Episode 336

Using Rare Disease Research to Unlock Common Diseases - Matt Wilsey, CEO of Grace Science

12-06-2022

Grace Wilsey was born with a deadly genetic mutation so rare that at the time of her birth, it had never been identified in another person. The disorder, NGLY1 deficiency, causes a wide range of physical and cognitive problems such as muscle weakness, speech deficiencies and seizures. “The NGLY1 gene is in every cell in the body. It's almost like a firefighter that's on call, ready to go when there's a problem. Without it, the cell just kind of overwhelms itself with stress and starts to die,” explains Matt Wilsey, Grace’s father, who joins us on this episode of Raise the Line to talk about the daunting journey he and his family have been on since Grace was born in 2009. That journey involves starting a foundation and biotech company that’s fueling research on NGLY1 deficiency which could have an impact on more common diseases such as cancer, diabetes and Parkinson's. The researchers the Grace Science Foundation supports include several Nobel laureates whose work is providing reason for optimism. In fact, Matt says they hope to start a clinical trial in early 2023 to study a gene therapy that has shown promise in animal testing. Listen to this fascinating conversation with host Shiv Gaglani to learn about the race with time to unlock the secrets to a gene that is fundamental to human life. Mentioned in this episode: https://gracescience.org/

Transcript

Shiv Gaglani: Hi, I'm Shiv Gaglani. Grace Wilsey was born with a genetic disorder so rare that at a time of her birth, it had never been identified in a single individual. NGLY1 Deficiency involves a single mutated gene, but it causes a wide range of physical and cognitive problems including muscle weakness, speech deficiencies and seizures. Grace's father Matt is with us today to share the journey his family has been on since her birth in 2009, which includes starting a foundation and a biotech company that are fueling research into NGLY1 Deficiency that could have an impact on more common diseases such as cancer and Parkinson's. The researchers involved include Nobel laureates, Jennifer Doudna, Shinya Yamanaka, Brian Kobilka, and Carolyn Bertozzi. Before we get started, I'd like to thank former Raise the Line podcast guest, Chelsea Clinton, who speaks so highly of Matt and his family and Matt it's a pleasure to have you on.

 

Matt Wilsey: Thank you so much for having me. It's a real pleasure to join you.

 

Shiv Gaglani: Awesome. So, we’d like to first start with getting some highlights of your personal and professional journey before becoming a parent.

 

Matt Wilsey: Well, I joke that I'm a jack of many trades and a master of none. I wore many hats really, before I got into biotech. I started actually in government and public service. Since the earliest moments of my life, I remember just wanting to get into public service and to work on something that was really larger than myself, to help as many people as I possibly could. So, I trained as an undergrad to get into government and worked on a national presidential campaign, worked in the White House and worked in the Pentagon. I joke that I wanted to see how the biggest, most bureaucratic organizations work so that I could then apply the lessons to the startup world and what not to do, maybe. 

 

I went back to Silicon Valley after those tours were done, and helped start a couple of different tech companies in Silicon Valley and I really loved it. I felt, though, if I wanted to be a successful CEO and leader someday that I needed to go back to business school. So, I went back and got my accounting training, macroeconomic training, HR training, and I thought, you know, I'll try my hand at private equity. Business school is a good time to pivot. I went to New York and did private equity at the worst possible time, probably, in 2008 as the world was on fire and I quickly realized I wasn't very good at it. I prefer to be an operator. I like to build things and be involved from day one, sort of building and nurturing a team. Came back to Silicon Valley and started two more tech companies, and around that time is when Grace arrived. That, I would say, kind of derailed all career plans and trajectories.

 

Shiv Gaglani: I can imagine. I mean, just being a parent, and then obviously, with Grace's diagnosis. So, let's go into NGLY1 Deficiency. Our audience members are healthcare professionals and students, but part of our focus on rare diseases is because they often don't even learn about these deficiencies until they meet a patient and oftentimes, that patient may take years to get a diagnosis, as you well know. Can you tell us a bit about NGLY1 Deficiency, what causes it, why does it cause so many systemic issues, and then we're gonna go into Grace's personal story.

 

Matt Wilsey: Yes. So, it's an autosomal recessive disorder. Most of the audience will know that she then had to inherit two bad copies of the gene: one from me and one from Kristin. Really just kind of unfortunate luck. Then, we had a three-year sort of diagnostic odyssey because there wasn't a lot known about the disease. At the time, whole genome sequencing, even whole exome sequencing, wasn't largely available and so this disease, in particular, was a little bit hard to pin down. It was misdiagnosed as mitochondrial disease, or cerebral palsy -- these catch-all buckets that the medical community kind of wants to attach a label to -- and in a lot of ways it's beneficial because you get services through that. 

 

NGLY1 is really one of the most highly conserved genes known to science. It's fundamental to life. You can find it in just about everything. What it's really doing in humans -- and it's ubiquitous, so it's in every cell in the body -- it is responsible for the proteasome bounce-back mechanism. As the cell is under stress --oxidative stress or other kinds of stress -- you need the proteasome to step in and help the cell recover. Basically, NGLY1 is there to help that process. It's almost like a firefighter that's on call, just sitting in the fire engine ready to go when there's a problem. Without that there, the cell just kind of overwhelms itself with stress and starts to die. The primary place where it's most affected is the central nervous system, the CNS. We also see other issues in the liver, in the eyes and the peripheral nervous system as well, but the CNS is really the primary hub that we're trying to address and that's really where our first drug is going to go to.

 

Shiv Gaglani: That's amazing. Well, thanks for that explanation. So, tell us about Grace and about the diagnostic odyssey. How is Grace doing and how is it showing up?

 

Matt Wilsey: I would say overall, that she's, well...she's stable. I say that with a bit of trepidation because we have lost a number of patients over the last two years. Our global community is roughly a hundred patients that have been identified and we're probably at about eighty to eighty-five that are diagnosed and living at this point. We've lost nine in the last two years either to COVID, long-term COVID, or, I often think of kind of a broken heart, because these patients are largely nonverbal and they're very social and so without that element of being able to interact with teachers or therapists or friends at school, there's really not that same fight to keep living. 

 

But for Grace, overall, I say she's stable. She's very happy. She's very social. She's back at school, thankfully, with the vaccines. Where the disease really manifests itself for her every day-- she's fully dependent on care -- so toileting, bathing, dressing, feeding. She has a G tube. She has alacrima, so dry eyes, because of the loss of NGLY1 so we have to put in drops and ointment constantly. Honestly, if she was born maybe fifty years ago or a hundred years ago, she probably wouldn't have survived the birth. 

 

So, now as we se these patients get older, certain things are continuing to break down or fall apart much faster than they would in a typically developing child, or one of us as we age. When we would go see clinicians, my wife Kristen would explain it like Grace almost has baby Parkinson's. You try and attach a label to it to kind of frame it for them. Those kinds of clues, I think, are really important for clinicians that are watching.

 

Shiv Gaglani: Yeah, absolutely. That analogy of baby Parkinson's will definitely come back because certainly the work that you and Grace Science are doing could have implications to that far more well-known and common condition. So, you get this diagnosis. Obviously, things are confusing and going wrong with Grace, with the three-year diagnostic odyssey, and a lot of parents or loved ones of these patients who have these rare conditions turn that anxiety, that fear, that heartbreak into something positive. And you turn it into the Grace Foundation and Grace Science. We've heard that from people like Scott and Heather Fullmer, who we had on the podcast who founded the EB Research Foundation. You may know them or John Crowley, who is pretty well known, or David Fajgenbaum, who Chelsea Clinton is backing. Tell us about your story. How long was it until starting Grace Foundation and Grace Science, and what's the difference between the two?

 

Matt Wilsey: Yes. I remember it was an emergency C-section. Kristen was full term carrying Grace and I've never seen the red panic button hit faster in my life than that. I mean, the doctors and nurses were running all over the place, basically taking Kristen's clothes off in the hallway as they were rushing her down. I was just given a chair because I couldn't get my scrubs on to go in the operating room. So, I just sat outside, and I just honestly prayed to God, and I just said, "Just get them both through this, and I will do whatever it takes to develop a cure." 

 

So, I felt like that was my obligation to keep going forward. Initially we funded just through our family. We would write checks to Stanford or to Baylor in Houston. It might be for one or two principal investigators and we just said we're going to fund you to do X or Y and some other family and friends said we'd like to support that and they would write checks to those same centers that we had sort of vetted. But what became clear is that we could raise a lot more money if we took on the responsibility of truly vetting and managing these organizations day in and day out...making sure that they were staying on track, holding them accountable, almost more of a business than a foundation or just outright donations. 

 

So, we started the Grace Science foundation and so far it’s deployed about ten million dollars, which obviously is not much for developing a cure, but it's a lot when your disease is starting at zero dollars. We wanted to build the Manhattan Project, essentially what we've seen in COVID, and that mobilization is what we were doing years ahead of time for NGLY1 Deficiency. It was like, get the best and the brightest in the world working on this disease and see what happens. I knew that we just had to be patient and wait for that one breakthrough and that really came through Carolyn Bertozzi, who was one of our grantees. She sort of flipped the script, and we said, "Okay, this is our a-ha moment. Now we have to start a company because that's really what it’s going to take to make these discoveries and translate them into humans."

 

Shiv Gaglani: That's fascinating, and again, turning that fear and heartbreak into something so positive. Ten million from zero is incredible, especially when it comes to something that right now we've only had about a hundred patients with it. But again, the underlying science is fascinating. So, can you tell us about the kind of the research with a prestigious group of collaborators you have? How's it going? Are there promising developments, both for curing it, but also just treating the symptoms?

 

Matt Wilsey: Yeah, there's a lot of promise. We've tried to get as many lines in the water as possible. This actually was one of the early lessons from John Crowley, who has been a mentor, which is the first therapy probably isn't going to be the end-all-be-all. We're going to probably layer on top other therapies, especially as the patients age and new things evolve, you have to attack with those phenotypes. We really believe that the number one way that we can help these individuals is by delivering gene therapy directly to the brain. Over the last few years we've developed an AAV9 gene therapy that we've done a tremendous amount of animal testing on and we're actually submitting our IND to the FDA tomorrow. We're hoping to be in the clinic early next year in 2023 and it can't come fast enough. We're trying to push as hard as possible. But beyond that, we have some other exciting therapies that are kind of backing up in the pipeline that I think will have some good potential for these patients and beyond.

 

Shiv Gaglani: Tell us about some of that. Because that's one thing we heard in our conversation with the Fullmers on Epidermolysis bullosa. They're very hopeful that in the next five years, there'll be a cure for it. But similar to what you've described, it's multiple lines in the water, because you need to do things in parallel. You don't know which ones will work, and hopefully we can find one of these things will work. So, what are some of the other things that kind of excite you that are coming down the pipeline?

 

Matt Wilsey: For NGLY1 Deficiencies specifically, there are some small molecule potentiators and small molecule inhibitors that are really enticing. The thing that obviously keeps me up at night is what are the off-target effects? What are you helping, but on the same side, what are you potentially hurting because we fundamentally believe in the 'do no harm' mantra? I think a lot of rare disease advocates such as myself might get mistaken for moving too fast and the fact is, we have the greatest incentive to make sure that the drug is max safety. It's very different than another type of organization that is not living with the patient. But the thing that really kind of blew my mind is Carolyn Bertozzi's work which really opened this whole new world for us. I joked that it's like we were stepping through the looking glass. 

 

We just didn't even know this world existed. Initially, we thought NGLY1 one was just sort of a boring housekeeping gene and she was the first to say, "No, this is actually more fundamental. This is really responsible for handling cell stress." And that's where we knew that it was really a gateway, almost a Rosetta Stone, probably, for multiple oncologies. We are working now on a small molecule inhibitor for cancer. It's still not going to be in the clinic next year, but we hope in the next couple of years that it will be and it gives us a lot of hope, not just for the patients that started this -- that is really our North Star -- but how does this impact potentially millions of families. That gives us a lot of incentive and motivation to keep going on the hard days. You just can't give up. If we don't pursue this, no one else is going to and so we really want to be that spark and then look for partners that can help us take it beyond our expertise.

 

Shiv Gaglani: Totally. Part of the benefit of investing in these rare disease research studies -- apart from obviously, the number one thing being Grace and families and patients affected with NGLY1 -- is the potential impact that the research itself can have on other more common conditions. The examples we often cite are statin development from research on familial hypercholesterolemia, or pertuzumab, which was developed for Castleman's Disease being very useful for severe COVID-19 cases. Tell us a bit about the science. I mentioned cancer, Parkinson's...how come the research that your team is doing, or funding at least, can impact such disparate types of diseases or seemingly disparate diseases?

 

Matt Wilsey: I'm dyslexic, so I think oftentimes in terms of analogies. I think that NGLY1 is almost this airplane engine. It's like controlling the 747 engines, and we can throttle it up for more power -- and in that case, we would want it for neurodegeneration -- and we want to actually throttle it down, or maybe off completely, in the case of cancer. It goes back to that cell homeostasis. Sometimes the cell needs more and sometimes the cell needs less, or very little, and maybe that's for just a short period of time. So, that's really what we're trying to dedicate a big part of our team now is unlocking this. 

 

It's funny...Grace is thirteen. If, when she was twelve, I went to a hundred investors or donors, and I said, "Rare diseases unlock common diseases that we as a society are probably spending billions of dollars on every year," I think I might have gotten like one out of a hundred to agree with me. If I do that same conversation now, it's like ninety-nine, out of a hundred. It is shocking how fast it has changed.  It's like the story you hear about baby aspirin and how quickly that was adopted by cardiologists and general practitioners -- it took something ridiculous, like seventeen years. In this case, the idea that a rare disease unlocks a common disease happened lightning fast. We're not even scratching the surface of the potential, not just within NGLY1 Deficiency, but every rare disease. And there should be, in theory, twenty thousand rare diseases, right? If you think about every gene could be a rare disease, we're not even halfway there in terms of identifying these diseases, and then understanding what's the hub and spoke from those hubs. So, I'm super excited about it, as you can tell.

 

Shiv Gaglani: That is really exciting and you're actually the first guest we've had on who has actually made that full connection, because we often cite seven thousand rare diseases and some people say ten thousand or twenty thousand genes. There's someone in the world -- we may not have met them, they may have been born in rural Uganda, we just can't reach them yet -- who has a rare disease we've never even heard of. 

 

Our audience at Osmosis used to be just health professions students primarily, as well as patients and family members. Since we joined Elsevier a year ago, we now clearly have a large audience of researchers and one of our hopes -- and what we've been able to do is make this rare disease research more accessible. That includes our CEO, Kumsal, who has been super supportive of the initiatives we've done in rare diseases. What advice do you have for researchers and clinicians about even entering this space and maybe dedicating their careers to helping rare disease patients and family members?

 

Matt Wilsey: The first thing that comes to mind is, one, "thank you." I mean, we all so appreciate what you're doing. It's often a very thankless job. With another NGLY1 dad, I wrote an editorial for Nature, and in that I close by saying, "There are people like me that are dreaming about finding you. We just don't know where you are." So, try and seek out the outliers like Grace. What our experience has been -- especially our experience with American doctors -- is they go above and beyond. They don't just go the extra mile, they go an extra twenty-five miles on top of already a very busy and hectic schedule. And there's so much pressure and we see this at Stanford and other major clinical centers, where it's either focus on the number of patients in the clinic or focus on research. 

 

It's very hard to do both with that pressure. It's kind of like you're just moving A to B, or A to C. It’s very meat and potatoes, so try and sprinkle in a few of these outliers -- or maybe it's just one outlier, like Grace -- that can truly change science and medicine, and it could potentially change your career. It could be something that you are now the world's expert in. It's really amazing how one little case like Grace's has shaped so many different individuals throughout science, and I think it will have profound effects long after she's gone. So, my sort of leaving moment for all the scientists and clinicians and researchers that are watching is find those outliers and try and nurture those relationships, because it's really amazing what can happen.

 

Shiv Gaglani: Totally. That's very much a common theme. One of my guests that I loved having on was Philippe Pakter whose daughter, Lysiane, is five and has Pierre Robin sequence. He said something similar where anything a clinician or researcher does is very mission-oriented and good for humanity as a whole, and there are patients that they see and treat. But oftentimes it's the difference between curing a million people who have a headache versus ten people who have cancer or something much more devastating generally than the headaches, and so you get enormous gratitude from patients and family members. This space also gives you that sense of purpose...being able to put a name, put a face, put a story to what you're doing. And then you have that race against time, which adds that urgency. It isn't like, "Oh, it'll be cured in fifty years," you want to do it now. It's truly motivating and that's something we recommend our listeners take full attention to, as they're deciding how to dedicate their career. Spend a summer, spend a year, spend maybe a career at some point, researching these conditions.

 

Matt Wilsey: Yes, absolutely. Google kind of made this famous where they said 75% to 80% of your day is technically your job and the activities that you're supposed to get done, and then the balance is just pie in the sky. I know there's a lot of different pressures for a clinician or researcher -- especially with tenure and other things, and publishing is the name of the game -- but there still is opportunity, I think, to nurture these even at a very small level. Even if it's 5% of your time, it can really have a huge impact and I think it's very rewarding, personally.

 

Shiv Gaglani: Totally and my hope is foundations as well as centers of excellence will cultivate this because by you bringing together this group of people through the Grace Foundation and funding researchers...now they have the money to dedicate, and you can talk to their tenure board about the work that they're doing. 

 

As you know, Osmosis is a teaching company. We like to fill in knowledge gaps and one question we like to ask our guests is, if you could snap your fingers and teach any group of people anything, what would it be and why?

 

Matt Wilsey: Well, there are a couple of things that come to mind and one of them I would challenge people to think about is a solution for manufacturing. Cell and gene therapy manufacturing is very, very expensive. If we were able to figure out a way to do that faster and cheaper it would accelerate the therapies and cures more than just about anything that's out there right now. These therapies work. It's still early, right? It's not perfect. We can get better vectors that transduce even a higher percentage of cells. We can improve the empty/full ratio within AAV. There's a lot of things, but that would be one of my biggest ones, which is how do we do this faster and cheaper. 

 

The other thing is biomarkers. At the end of the day, biomarkers are so fundamental and you see this debate that's going on with the FDA right now with some of the larger diseases about whether a particular biomarker is actually measuring success or not. Things like the six-minute walk test just don't work for a lot of diseases, especially these rare neuromuscular diseases. But a drug could work, and the biomarker shows it, but the FDA or others might say, you know, that's not good enough. And at the end of the day, what else do we have to offer these patients? We can't just let them go home and die. So somehow, we need to do a better job educating on biomarkers and not only discovering them, but proving them, I think, is really a key one-two punch.

 

Shiv Gaglani: Those are two really good examples that you shared and certainly when I was in med school, we weren't being taught about either of these things much. But every year, it's exponential gains. We had a guest, Brett Kopelan, whose daughter, you may know, also has Epidermolysis bullosa. He's very involved in policies around cell and gene manufacturing. And here at Elsevier, we do a lot of ‘in silico’ biology. That's how David Fajgenbaum and I got in touch to talk about trying to speed up identifying what drugs can be repurposed for which targets based on AI models for where we should look. You know this better than I do, you're in Silicon Valley so you probably keep in touch with all those developments.

 

Matt Wilsey: Exactly. I mean, again, I think we're barely scratching the surface and that's the hard thing with the war in Ukraine, inflation, COVID...a lot of those efforts really screeched to a halt, or slowed down dramatically, and so getting those back and operational again is super important. A lot of investors sort of thought rare diseases were cool and sexy and they've also stopped funding there because they've gotten into to hunker down mode. But kind of going back to my tech entrepreneur days, this is the absolute best time to start something. The troughs are where you really see great companies started. So, if you have a great idea, get out there start it.

 

Shiv Gaglani: Totally, yeah, exactly. That's great advice. So, I know we're at a time. I did want to leave you with one more question. Is there anything else that you want to get across to our audience that I haven't asked you about yet?

 

Matt Wilsey: Gosh, not that I can think of. I would say that it really does take a village, honestly. Not just on the clinical and the research side, but it's brainstorming with John Crowley or David or the EB team or any of these guys. It is so fundamental to our success. There's no way we would be where we are right now without those people really supporting us, and I hope that we do the same thing for them. The days are tough. It's hard to see and get connected with these families, and then the patients die. But just kind of keep pushing that envelope, is just really, really so important in supporting each other.

 

Shiv Gaglani: Absolutely. That's great advice to end on and the importance of having a strong community. One thing I've learned having interviewed wonderful people like yourself over the past several months, especially, is how well connected and supportive they are of each other even though the conditions are very different, and maybe the causes are different. So, Matt, I really appreciate you taking the time to be with us and more importantly, for the work that you do not only for Grace, but for any family who has a rare disease and for bringing together these researchers and clinicians in the way you have.

 

Matt Wilsey: Well, thank you so much for having me. It's great meeting up and I hope to do it in person next time.

 

Shiv Gaglani: That'd be wonderful. Well, thank you again and to our audience, thank you for listening. Remember to do your part to raise the line and strengthen the healthcare system. We're all in this together. Take care.