S4, E01: Project ALS: Fueled by Love

Valerie Estess:
The love of sisters is a big thing. It kicked off a movement. I think the legacy for Project ALS is not just a blind hope, it's hope based on aggressive, rational research. It's the only way we're going to get there, and we're committed to that to the end.

Todd Poley:
Over the last two decades, there's been a steady rate of approvals of new therapies by the FDA. We've seen expedited green lights for biologics and anti-cancer drugs. However, the market has not seen as many advancements for neurological disorders like amyotrophic lateral sclerosis, or more commonly known as ALS.

On June 23rd, 2022, the FDA announced a new five-year action plan to develop new ALS therapies, including the establishment of a private-public task force to advance neurodegenerative disease research. What momentum might we gain by bringing researchers to the same table? One longstanding ALS non-profit, and our guest today, demonstrates the progress that can be made when scientists join forces in the name of ALS research.

I'm Todd Poley, a marketing leader at Charles River, and I'll be joining you for season four of Vital Science. In this episode, we talk with Valerie Estess about Project ALS, the nonprofit she and her sisters founded in 1998. We'll discuss the patients affected by this debilitating disease, the gene therapies being developed for rare mutations of ALS, and why the future looks brighter than ever for ALS drug development.

Gina Mullane:
Welcome to Vital Science, Valerie. We are honored to have you. Tell us about yourself and your role at Project ALS?

Valerie Estess:
It's great to be here with you today, Gina. My role with Project ALS is as a co-founder. Project ALS started as a non-profit 501(c)(3) back in 1998. When my sister, Jennifer, who was 35 at the time, was diagnosed seemingly out of nowhere with ALS. And so my sisters, Meredith, Jennifer, and I, we were actually about to go into business together. This was completely unexpected, an ALS diagnosis, but we got to work. We tried to hook our wagon to other nonprofits that were making an effort to understand or treat ALS as a disease. But what we found is that there were some really well meaning and great nonprofits, but they were mostly devoted to patient services. In other words, they helped patients to adapt to the disease once they were diagnosed. And my sisters and I were in our thirties, and we just kind of had something else in mind. We wanted to try to identify scientists, researchers, clinicians who were making an effort, a concerted effort, really, to understand a very complicated brain disease that is ALS. Couldn't really find that, so we started Project ALS in 1998.

Gina Mullane:
It sounds like this really has been a labor of love for you. What are you most proud of at Project ALS?

Valerie Estess:
You know, Gina, I'm most proud of that love, that love is an actual fuel for discovery. The love that my sisters and I had, and that we will always have, has really been at the heart of really some significant scientific discovery. A lot of progress has been made toward our ability to understand ALS, and in relation, other neurodegenerative diseases like Alzheimer's, Parkinson's, and Huntington's. So what really stands out to me, Gina, over the years, and it's now been 20-something years, my math is not great, but that love has driven this effort. And I think that's my takeaway forever.

Gina Mullane:
That's great. That's very heartfelt and special. So Project ALS' mission is to identify and fund research that will lead to the discovery of a new treatment for ALS. And I think the perception of an ALS patient is, the most prominent is Lou Gehrig, or older white males, but that's not always the case. Who are the patients that suffer from ALS?

Valerie Estess:
The people who suffer from ALS range in age from late teens, sometimes even early teens in particular genetic mutation-driven ALS, to older age. I think you hit the nail on the head. I think that ALS has been perceived as an older white man's disease, but in fact, if you really go back to the actual history, Lou Gehrig was only 37 when he was diagnosed. But there are many young women for example, who are diagnosed with ALS, people in the primes of their lives, young men and women from a diversity of backgrounds. So I think a proper census of the disease has not been taken, if ever, not in a while, not in a long, long time. So there are lots of misconceptions about it, but it strikes young and old. Adults of all ages, I would say.

Gina Mullane:
Interesting. And as part of your work, how have you seen the ALS community work to increase awareness about the disease recently?

Valerie Estess:
Well, I think the ALS community is starting to come together as never before, and I would say awareness of the disease as a critical health issue is at an all-time high. I think that one of the things that Project ALS hopes to get across, we're working to do this, and it's a tough message, but that the true hope for ALS is actually in the research. We can advocate for legislation and other things, and that's so, so important, but what we want to do at Project ALS is to communicate to people who've been diagnosed, the people who love them, but to everyone, unless we advance brain disease research aggressively and rationally and now, a lot of people we know and love are going to perish, which is unAmerican, and we can't stand for it. So my excitement is that awareness is at an all-time high, and my wish is that in the next couple of years, we're able to infuse that awareness with this respect for research to go forward faster.

Todd Poley:
ALS research saw a boost in federal funding, due in large part to the advocacy of ALS organizations like Project ALS. ALS advocates helped increase the Department of Defense's ALS research program budget from $10 million in 2019 to $40 million per year in 2021. While this is a notable increase, it does not cover the many pilot Projects that go unfunded by the National Institutes of Health each year.

As the world's first ALS nonprofit organization focused exclusively on research, Project ALS has raised over 110 million to fund ALS research programs at leading academic institutions, including Harvard University, Columbia University, UCSF, and the Salk Institute, which have made significant progress toward a cure for ALS. Let's hear more from Valerie on some of the research that Project ALS has chosen to invest in.

Gina Mullane:
I'm sure several worthwhile research Projects have crossed your desk at Project ALS. I know one of them was related to the mutation in the fused in sarcoma, or FUS gene, which can lead to an ultra-rare form of ALS called FUS-ALS. Can you explain how that happens?

Valerie Estess:
I wish I could explain how it happens, because I think we'd have a much better means to fix it and to cure it, but we are on our way, Gina. We're on our way. It's actually, so FUS-ALS strikes probably a very small number of patients when one considers the universe of people who are affected by ALS, but FUS-ALS is a particularly virulent form of ALS. It usually strikes teenage girls. And one of the reasons we talk about it so much is that Project ALS, along with partners, including a drug company called Ionis and Charles River, people really banded together around a very personal issue regarding FUS and started working together, and actually generated the world's first ASO or gene therapy for FUS-ALS, which was a bit of a miracle.

And so I love to talk about that story, because it shows that when different people come together and work around one goal, that goal can be achieved faster. Now, this is something we learn in kindergarten, but we don't always execute very well in adulthood. But I think in the case of FUS-ALS and our drive to create this world's first medicine for FUS-ALS, called jacifusen, is an exception, and it's just a shining example of what can happen when people work together.

Gina Mullane:
That's an amazing example and an incredible story. So what is it about ALS and neurodegenerative diseases that make this research so important? Is it the criticalness of the timing? Is it the condition that develops? Is it all these things and more? What is that from your perspective?

Valerie Estess:
Yeah, it's a great question. What makes ALS so important, and neurodegenerative diseases related to ALS so important for us to pay attention to is the fact that the brain is the last frontier in human health. Let's think about this. Cancer, heart health, reproductive health, we've made so many breakthroughs over the last hundred years in these areas, and yet brain diseases such as ALS have gone untreated, definitely uncured. And the truth is, Gina, is that as our population ages, more and more of our population will be diagnosed with a neurodegenerative disease. So unless, and until we come to a deeper understanding of how the brain works, let alone what we should do to fix a brain that's not working properly, we're going to see lots of death and destruction. So if that's not a motivation, I don't know what is.

Gina Mullane:
Absolutely, and you've shared a great case study of how impactful scientific collaboration can be. Are there other ways in which Project ALS has transformed the ALS research landscape?

Valerie Estess:
Project ALS, I think when we founded as a nonprofit in 1998, we set out to do things in the way that made the best sense to us as sisters, Jennifer, Meredith, and I. We didn't consider it radical at all. We just thought that if we could go out and recruit the world's best scientists, researchers, clinicians to ALS, and to discuss the problem and to start working out strategies toward understanding what makes a brain healthy, and then what makes an ALS brain go wrong, that that was going to be a good start. But it turns out, over the last couple of decades, we've seen this culture shift, that a lot of people who focus on other diseases of the brain and the body have now come around the table to work on Project ALS focused experiments and develop therapeutic strategies that were just a pipe dream in the late nineties.

Todd Poley:
Project ALS has bolstered the work of some of the brightest minds in neurodegenerative research. This includes Dr. Neil Shneider of Columbia University, who worked on the leading-edge FUS-ALS treatment, jacifusen. As Valerie mentioned, the FUS gene has serious implications for ALS, but it is also associated with rare and aggressive forms of frontotemporal dementia, or FTD. In a study of knock-in mouse lines that express an equivalent FUS protein, Dr. Shneider and his colleagues show that jacifusen silences FUS and delays motor neuron degeneration. These findings, which also included the first in human protocol with jacifusen, discussed later in this episode, were published in Nature Medicine and provide evidence that supports FUS silencing as a therapeutic strategy and FUS-dependent, ALS and FTD. Let's hear more from Gina and Valerie on how gene therapies like jacifusen can play a role in the future of ALS treatment.

Gina Mullane:
It seems that new model and gene targeting approaches are showing promise for ALS therapies. Can you tell us about Project ALS' involvement in the groundbreaking collaborative effort to develop a new tool to study ALS mechanisms and therapies?

Valerie Estess:
Project ALS, our biggest contribution to the field has been basic research into the brain. So for our first two decades, we were involved in the identification of almost 50 new genes that contribute to both inherited and sporadic forms of ALS. We were instrumental in identifying the cellular and molecular pathways of the disease so that we could figure out how to target therapies, and then we started to drive the first models of the human disease. Back when we started, there was one mouse model of ALS, but it wasn't necessarily predictive of outcomes in people, which makes sense. And by the way, that mouse model is incredibly helpful for so many reasons, but when it had to do with drugs that might work in people, they didn't always work in mice. So what Project ALS has committed to is the generation of better discovery platforms, better models of the ALS disease, including human ALS.

Gina Mullane:
That's incredible, and it seems really clear that this is an important step forward toward developing therapeutics for people living with ALS. How does this show promise for some of the early and preventative care in those who might develop FUS-ALS in the future?

Valerie Estess:
So the FUS story is really remarkable, and I think it informs all of our efforts across developing therapeutics for all forms of ALS. The FUS story started with a mother and her children. This mother lost one of her identical twin daughters to FUS-ALS, and it was thought that her surviving daughter would escape that bullet. Unfortunately, her daughter Jaci was diagnosed with FUS-ALS in 2018. At that point, Project ALS had already been in touch with Lori Hermstad and her family, and when Jaci was diagnosed in 2018, because Jaci had already provided patient samples to a program called the Families Program that is funded by Project ALS, we were able to generate some very specific models of Jaci's ALS. We were able to work with Charles River and Ionis Pharmaceuticals and leading ALS geneticists to develop a gene therapy for Jaci, initially.

But this FUS ASO, you have to understand, Gina, it's taken off now. It did not come in time to save Jaci's life, because by the time she was treated with jacifusen, as we came to call it and as it will forever be known, jacifusen, although Jaci had 12 infusions of this novel gene therapy, or ASO, she passed away from ALS. And one of the ideas there is that, unfortunately, she tried it when she was too late into her disease, but based on her contribution and sacrifice and the love of the Hermstad family, and Project ALS and Charles River and Ionis and world-renowned geneticists, other people now with FUS-ALS are beginning to benefit. So jacifusen is now in a phase-three trial all over the world for patients with FUS-ALS, and it is hoped that we can reach people earlier in disease, even pre-symptomatically, so that they can begin to benefit from all of the sacrifice and bravery that Jaci showed us in 2018.

Todd Poley:
Although jacifusen aims to treat a single rare form of ALS, its development provides a model by which other forms of ALS may be treated. By funding the ALS Families Project at Columbia University, Project ALS is able to follow families that have other genetic mutations of ALS in the hope of developing ASOs or gene therapies for additional ALS genes. The project also aims to further investigate sporadic ALS, which is the most common form of ALS in the US. These cases occur randomly without any known cause or family history. By following the individual cases of ALS patients and their families, Project ALS hopes to develop gene therapies that can be tailored to everything from inherited ALS to sporadic forms. Let's hear more from Valerie on why jacifusen has become a beacon of hope for the organization.

Valerie Estess:
I feel like gene therapy, ASOs, viral-mediated delivery of gene therapy is a whole new day in the treatment of a range of diseases, especially brain diseases, especially in neurodegenerative diseases. Project ALS is thrilled to have put the FUS ASO called jacifusen on the map, because we knew, and Jaci herself, Jaci Hermstad knew that this was the beginning of something big, and she gave herself to that fight.

Our partners, Project ALS, Charles River, Ionis, Dr. Bob Brown at the University of Massachusetts, and especially Dr. Neil Shneider at Columbia University, and I must also call out Lauren Black, who is a career scientist at Charles River, we huddled, we huddled hard and we pushed it over the finish line. And thanks to that team effort, led by Jaci Hermstad, I think a lot of boats will rise. I think that there will be new therapies, not only for different forms of ALS, but other brain diseases.

Gina Mullane:
It sounds like an incredible partnership and collaboration came together for this drug development. How did this all start? How did the connections get made in the early days for this incredible partnership?

Valerie Estess:
I would say Project ALS was founded on this type of approach, to gather experts that would be most helpful in answering the questions under the heading of ALS and then asking these people to work on a game plan that they could execute, we could fund at Project ALS, and that would have a readout at the end of the day. So academic science, in our view, was no exception. If we were going to fund the work, we were hoping to get, we were going to get readouts. And you know, science is science. The data isn't always good. It's kind of like baseball. It's like you hit one ball out of 10... Well, maybe I'm getting that wrong. Two out of 10, I guess, and three out of 10 is ridiculously successful for a baseball player, but science is comparable in that sense. But I think that that kind of idea drove the jacifusen effort, because when Jaci got sick, Project ALS knew that the only way to deliver hope to her was by hand picking the experts, the companies, people who gave a darn, to get them all together and push them all forward. So it sounds kind of corny, but it's really the way Project ALS has been doing things since it's founding. We feel that the best minds, and people who work the hardest, who are working together, are going to get us where we need to go, and that's toward the first effective treatments for ALS. So the jacifusen fight wasn't the first time we had worked together, or forced work together, but it certainly was an effective example, and one that we hope will set the stage for breakthrough discoveries for so many.

Gina Mullane:
There is so much research going on now that doesn't always have the same outcome you saw with jacifusen. What, in your opinion, made this particular effort successful, or led to the development of an effective outcome in jacifusen?

Valerie Estess:
I'm going to go back to it again, Gina, and I sound like a Hallmark card, but Project ALS ends up kind of falling in love with people we work with, and Jaci Hermstad and her family were a real interest of ours. In fact, we became interested in the Hermstad's FUS-ALS story when my sister Meredith found Lori Hermstad, the mom, on Facebook chatting with other mothers who had lost their 16, 17-year-old daughters to this FUS-ALS, as I said, one of the more virulent forms of the disease. And the mothers had formed a support group, and this was back in 2017-ish.

And in May of 2018, Project ALS brought the mothers to New York, because we wanted to meet them. Not just that, we also wanted them to meet with a researcher, Neil Shneider at Columbia, who had been studying that exact gene, the FUS gene. And we thought it could be really kind of a healing experience for moms who had lost their children to FUS-ALS to learn about the FUS gene and its role in ALS and the progress that had been made, and it was a really powerful visit to New York from mothers all over the country. And that's really how we met Lori and Jaci Hermstad, and actually, Jaci developed the symptoms of FUS-ALS only months later. Project ALS kickstarted the jacifusen program with Charles River, Ionis, Lauren Black, Neil Shneider, Bob Brown, months after that initial visit. Within the course of a year, Jaci was being treated with the world's first ASO for FUS-ALS. When I think back on it, it was just a miraculous time, and it was driven by our desire to do something for a young woman we really loved.

Gina Mullane:
As Jaci sadly passed away in May 2020, it's clear her spirit encouraged, lives on through all of the advocates and through jacifusen itself. You mentioned the efforts to expand the use of jacifusen to other patients. Is there anything more you'd like to add about that, how the therapeutic is helping others?

Valerie Estess:
So there really are people of all ages from all around the world who are starting to try jacifusen, and as I said before, what's interesting is that some of these people will be receiving jacifusen a little earlier in their disease process, and some people will even be pre-symptomatic. So it'll be very, very interesting in a few months to see the outcomes. We will see them, and I think that we'll be pleasantly surprised, because this was a program founded not only on love, but on hardcore science and ingenuity, so I think that the momentum is with us.

Gina Mullane:
That's really wonderful. You more than anyone knows that the rare disease development journey, from those early days of concept all the way through reaching a patient, it's not always straightforward. In what ways can collaborating with a contract research organization help programs such as yours?

Valerie Estess:
Collaborating with contract research organizations, CROs, it sounds so cold, because now I know the truth. When you connect with the right one, with the CRO that's right for you, you know it. And again, I'm not soft soaping this because this is a Charles River broadcast, but a CRO is made up of individuals, of people with hearts and brains, like really good brains, and all I can say is we're grateful to some of the people we met at Charles River early on, in the first days of jacifusen, because they came on board no questions asked.

Dr. Lauren Black really pulled it together, not only for Charles River and representing Charles River, but she had already had rare disease experience with the Food and Drug Administration, representing some drugs for patients who were affected with other rare diseases. So she said, "I've done it before. Let's do it here. Let's do it with jacifusen." And it's not a CRO so much, our partnership with the CRO, it's our partnership with the people of Charles River that has made the difference. I mean, I just feel like we're building something together. And we have another drug that's now in phase-one, a clinical trial for ALS, called Prosetin, and once again, Charles River has just become an invaluable partner in this process. So it's not just a question of, oh, I guess I'll go with Charles River and put a check in the mail. It can't be that. In order to beat these diseases, it cannot be that. It's got to go deeper, and Charles River is an example of a company that gets it.

Gina Mullane:
Thanks for that. I really appreciate hearing that, Valerie. I'm sitting here thinking it's been three years since that first dosage of jacifusen, and so much has happened in such a short time. If you step back, what does the future hold? What do you see for ALS research and drug discovery?

Valerie Estess:
It is, it's, remarkably, just past the third anniversary of Jaci Hermstad receiving that historic first dose of the FUS ASO known as jacifusen. So much has happened since. More people are getting to try it. Scientists at Ionis and in academic laboratories are learning more about why these ASOs may be effective, and how to change them and improve them. It's more of a question of what hasn't happened. I think jacifusen really flung open the door to discovery when it comes to gene therapies, primarily ASOs for ALS and neurodegenerative diseases.

Gina Mullane:
And with Project ALS, how do you see the organization paving the way for even more exciting innovation?

Valerie Estess:
Project ALS is just getting going, Gina. So what we've done is we've taken the basic research that has spilled out over the last two decades, and we're now concentrating a lot of it in something called the Project ALS Therapeutics Core. It's based at Columbia University, but it actually involves collaborations with companies, with other academic laboratories and biotechs, and the purpose of the Project ALS Core, we affectionately call it, the Core, is to convert basic knowledge into therapeutic strategies. So ASOs is one of the areas of great interest at the Project ALS Core. We're also working with medicinal chemists to drive forward small molecule compounds that haven't been able to get into the brains of people with ALS or other brain diseases, and that's kind of paying a lot of dividends right now, very exciting days. In addition to which, and I'll go back to what we were talking about at the beginning, the Core at Project ALS is completely committed to developing better models of human ALS, because if you have better models, you can find better drugs. It's not a complicated concept.

I mean, unlike in cancer, when a doctor can go in and biopsy the cancer and learn how we might approach the treatment of that cancer, you can't do that with a brain disease. You can't go in and take a chunk of someone's spinal cord or brain, so you have to create model systems that are predictive and helpful and relevant so that we can find drugs for untreatable neurodegenerative diseases. That's the job at the Core, and we're just getting started.

Gina Mullane:
Well, Project ALS was started with a very personal motivation, and I know that continues to be the case. What do you hope the legacy for the organization will be?

Valerie Estess:
The legacy for Project ALS is that we all are in this together. The love of sisters is a big thing. It kicked off a movement that I think is growing in momentum, and there's lots of progress to be hopeful about. But again, I think the legacy for Project ALS is not just a blind hope. It's hope based on aggressive, rational research. It's the only way we're going to get there, and we're committed to that to the end.

Gina Mullane:
And how can our listeners of the Vital Science podcast help you get there?

Valerie Estess:
Well, gosh, I mean, come visit us at ProjectALS.org. We're involved in generating some new drugs for ALS, and we could use all your help. As I said, we're all in this together, and Gina, I swear, unless we do something as a country, we are going to see these neurodegenerative diseases affecting more and more of the people we love. So it's upon us, not only at Project ALS, but upon all of us to give where we can and to start paying attention to the brain.

Gina Mullane:
Well, Valerie, very informative, really motivational, and really just incredible to hear from you. I admire you and your work and your organization, and really appreciate your time today. Thank you.

Valerie Estess:
Gosh, Gina, it's been such a pleasure talking to you.

Todd Poley:
Valerie Estess is the co-founder and director of research at Project ALS. For more information, please visit ProjectALS.org. We look forward to sharing more leading-edge science with you in our October episode, the second in our rare disease series, when we welcome Rich Horgan, founder of Cure Rare Disease. I'm Todd Poley. Thanks for listening.