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Home U Rising Breakthroughs await: This research lab seeks treatments for rare diseases


Rare diseases often don't get much attention because they're just that — rare. Each one affects fewer than 200,000 people in the U.S., but collectively, they're surprisingly common. And there are no treatments available for the majority of these diseases. In this episode of U Rising, host Julie Kiefer talks with Jill Hawkins, who has two children with a rare disorder, and Clement Chow, an associate professor of human genetics, whose lab is searching for treatments that may benefit Jill’s children and others with rare diseases.

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Julie Kiefer: Rare diseases often don't get much attention because they're just that — rare. Each one affects fewer than 200,000 people in the U.S., but collectively, they're surprisingly common.

There are 10,000 rare disorders that affect 10% of the American population. Even so there are no treatments available for the vast majority of these diseases.

I'm Julie Kiefer, associate director of science communications at University of Utah Health. My guests today are Clement Chow, associate professor of human genetics at the Spencer Fox Eccles School of Medicine, and Jill Hawkins, who has two children with a rare disorder. She and her family are one of several who are working with Clement to search for treatments for their children.

Jill and Clement, welcome to U Rising.

Clement Chow: Thanks for having us.

Jill  Hawkins: Thank you.

Julie Kiefer: Jill, tell us about your children, Charlotte and Cooper, and about the rare condition that they have.

Jill  Hawkins: Sure. Charlotte is a teen. She's spunky and feisty. And Cooper is 13 and he is darling and a little cuddler. Unfortunately, they're both suffering from a rare disease caused by loss of function of a gene called FAM177A1. This is a gene that was really unknown to scientists until quite recently when they discovered this variant in Charlotte and Cooper and were able to determine that this was the disease-causing gene for them.

And so without this gene, Charlotte and Cooper and the handful of other kids we've identified around the world have seizures. They have intellectual disabilities, global developmental delay. They have behavior disturbance. Often autism. They have muscle tone issues and what looks like progressive motor decline and a myriad of complicated medical issues.

Julie Kiefer: So, paint that picture for us. What's daily life like for you and your family?

Jill  Hawkins: Well, we try to make it as joyful and as enriching as we can, but it's really challenging. Charlotte and Cooper both need help with every aspect of daily living. They need help getting dressed. They need help walking. Neither child can walk by themselves anymore. They used to be able to and they both need full support to do that now.

Jill Hawkins has two children with a rare disorder. She and her family are one of several who are working with Clement Chow's lab to search for treatments for their children.

Cooper is completely nonverbal. Charlotte has some words. She's hard to understand. So, things are tough. Their days are full of therapies. Appointments. Yesterday was a particularly tough day. Cooper had more than 30 seizures yesterday. Charlotte, it was her day to get her injectable meds, so that's never fun. And yesterday was a really bad day.

Julie Kiefer: You hanging in there okay?

Jill  Hawkins: Yeah, I mean, we don't have a choice, right? We just have to keep going, but we are going to fight for them and that's what brought me to Clement.

Julie Kiefer: Jill, besides Charlotte and Cooper, how many people have this disease?

Jill  Hawkins: Well, I've personally connected with two other families in the United States that have two affected kids each, one family overseas that have two affected kids, and through researchers we've identified about 20 patients in the world.

Julie Kiefer: So not very many.

Jill  Hawkins: No, we're nano rare. We're going to find more. Our gene is still considered a variant of uncertain significance because there's so little published about it yet, but it'll soon move into the pathogenic category and as more patients are sequenced, we're going to find more patients. But this is an autosomal recessive disorder, so it's probably always going to fall in the ultra-rare category. I would say still very, very valuable to study because we have common pathways with more common diseases.

Julie Kiefer: Right. So, you've been searching for answers for your kids for a long time. Tell us a little bit more about that journey.

Jill  Hawkins: Yeah, so my husband Doug and I had our first child 20 years ago, Nash, and he was healthy and developed normally. And then we had Charlotte shortly after that and she was also healthy at birth and just fell behind developmentally, just wasn't hitting the marks. And she had a lot of therapy and a lot of tests, extensive medical workup really, and a lot of genetic testing for the time, which included ruling out of known disorders like Angelman's, Prader-Willi, Fragile X. Her chromosomes were normal, so they said, “Well, it's probably genetic, but we're not sure what it is. Probably not going to happen again.”

So, a few years later we decided to have a third child. We had Cooper and he just fell behind developmentally. And I just knew in my gut right away that lightning had struck twice and he had to have what Charlotte had.

So that set me on a mission to figure out what this was. And so, it was “probably” genetic became “definitely” genetic. And at this time the genetic testing had evolved a little bit, but they still were both undiagnosed.

We live in Seattle and a team here did whole exome sequencing and didn't find anything. They told me there was whole genome sequencing at the time, but it was cost prohibitive and people weren't very good at interpreting it yet and they asked me to give them five more years, and I didn't want to wait five more years.

And I heard about the Undiagnosed Diseases Network, in the division of the National Institutes of Health, and applied and was accepted down at Stanford. And they did whole genome sequencing three times before they ultimately found these compound heterozygous variants on Charlotte and Cooper's FAM177A1 gene. And like I said, at the time, there were only five publications total about this gene, but one of those was a paper out of Saudi Arabia that referenced the family that had four children with overlapping symptoms to Charlotte and Cooper and issues with this gene.

So, they'd found it! And then we got to work. So, I started a foundation to raise money and fund research, and it's been quite a ride, a heavy lift, but we've made really great progress. So, I'm happy to be here today and talk about one of the projects that we funded in Clement's lab.

Julie Kiefer: Yeah, you're persistent to say the least! So how did you find Clement? What brought you to him and what brought you to bring this situation to his lab?

Jill  Hawkins: I just started reading and reading and connecting with other rare disease warrior parents who do this because we don't have a choice. Nobody else is going to become the world's expert in our kid's disease except us. And the rare disease community is really special and they share their homework. And so, everybody was talking about doing these drug repurposing screens and Clement's name kept coming up as an excellent partner to do this with. And I work closely with Ethan Perlstein with Perlara PBC, and they guide groups like ours in their cure. And Ethan had done several projects with Clement and so we reached out to him and he said, ‘I'll take a stab at this.’ And we've been working together over the last year.

Julie Kiefer: So Clement, tell us a little bit about that. First of all, you've been searching for treatments for rare diseases and this is actually a pretty new direction for you in your lab. What led you down this path?

Clement Chow: My lab has been interested in figuring out rare diseases in general. We've been taking the pretty standard path of studying a model of a disorder and trying to figure out what's wrong, what's behind the problems we see in the kids, and hoping that that would lead to a therapy.

Clement Chow is an associate professor of human genetics at the Spencer Fox Eccles School of Medicine.

But a few years ago, we were really getting frustrated that that’s not what happens. You end up studying the disorder forever and not really finding a therapy. And we thought, well, what better way to find a therapy then to look for a therapy? And so that's kind of how we got down this path of trying to find therapies for people living with rare diseases.

Julie Kiefer: So, what's the larger need that your lab is trying to fill? I mean, why is this so hard to do?

Clement Chow: I think Jill's story really highlights the larger need. Each rare disease is rare, as the name implies. And oftentimes these families go through this incredibly long diagnostic odyssey and they come to the end of it, if they're lucky to get a diagnosis, and then they don't know what to do. And there's nothing left oftentimes besides a genetic mutation. And a lot of these disorders are rare so companies aren't actively working for therapies for any one of these disorders. Maybe they hit onto something and then that's really great for that patient population, but for most families, there's nothing. And I think we wanted to try to fill that niche in kind of the rare disease community to try to bring some hope and try to help these families a little bit.

Julie Kiefer: And so your lab uses fruit flies to search for these treatments. I mean, first of all, Jill, when you heard that, what was the first thing that went through your head?

Jill Hawkins: I was like ‘Those pesky little things that I shoo around in the summer around my food?’ I was amazed. It's phenomenal that they found this creature that has such an overlap to the human genome and they can use it to study human disease. I think it's fascinating.

Julie Kiefer: So, Clement, tell us a little bit more about how that works.

Clement Chow: Yeah, I mean, Jill's reaction to this is exactly spot on. People can't believe that this pest that's on your bananas might be the answer to some therapies for some of these people living with rare diseases.

But the fruit fly is kind of this biomedical workhorse. There's lots of labs using the fruit fly to study basic biology, some disease models, evolution, development. And the reason why it's an incredible model for research is the same reason why it's an incredible model for looking for therapies. They have a short lifespan, they're very cheap to maintain in the lab. And for us, they really kind of sit in this kind of midpoint between complexity and efficiency. We can generate many, many of these flies, thousands and thousands, for very little money, but they still have the complexity of a human body, a brain, a digestion system, a circulation, blood/brain barrier. So, they have all those things that may be challenging to treat in a human patient and flies have that. So, we think that because of all the properties they're really good models for rare diseases and in particular looking for drugs.

Julie Kiefer: How does it work exactly? What are you doing?

Clement Chow: We build models of rare diseases in the flies and we look for a particular trait that is different enough in the disease model compared to wild type, regular healthy flies. And then we expose those disease model flies to a couple of thousand drugs, FDA-approved drugs, to see if any of them work to improve the outcome of that particular model and move it closer to what a kind of wild type, healthy fly looks like.

Fruit flies are good models for rare diseases because their biological systems are similar to those of humans.

And we use FDA-approved molecules because they can be moved into the clinic really fast. They are already approved by the FDA, they're safe in most cases and there's some obvious path forward to how to dose. And so, the hope is that we find an FDA-approved molecule that works in the fly. We can move it very, very quickly without the need for starting over with the approval process at the FDA.

Julie Kiefer: So, when you say you're building models in flies, I mean, what do you mean exactly?

Clement Chow: We mutate the gene or alter the gene function in a way that's either identical or similar to the rare disease patient or family that we're working with. And people like to call these patient avatars or models. Either one is fine, but we're really trying to mimic as closely as possible to what's happening in the patients in the fly and so we can more closely screen for what's going on in the patients.

Julie Kiefer: And so then you expose these flies to these different drugs and see if there are some that kind of make them look better, I guess, essentially?

Clement Chow: Yeah, make them healthier, yeah, for sure.

Julie Kiefer: And how quickly does this happen? This work?

Clement Chow: Once we start the screen, we can do the screen in about four months. And that's not me working in the lab, right? I have an incredible team of four scientists that do this full time for our partners. And it's really their hard work that gets this done really fast.

Julie Kiefer: And this is a lot faster than, say, a drug company trying to create a new drug. Is that fair to say?

Clement Chow: Yeah. So, the purpose of repurposing is to kind of cut out all that early work that's required to find a molecule and then develop a molecule into an actual medicine. And so, we're trying to cut all that out and just get right to the chase of these known, approved molecules. Some of them might work for rare disease and if they do, we want to be able to find them and use them.

Julie Kiefer: And so how has it been going? I mean, how many families are you working with now?

Clement Chow: It's been going really well. I think that there's a real need in the rare disease community. We've done about 16 of these screens with different partners and they fall along a spectrum of what happens next. But I think that we have a couple that have gone straight from the fly result into kids because the drug’s rather safe or made so much obvious sense that there was no downside to trying them.

And others we have, where other screens, we have found molecules that maybe made a little bit of sense, maybe needed a little bit more work to figure out what's going on. But I think they've gone really well. We field two to three requests a month. We don't take them all for a number of reasons, but there's a real need and I think that's not stopping anytime soon.

Julie Kiefer: You're working with different families and all of these families are at different stages. Some have had the chance to try some of these drugs and have had some success. I know you can't get too specific, but I think there's some indication that this is something that could potentially work. Is that right?

Clement Chow: Yeah, for sure. And I think that there is a history of repurposing being successful for rare diseases. We're not the only people doing it. There are examples that are out there in clinical trials from repurposing. There are a couple pretty famous examples as well, but from our screens, it's tricky to test them in patients in kind of a one-off situation where you only have a single patient and you don't have a control group, but we are seeing a lot of promise. We see kids improve on the drugs we find. And I think that as we do more and more of this, especially in bigger patient populations, we will start being able to do bonafide trials to be able to say for sure that this is working. But we are confident that some of the drugs that have been tried in kids are having a positive benefit.

Julie Kiefer: And so, this is where you're heading, I mean, because right now you're able to work with a handful of families, but you're hoping to be able to scale this to something bigger.

Clement Chow: Absolutely, I think that that's needed for sure.

Julie Kiefer: Jill, Clement's lab has started searching for treatments for Charlotte and Cooper. How is that looking so far?

Jill  Hawkins: Yeah, it's looking very promising. But I wanted to back up a little bit when you asked how I found Clement and just sort of paint a picture of where we were when our kids were first diagnosed and where do you start and where are you headed?

And so, drug development is very, very expensive and very lengthy as you mentioned. I've heard on average from 10 to 15 years to develop a new drug and hundreds of millions, if not billions, of dollars. And these are resources that rare diseases almost never have. And so we have to think out-of-the-box. And so, it's this idea of what if there's a drug sitting on a pharmacy shelf that might work for our diseases and what's an efficient way to figure that out? And so, you need to come up with a disease model, like Clement has mentioned, and maybe it's a fly, maybe it's yeast, maybe it's a fish.

And it depends on the genetic disease, like, does the animal even have your gene of interest? And so fortunately the fly has FAM177A1. That was why we went down the fly road. And Clement was able to create a model of the fly, a fly that's deficient in FAM177A1, just like patients are deficient in FAM177A1. And when he did that, the flies were very unhealthy. Many died before they could reach adulthood, and 100% of the boys died in the pupa before they could reach adulthood. So that was a really, really, strong phenotype that we could then screen against.

Julie Kiefer: And phenotype. What does that mean?

Jill  Hawkins: A phenotype is a symptom that you can see. It's something about the disease causes something that we can observe. And why that's important for these screens is that then you can continue to observe them after treatment and see if that phenotype changes, if you can rescue that change. So, in our case, we're looking to rescue male lethality. So 100% of the boy flies died before they reached adulthood and then we fed them the drugs and Clement’s team observed to see if any of the boys lived after eating some of these drugs. And most of the drugs had no impact, but quite a few did. And some of these drugs had a really significant positive effect on the health of these flies. And we had over 30 drugs rescue our male flies, more than 80%.

So, we have some great hits to go on now. It's very encouraging results. Clement's team is doing some validating studies now looking at different phenotypes and dosing on some of our top hits. And we had one, I don't think he minds sharing, there's other findings that you can get when you look at your hit list and see maybe there's something in common with some of these drugs that could tell us something about the biology of this disease.

I mean, we're talking about these diseases where we know nothing about the mechanism of this disease, right? And so, it's almost like we're going to reverse engineer this. The old model of, ‘Well, we're going to study the disease and we're going to learn the mechanism.’ And as Clement said, this can go on for decades and we're just creeping along trying to understand the mechanisms of the disease, but never translating that into anything that's impactful for patients.

And now we are able now to jump straight to this translational medicine and without ever knowing, really, the mechanism of this disease, we might find a treatment. So about 60%, more than 60% of our top hits have a documented acetylcholine relationship. So as somebody in his lab said, the biology's telling us something, we don't know yet what it's telling us, but there's a clue there. there's a thread to pull on that we're excited to pull on and figure out how this is going to shake out. But things have gone great with the study. We're getting close to deciding which drug we're going to try in our kids. We're talking to the makers of these drugs and doing our due diligence around safety and engaging clinicians now. And we want to do this in a thoughtful and safe way, but we have items that we can act on and that's really exciting.

Julie Kiefer: Yeah, that's really great. So yeah, I mean I think that's an important point here. I mean, the whole goal is figuring out what works. It’s not necessarily how is it working, but let's get this treatment into people as fast as we can or find a legitimate treatment that could be safe and work and try it out. Clement, what else would you say about how things are going there?

Clement Chow: First off, Jill will have done her homework!

Julie Kiefer: Yeah, absolutely!

Clement Chow: So, that was a really nice summary of the whole project, but things are going really well in the project and Jill covered it all. And I will emphasize that this is basically reverse engineering a therapy, right? We really are just saying, look, the drug biology tell us what's going to work. Let's not guess based on what we think we know about something, let's throw everything at it and see what works and go in that direction. And I think that that's the power of this. It's kind of hypothesis free, which sometimes is a dirty word in science, but it turns into results really, really fast sometimes.

Jill  Hawkins: It's an unbiased drug screen.

Clement Chow: That's right. Unbiased by our assumptions.

Julie Kiefer: Right and so the significance of a lot of these drugs having something in common, you said they were acetylcholine receptors and most people won't know what that is, but basically the significance is that's kind of saying you think that's probably saying this is the type of treatment that's going to do the best in this situation. Is that right?

Clement Chow: That's right. And it not only tells us that this pathway, this particular neurotransmitter, which is what acetylcholine is, it might be the key to therapy. It really tells us that specifically drugs that hit this pathway might be what's working, right? And so, it's not only just this pathway. Again, we want to get beyond what the pathway is, what the biology is, we want to get right through the therapy. And it's just telling us that drugs that move this pathway in a particular way might be the key. And that, as Jill said, could take decades if you're just searching for it, if you're hoping that the science will lead you to that.

Julie Kiefer: But here's this big neon sign pointing you in this direction and it took a couple of months, right?

Clement Chow: Yep.

Julie Kiefer: Which is pretty amazing. So, Jill, you and your family visited Clement's lab a few months ago. What was that like for you?

Jill  Hawkins: Yeah, it was amazing. And what I haven't mentioned so far is that our oldest son, Nash, happens to go to the U. So, we were in Salt Lake City visiting him for parents' weekend, and I asked Clement if we could come meet the FAM flies in his lab. And he said sure.

Jill and Doug Hawkins, their son Nash, and Jill's mother Charlotte Minich, with Kate Beebe, a research scientist, during their visit to the Chow Lab.

Unfortunately, he wasn't there, but I got to meet the rest of his team. It was incredibly impactful to see this work firsthand. It made me appreciate how far we've come in such a short amount of time. Going from undiagnosed to the development of an animal model to a drug screen with promising hits is truly remarkable. And it made a big impact on our son as well. And he said, ‘I can't believe I can look at campus and know they're working on Charlotte and Cooper's disease.’ And it just gave us all a lot of hope. It was a great day.

Julie Kiefer: Is he ready to become a scientist now?

Jill  Hawkins: No! I mean, I really could see him working, trying to make an impact on Charlotte and Cooper in some way. But he's not drawn to the microscope — not yet anyway.

Julie Kiefer: I'd like to mention in addition to all this work you're doing, caring for your kids and pursuing treatments for them, you're also founder and president of the FAM177A1 Research Fund. Tell us a little bit about why you're doing that. Why is that so important?

Jill  Hawkins: Well, I am doing this because I want to develop treatments for our children because it's possible to do that and because industry is not going to invest in us. We are too rare. We are ‘too rare to care’ as the expression goes. So, it falls on families to do this.

And I also want to support other families. I don't want them to feel alone. I want to create a community. We're definitely stronger together. So, I created this beacon, this lighthouse, for anybody interested in FAM177A1, whether you're another family or a researcher. I've now been contacted by families on the other side of the world saying, ‘My children were just diagnosed with this,’ and we can support each other through it. And I want to be able to tell them we are working on this, we are working on this and we are going to come up with something, there is a path to a cure for this disease, there's an absolute path to a cure, and it's just a matter of resources to get there.

So, this drug repurposing? This is the low-hanging fruit. This is a stop gap. A gene therapy is a cure for our disease, and we're going to get there, but in the meantime we're going to find treatments, you know, and maybe . . . I am not so Pollyanna that I think this treatment's going to reverse the course of the disease, but maybe one of these [treatments] slows down or stops Cooper's seizures. That's a win. That's a massive win. And what if this progressive motor decline stops and we can keep both of our kids walking? That's going to change the trajectory of their life, and so that they're not both in wheelchairs and we have to think about adapting our life to that.

That is the possibility of doing these drug screens. And we are on the edge. We are right on the edge of finding that thanks to this project. So, I started this foundation so that we could do exactly this, that we could give families hope and improve lives, potentially life transforming therapies, in a time frame that matters for my kids, and for the ones that come next.

Julie Kiefer: And Clement, you're a part of that. Why is that important to you?

Clement Chow: It's important because this is why I got into science. I wanted to make a difference for human health and human disease, and I just kind of think, what's the point of doing biomedical research if it doesn't have any impact at all on the people living with these disorders? I like to remind my lab that these aren't research projects, right? We're on a mission to try to find cures for real people living with these disorders. So that's why we do it. We do it for all the people who are living with these rare diseases.

Julie Kiefer: Well, very good. Jill and Clement, we wish you both the best and we look forward to hearing more about this as your work continues. Thank you very much for being here today on U Rising.

Clement Chow: Thank you.

Jill  Hawkins: Thank you! It's been my pleasure.

Julie Kiefer: Listeners, that's it for today's episode of U Rising. Our executive producer is Brooke Adams and our technical producer is Robert Nelson.

I'm Julie Kiefer. Thanks for listening.