed clinic appointment, it’s happening at home. You could have your loved ones come and listen in, you can send content to your loved ones, et cetera. So you can kind of absorb this complex topic at your own pace.

Daniel Levine: And just to clarify, if you were found to have a mutation that’s known to drive the disease, is it a guarantee that you’ll eventually get it or is it just that you’re at a heightened genetic risk?

Paul Wicks: No, so there’s no guarantees. And that’s something, again, that has been a relatively recent understanding that we’ve had. Some people have been listening to this program and they’ve had some genetic findings around ALS, like C9ORF72 that I mentioned earlier. In the past, people may have been told it’s almost guaranteed that you will get this disease at some point in your lifetime. We now know that’s not the case. So, we now know that there is incomplete penetrance of the gene, which means that you could carry this gene and never get ALS. There are probably hundreds of thousands, millions of people walking around with some of these genetic variants that will never express disease. And the reason we were confused about this is because obviously everybody that presented to an ALS center, who are most of the people that took part in research, did by definition have ALS. So, when we went to look at their genomes then, of course, they had the gene. And of course, what we didn’t have at the time was a sort of background population of people without ALS so we could see how common these variants were, but some of them we do find are not uncommon in the general population. So yeah, I mean to use the nerdy term, this is all probabilistic, not deterministic, right? So we’re saying risk. We’re not saying black and white, and part of the counseling part of the education is to ensure people are comfortable with that. If you want a really clear cut, yes-no definite answer, you may be disappointed.

Daniel Levine: What percentage of people who use this test might be found to have a gene that implicates ALS?

Paul Wicks: So, this is going to really vary by the type of person who’s using it. If someone’s diagnosed with ALS and they say had a parent, aunts and uncles, grandparents who also had ALS who may already have died by the time they’ve done this and they know what gene they had, then depending on their family history, then the risk of them being positive, it could be as high as 50 percent if they had a parent who had the disease, expressed that disease, and so on. But it could be much lower for people who’ve got, say, slightly more distant relatives than a parent. If it was aunts or grandparents or something like that, then their risk could be lower. But I’m slightly hesitant to say exact percentages just because, like I say, it’s different for different family situations, different for different genes. And then of course this point that we’ve said, just because you carry the gene doesn’t mean that you’ll definitely get the condition. So yeah, certainly this is part of the point of the research aspects of this that we want to actually share with the community what percentage of people we are finding that might be positive, negative, or have one of these variants of uncertain significance. And it may be that it differs from country to country. So, for example, in North America, the most common SOD1 variant is very aggressive. It’s called SOD1 A5B, and people with that condition, they’re on the shorter prognosis side, more in the 12 to 18 months side of things. Whereas over in Sweden, there’s a SOD1 variant called D90A, and people with that condition might live for 10 or 20 years. So again, it can be important what your family background is. Maybe you live in New York, but you’re actually a first generation immigrant from Sweden. It’s really important that we have your family background. It’s really important that we know your ancestry so we can help interpret what those findings might be.

Daniel Levine: It’s interesting to me that people are on very different minds around submitting themselves to this type of a genetic test. Walk us through the thinking of people. Why do some people choose to get the test or choose not to get the test?

Paul Wicks: Yeah, that’s a great question. And there have been some qualitative research studies. There have been some interviews both with people who’ve been through it as well as people who decided not to get testing, as well as the professionals who deal with this every day who are genetic counselors or clinical geneticists, as well as the neurologists that specialize in ALS. So what would be some reasons to do it? Okay, one reason would be if you’ve been diagnosed with ALS in general, it comes out of the blue and blindsides you and absolutely changes the rest of your life. If you can find a genetic course for it, then you at least have an explanation, right? It’s no longer just a roll of the dice. Now you actually can say, ah, well, I inherited this condition from my mom or my dad, and now we know what this is. We know we have more information that we can use. Another element is to take part in research, whether that’s in a clinical trial, to try and find an experimental treatment or to volunteer to be followed for natural history or to donate blood or have brain scans, or some people even choose to donate their body to science for medical research—looking at things like brain tissue and that sort of stuff. So, there can be a strong feeling of altruism because anything that a patient is benefiting from today in terms of therapy or treatment is only possible because of the sacrifices made in research of other generations of patients prior to that. So that’s a really strong driver in this community. Another reason is the implications for their family members. I mentioned to you earlier, generally speaking, people that have ALS are their late middle age around fifties, sixties. Typically, their children are grown, typically their children may be in their twenties or their thirties, but the implication of the patient having a genetic form of the disease could have an implication for their children and could then mean that those children need to think and be informed about their decisions on effectively having the patient’s grandchildren, if you like. So again, that’s a really key issue, and that’s why there can be some quite complex family dynamics. And then the most recent one is to access this treatment. So, if you knew that you had SOD1, you can get onto this SOD1 treatment that’s been approved, and it’s been approved by the FDA, there’s good clinical evidence that it can potentially slow the condition down quite substantially. And then in the queue behind that drug, there are experimental treatments for other genetic variants that are showing some really promising results. And right now, I think that’s the best hope that a lot of people can offer. So that’s in the ‘why you might get tested’ camp. Let’s talk a bit about the ‘why you might not get tested’ camp. It may be that you already know your family history and you know that SOD1 is not a part of it, in which case, maybe that treatment option is not going to be available to you if a clinical trial were available. You might not live somewhere near a clinical trial site if you live in a rural area. If you don’t happen to live near a major center like Boston or San Francisco or something like that, it’s quite likely that it might be really burdensome to go to a clinical trial, maybe too burdensome to actually take part. It can cause a lot of anxiety just to be straightforward with you. The fear is that there’s this sword of Damocles hanging over you and all your family, and that actually some people just find that this is not something they feel they can cope with in the midst of also getting this terminal and severe diagnosis. And I think that’s perfectly appropriate for some people, to be able to manage their own mental wellbeing and say, well, I’m going to manage my time that I have with this condition and I’m going to treat it in my own particular way. I don’t want to be more distressed than I need to be. So I think that’s perfectly reasonable. Another reason could be the fear of discrimination. And there’s a couple of areas here. One is it just maybe stigmatizing, so people might think, oh, you’ve passed this on to your kids, or if you had a family history of ALS, maybe you shouldn’t have started a family in the first place. I think people can be afraid they’re going to be judged. The other aspects are more, should we say logistical or legal? One fear might be insurance discrimination. Prior to the Affordable Care Act in the United States, there was, as you probably remember, a higher risk of being excluded from medical insurance, health insurance because of pre-existing conditions. Now, changes in the ACA have meant that’s less of an issue. An act was passed, I think, in George W. Bush’s administration called the Genetic Insurance Non-Discrimination Act, or GINA. And that does protect most employees from discrimination on the basis of genetic tests. However, there are two types of employees that are not covered. One is federal employees. So, if you are an employee of the federal government that actually genetic information could potentially be used against you in employment matters. And then the other group are employees of a company with less than 15 employees—so a small business effectively, and many, many Americans are employed by small businesses. GINA also only applies to health insurance. It doesn’t necessarily apply in the same way to other types of insurances that can exist. There are more stringent protections in the United Kingdom. So really only Huntington’s disease is a test that has insurance implications, but this varies region to region. And potentially, let’s say for the sake of argument, you’re a fighter pilot and you work for the US Air Force, a genetic test could have implications for your career. So these are the types of issues why people might not to. And then the last category, just to say is there’s often an awareness within a family that ALS may be genetic, and particularly if it has this frontotemporal dementia component as well, people will have noticed that multiple members of the family have had a neurological disease, and there can be a lack of agreement within a family about what one should do. So if it’s going to be a cause of major stress, of major drama, or if it’s going to cause Thanksgiving to be really difficult or potentially worst case scenario, lead to estrangement of family members. Again, sometimes people prefer to keep Pandora’s box closed. And like I say, we approach this from a position of total non-judgment. This is people’s individual decisions to make.

Daniel Levine: Individuals may have the benefit of finding a community, getting support, getting early intervention, or participating in a clinical trial, but taken as a whole, what do you think this kind of broad testing might do to advance an understanding of ALS and advanced treatments?

Paul Wicks: Yeah, so my hope and the whole reason why I’ve committed to studying ALS for my career, for my life, is I do think that we are going to find the little pieces of the puzzle that unravel this thing. We have seen great leaps in Parkinson’s disease, in multiple sclerosis, in cystic fibrosis, in Duchenne’s muscular dystrophy, in other conditions where once we understand the mechanism of the disease, whatever disease it is we’re talking about, what we pretty quickly realized is that what we had called breast cancer or what we had called hepatitis was actually probably a bunch of different conditions all starting from a different place or going down a different pathway and then just ending up looking the same. But once we got better at categorizing them, at putting them into the correct buckets and saying, well, this is how we’re going to treat bucket A, this is how we’re going to treat bucket B, then we started getting much better results. And this is the whole concept of precision medicine. So I think my hope for this program is that we accelerate precision medicine. That’s very much the mission of Sano Genetics and that the key aspects of this are education to offer up equitable and inclusive access to counseling and to testing, so that on the whole, we are building our army of genetic ALS warriors who are willing to share their data, who are willing to take part in trials, who are willing to advocate, who are willing to fight on legislation issues. We work very closely with a nonprofit called End the Legacy. And they, for example, are looking at fighting this genetic insurance discrimination issue on a state by state basis. And they are the most clued up, most well informed, most passionate people you’ll ever meet. And every time we help identify a family and we help support them, we help connect them, we’re growing that base. We’re really growing that strength in the community. So yeah, I think this may still be a longer fight than any of us want to admit. It may be a marathon, not a sprint, but I think the more we can strengthen that community, the better.

Daniel Levine: Paul Wicks, vice president of neuroscience for Sano Genetics. Paul, thanks so much for your time today.

Paul Wicks: Thanks for having me. Great to talk to you.

This transcript has been lightly edited for clarity and readability.

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