Research screenings give rare disease families hope

Podcast: Biomarkers help researchers learn more about debilitating brain disease in children

Research screenings give rare disease families hope

Episode Transcript

Alan Helgeson: Hello, and welcome to the “Reimagining Rural Health” podcast series, brought to you by Sanford Health. In this series, we explore the challenges facing health care systems across the country from improving access to equitable care, building a sustainable workforce, and discovering innovative ways to deliver high-quality, low-cost services in rural and underserved populations. Each episode examines how Sanford Health and other health systems are advancing care for the unique communities they serve.

Today’s topic is a conversation on medical research and a potential breakthrough in screening for a rare disease. Our guest is Dr. Jill Weimer with Sanford Research. Our host is Simon Floss with Sanford Health News.

Simon Floss (host): We’re talking to Dr. Jill Weimer, who heads up the Weimer Lab at Sanford Research in Sioux Falls, South Dakota, about a potential breakthrough in screening for a rare disease. Dr. Weimer, thanks for being here.

Dr. Jill Weimer (guest): Thanks for having me.

Host: So, you are one busy person. Can you explain a little bit about, you head up a lab and then you’re also in Philadelphia quite often?

Dr. Jill Weimer: Yes. So I’ve been at Sanford Research for 13 years. I started my research program here right as Dave Pearce was launching the Children’s Health Research Center, which has kind of evolved over time to really have a heavy focus on rare diseases. Initially my research team was very basic in our biology. We were understanding how the brain develops and how when you have mutations in specific genes that can lead to rare pediatric diseases.

Over the course of the next five to seven years through some funding from the NIH and from several private foundations, we expanded our work to really focus on drug development. Specifically, early on, we were looking at how we could actually correct those defective genes using technologies like gene therapies.

And so our group helped in collaboration with a team at Nationwide Children’s Hospital to develop gene therapies for two rare lysosomal storage disorders called CLN3 and CLN6 Batten disease. Those programs then were taken on or taken over by a Philly-based pharmaceutical company called Amicus Therapeutics. And at the time, in early 2019, they asked me to come over and head their science division. But I really love my time at Sanford and my research team that I had built here, and I wasn’t willing to leave that. So, I actually negotiated to do both jobs. So, now I split my time between running the lab here at Sanford still, but also heading the science division at Amicus in Philadelphia.

Host: Do you have time for any hobbies?

Dr. Jill Weimer: Oh, well, I think I structure my spare time a lot of times around my passion. So I spend a lot of time, a lot of my free time working with the foundations that we support and that we work with for Batten disease specifically. But I do enjoy gardening and reading and hiking and being outside and scuba diving, so it’s crammed in there. Tightly.

Host: (Laugh) Okay, let’s get to what we’re going to be talking about here today. First, what is Batten disease?

Dr. Jill Weimer: Yep. So, Batten disease is actually a family of rare lysosomal storage disorders. So the lysosome in your cell, think of it as sort of like the recycling center. So it takes proteins that need to be turned over or broken down like a recycling center would, and breaks those down into amino acids so they can be reused by the cell to build new proteins.

In lysosomal storage disorders, the lysosome is dysfunctional. It doesn’t break that material down, so it accumulates and you get storage material that then can impact the cells. In Batten disease, there’s actually 13 different genes or 13 proteins that can lead to different forms of Batten disease. And how those differ really is around the age of onset – so anywhere from infantile to late infantile to juvenile to adult onset of the disease. But also sort of the order of the phenotype, how the disease presents can vary depending on which form of that disease the patient has.

Host: Talk about maybe the severity of Batten disease?

Dr. Jill Weimer: Yep. A lot of the work in our lab has focused on the, in the late infantile form. So just to give you a typical progression of a kid with a late infantile form: They usually are born relatively healthy. Around the age of 2 to 3, they start to have motor problems; they might present with seizures. Over the course of the next few years, their motor ability deteriorates their language ability deteriorates. They’re not meeting those cognitive milestones that a 3-, 4-, 5-year-old would make. When they’re hitting kindergarten, their seizures progress. They become wheelchair bound. In many cases, they will go blind and usually they succumb to their disease around the age of 10 to 12.

And there are no cures for any form of Batten disease right now. For one of the forms of late infantile CLN2, there’s an enzyme replacement on the market that’s approved, and as I mentioned in clinical development, a number of different gene replacement or gene therapies that are being tested.

Host: So, I understand we’re going to be talking a little bit about CLN1 and CLN3. Can you explain what those are and what the differences are?

Dr. Jill Weimer: Yep. So CLN1 is actually the classical infantile form. So that’s the most severe form of the disease. And it’s caused by a mutation in the CLN1 gene. CLN3 is the classical juvenile form. And so, the kids with CLN3 usually don’t have a disease onset until they’re about between 4 and 6. And their symptoms usually start with visual decline. So they could actually have visual deficits that persist for one to two years before they have any of those other symptoms.

We’ve worked on gene therapy programs for CLN3 and actually our lab now works on I would say drug development, non-gene therapy. Our Sanford team really focused on identifying small molecules that would have more of an impact across multiple forms about disease. So we actually work on CLN1, CLN2, CLN3, CLN6, and CLN8, all in parallel.

Host: Oh, wow. So, there’s not one that you’re studying more than the other, or would you say it is CLN3?

Dr. Jill Weimer: Yeah, I would actually say because of the tools that we have in hand, a bulk of our work over the last few years have been centered around CLN3 and CLN6, and maybe a little bit more on CLN8. But we’ve developed a number of tools that really take us all the way from the basic bench work, to the clinical work, and then also building translational tools in between.

Host: So, some terms that are critical for your line of work, and the average listener might not know exactly what these are talking about biomarkers and genetic mutations. So, what are biomarkers and within those, what are you looking for, and what are genetic mutations?

Dr. Jill Weimer: Yeah, so biomarkers are actually something that we originally started looking at as a way to kind of identify or diagnose the disease to track its progression. So, in our lab we work with mouse models. We’ve also developed a number of pig models for Batten disease. And really the way that we track the disease is to collect the brain from that animal, look at the pathology, but we also run what I call like our mouse Olympics. Like we have a battery of behavioral tests that we’ll put those mice through to look and see do they have vision deficits? Do they have behavioral deficits, motor deficits that correspond to disease? So that then when we treat them with the drug, we can see how they actually respond. Do we stop the progression of coordination deficits, right? Are they able to run better with the drug?

But in human patients, you can track those things, but they’re, as I mentioned, with C3 Batten disease, it may be very protracted. And so, as I mentioned, they may start to have visual decline, but they, you may not see motor changes for two or three years. So, imagine now running a clinical trial in patients, you’ve given them a drug and now you have to just sit and wait and see for two to three to four years, is this drug effective because it takes that long for the disease to start to progress.

So, what biomarkers allow you to do is collect information from let’s say a biofluid, like a blood sample, urine sample, even a cheek scraping, central spinal fluids, your CSF. It could also be things like imaging, brain imaging. MRI can be used as biomarkers. And these are things that are more readily available, that you can collect from the patient multiple times over a year, and use them to track disease.

And so historically, none of these biomarkers exist for Batten disease. So, it really, when you enter into a clinical trial and you’re testing a drug, it means it’s going to take years for you to have an answer. Is this working? So, what our lab has done is use those mouse and pig models that we’ve developed to identify novel biomarkers that we can identify in the animal models from blood samples. And so, the approach that I always said is, I think a lot of times when people look for a marker of disease, they’re looking for a needle in a haystack. And sometimes seeing that needle in that haystack is really difficult, but in the age of AI and big data, why not look at the whole haystack? So, our approach has been, let’s take as much information as we can. We’ll build these algorithms that then use that information to condense that, to create a biomarker scoring system.

So, we’ve done this with a number of our mouse models looking at neuroimaging and gait analysis, movement, motor movement to come up with a scoring system. We’ve also used blood samples to then start looking at the biofluids to see if we can mine those to look for changes in the, in different things that are expressed in blood and then use that information to develop better biomarkers that then can be used in the clinic. So we’ve taken that information now and validated some of these in CLN3 patient samples.

So, really the next step be then to develop a qualified assay that can be run in a diagnostic lab, that then the patients in clinical trials or Batten disease patients as they’re diagnosed, would send these samples into that lab. They would read those and give them, here’s where you are in your disease progression, and now if you’ve received a drug in a clinical trial, is it correcting the progression of that disease?

Host: I was literally just about to ask, what comes next for this process? So, you already answered my question.

Dr. Jill Weimer: And the other, the cool thing is too, that some of the biomarkers that we’ve discovered after a drug is approved, now you need to actually find a way to identify these patients. So, many of us are familiar with newborn screening of disease. In order, in most states to be added to the newborn screening panel, there has to be a drug that patients could receive to treat that disease, right? So they don’t want to necessarily do newborn screening and tell you, your kid is going to develop X disease, but there’s nothing we can do at this point. And so, really like the newborn screening panel is for diseases that we have treatments that we could get patients on right away. So the next step, usually after a drug is developed for one of these rare diseases is to then start working on a newborn screening panel. That can take years.

So, in the instance of CLN2, when I said there was an enzyme replacement therapy, that hit the market about seven years ago, and most states still do not have a newborn screening panel for CLN2, right? So, it takes usually about a decade behind when a drug is approved to get it on the newborn screening panel. And part of that is developing an assay that could be used to detect that. So, the nice thing about these biomarkers that we’ve discovered, we think that they actually could also be used for newborn screening. So, we’re kind of ahead of the game before we even have a treatment. We would actually have some of those tools lined up that would actually expedite getting these drugs to patients as quickly as possible.

Host: Yeah. Man, this is fascinating. Why is this so important?

Dr. Jill Weimer: I think for me it is giving these families hope. Rare diseases are so infrequent. And some of these diseases, for instance, CLN8, there’s probably less than 10 patients in the United States that have this disease. CLN1, two and three are a little bit more prevalent. And so, those are about one in 12,000 to one in 20,000 patients in the United States.

But the other forms of Batten disease we work on are one in 200 to 300,000 patients. Right? So when you think about Alzheimer’s, there are many people in the United States, scientists, clinicians, working on treatments for Alzheimer’s, understanding like how this is impacting the brain. But for some of these rare diseases, there are, like for CLN6, for many years I was the only person in the United States working on this disease, right?

So, it gives these families hope that there is somebody that cares about them, that there’s somebody fighting for them, that there’s potential, maybe not in their child’s lifetime, but in like, if we keep working, that we will get to cures, we will get to treatments that will help these kids.

Host: Yeah. And just to put it into context even though it’s a rare disease, there are, it’s, I assume many, many people affected by the Batten disease or variations of it. Yes. How, off the top of your head, do you have any numbers of how many people that might be?

Dr. Jill Weimer: Yeah, there’s probably 500-plus patients living in the United States with all the forms collectively of Batten disease. Like I mentioned, CLN1, two and three are the more prevalent forms. And so those are the ones that people would be more familiar with. But it doesn’t make those other forms any less important.

Host: Lastly like I just said, it’s a rare disease and Sanford Health, whether people know this or not, is a huge player in studying rare diseases in this realm. Can you talk about the CoRDs registry and how involved we are in researching rare diseases?

Dr. Jill Weimer: Absolutely. So, the CoRDs registry is really a way to help us identify those rare disease patients. So essentially, initially it was set up as a registry where different foundations, or even it’s disease agnostic, but they have foundation partners where a patient can go in and enter their information on the back end. Scientists, researchers, clinicians can access that registry to be able to identify patients, do research, ask questions, connect with those patients. Say a clinical trial becomes available. It’s a way to reach out to reach out to those patients.

But I would point out that CoRDs is instrumental to what we do in rare diseases at Sanford, but it’s only a small fraction of the rare disease work that we do. So, when we really started recruiting scientists into that original children’s health research center 13 years ago, we were fortunate that we started recruiting a number of scientists that actually work on rare diseases.

So, I would say about 15 of the 30-plus labs that we have at Sanford Research work on some different rare disease. So, we really have become this like hub. CoRDs is sort of the part of the infrastructure that we’ve built to be able to do that.

But we built other things too, in place. So, we have like a drug screening facility and a translational sciences facility. So, say a scientist here is working on Friedreich’s ataxia and they want to be able to get skin samples to make a cell line from a patient with particular mutations. CoRDs can help them identify those patients, consent them under an IRB to collect that, that skin biopsy, to then bring it into our translational science core to build those cell lines that they can then study for basic biology or drug screening, or a number of different things that they might need to do with their work.

Host: Wow. This is just so fascinating and it’s no surprise we ran out of time. We’ve got to go (laugh). So, Dr. Weimer, thanks again so much for being here, but more importantly, everything that you do.

Dr. Jill Weimer: Absolutely. Thanks for having me.

Alan Helgeson: You’ve been listening to “Reimagining Rural Health,” a podcast series brought to you by Sanford Health. Hear more episodes in this series or other Sanford Health series on Apple, Spotify, and news.sanford For Sanford Health News, I’m Alan Helgeson, and thank you for listening.

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