When Proteins Go Rogue: The Prion Paradigm in Neurodegenerative Disease

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Daniel Simon, MD: Hello everyone, this is your Science@UH host Dr. Dan Simon. Today I am here with our guest Dr. Brian Appleby, neuropsychiatrist at University Hospitals Cleveland Medical Center, Professor of Neurology, Psychiatry and Pathology at Case Western Reserve University School of Medicine, Director of the National Prion Disease Pathology Surveillance Center and Medical Director of the Creutzfeldt Jakob Foundation.

Welcome, Brian.

Brian Appleby, MD: Thanks, Dan. Appreciate the offer.

Daniel Simon, MD: So it's so great to have you here today. This is definitely our first neuropsychiatric pathologist podcast. And so, I guess you know the first question, of course, is what inspired you to become a physician, and how did you get involved in this interesting multidisciplinary training around neurology, psychiatry and pathology?

Brian Appleby, MD: I suppose as most things in life it's kind of a happy series of accidents.  So, I never really knew I wanted to go into medicine. Originally when I was in high school, I actually wanted to be a Catholic priest and that kind of fell through, obviously. But at the time I didn't know what I wanted to do when I was reading Ben Carson's book Gifted Hands. And I said, well, you know, I can see some corollaries between the priesthood and maybe being a physician. And then fast forward about 10 years, I'm working at the same place as him doing neuropsychiatry. So, when I was at Hopkins, I got really interested in a lot of the neurologic underpinnings of neurodegenerative illnesses. And I was very interested in something called frontotemporal dementia, but there was already someone there doing that. So I had to find something else. And at the time I had a couple young onset dementia patients that wind up having Creutzfeldt Jakob Disease, a prion disease and I really enjoyed taking care of those patients for a lot of the same reasons. Back then, it was extremely difficult to diagnose the illness and there's a lot of caregiver burden and just a lot of work to be done in the field. So, I met with the retired NIH Division Director of Prion Disease, and he was kind enough to have me over to his home for lunch. And he said, I think you should do this; there's a need and there's no one else doing it, but be careful because if you do it, that's going to be the only thing you're going to be able to do; you're not going to have time for anything else. So, I brought this back to my mentors and they thought I was maybe a little bit crazy and they said we can't justify telling you to do this with your career, but in the end it worked out.

Daniel Simon, MD: Ok, so, Brian, you know I'm a simple cardiologist and we had our microbiology courses in medical school at Harvard, and we learned about bacteria, viruses, fungi, but just a little bit about prions. Can you tell us what prion disease is? What exactly is it? And we know it's a rare disease; it only affects one or two new cases per million people, but tell us a little bit about it and what its forms are.

Brian Appleby, MD: Yeah, so prions are both unique and also not unique when you look at the broader spectrum of things. Prion diseases as a whole including things like Creutzfeldt Jakob disease are due to a protein that we all make, a hosting encoded protein, that for whatever reason it changes its 3D shape and that's what causes it not only to be toxic to brain cells, but also to propagate not only amongst someone's own brain, but also between individuals and in some instances across species. So, in in this case it's the prion protein which we all make and causes the problem, but we now know that this prion paradigm of this misfolded normal protein that propagates also underlies pretty much all other neurodegenerative diseases like Alzheimer's, Parkinson's, ALS. It's just the protein that's involved is different.

Daniel Simon, MD: So, when you said that this protein that misfolds can spread from cell to cell, from person to person and even from animals to person, so it sort of means in a way that prions can be infectious. Can you clarify that for our listeners?

Brian Appleby, MD: Sure. So, it used to be considered infectious and used to be called a slow viral illness because we never knew what caused these illnesses and the incubation periods are so prolonged, usually measured in years, to decades. You know, I think perhaps the best term to use for these illnesses is that they're transmissible because it's protein only; there's no nucleic acids, it's not like bacterias, fungi, or viruses. And it's actually quite difficult to transmit these illnesses. We have to have very specific scenarios. So, for example, you have to have highly transmissible tissue, which was be brain tissue primarily in most cases and then either have to inoculate it in another person's brain, inject it into them in large quantities, or consume it orally. Now that doesn't happen in most medical practices nowadays. So, I think of it more as a transmissible illness and perhaps a good analogy for that that I use is if you look at rust, we don't consider rust an infectious disease. However, if you put a piece of rust on a bumper, it will spread. It will propagate, transmit, but that's not an infectious disease. So maybe it's a little bit of semantics, but you're not going to walk down the street and catch a prion disease; very specific things have to happen.

Daniel Simon, MD: So, you lead the national prion disease Pathology Surveillance Center at CWU and UH, and it is the only site of its kind in the US. Why do we need to create such a center? And what does the National Prion Disease Pathology Surveillance Center do?

Brian Appleby, MD:

Yeah. So, the NPDPSC is really a unique institution. We were funded back in 1997 in that case primarily out of response to the variant CJD epidemic. Variant CJD is what we call the human form of mad cow disease, or bovine spongiform encephalopathy. And the only way to diagnose the disease definitively is by looking at neuropathologic tissue and very importantly, the only way to know where it came from is to look at the tissue underneath the microscope and characterize the abnormal prion itself. So, the CDC really wanted to do laboratory-based surveillance of prion disease, and that's continued. And we've been very fortunate in the US . We've only had four cases of variant CJD, all of which were thought to have occurred overseas, but that serves an important purpose, not just to say that we don't have it, but economically it's important for exported beef to say that we don't have local variant CJD. Over the years it's kind of transformed to other important aspects. There are human to human or iatrogenic causes of CJD. They're pretty rare nowadays because we don't reuse cadaveric material in healthy human, for the most part, that eliminated at least most of the exposures. Although we still see these cases even though they're exposed almost 50 years ago, but nowadays the main purpose of the prion center is this other animal prion disease that, unfortunately, is epidemic in our country called chronic wasting disease, which is a prion disease of the cervid species. So that includes things like deer, elk, moose, caribou and it's probably the most infectious prion disease amongst its own species because it's excreted in their saliva, urine and feces, and it contaminates the environment. So not only do these free-ranging animals easily transmit these illnesses across the US, but other animals could graze behind them and also get the illness. And we're a little bit fortunate with mad cow disease and that it's not a naturally transmitted illness. We're refeeding cattle to one another and that's how we were transmitting the illness amongst that species. Once we stopped doing that, it ended the epidemic. And of course, these are domesticated animals, so we can call them if they're infectious and slaughter them and remove the problem. You can't do that with free-ranging animals like deer. So, right now we're up to 36 states affected by chronic wasting disease and our main purpose is to determine whether or not chronic wasting disease can be transmitted to humans. Right now, we don't have any evidence of that, but as I said before, the incubation periods are quite long. So it could be that it's already transmitted and we don't know it. And of course, anytime you have any kind of easily propagated transmissible illness, you have strain variation, so it could be that earlier strains were not easily transmitted to humans or other animals, but current or later strains may be. So, longitudinal surveillance is important for that. The only way to detect whether or not we have a new prion disease in humans is by looking at brain tissue.

Daniel Simon, MD: So, Brian described to our listeners what is the natural course of Creutzfeldt-Jakob disease and obviously before we said that these were untreatable and that's all changed now. And you're obviously leading a groundbreaking clinical trial, a Phase 12A trial for early symptomatic prior disease. Could you tell us a little bit about the future now that we maybe have a treatment for prion disease?

Brian Appleby, MD: Sure. So unfortunately, prion disease still is untreatable and these are investigational treatments. But it's a very unfortunate illness. It's 100% fatal and it's a really rapid illness. It's really hard to see a loved one go through it. They have an extremely rapidly progressive dementia. Most people from illness onset until they pass; it's about four to six months in our country, the average time from diagnosis to death is about one month. So, extremely dramatic illnesses. Most are sporadic, meaning they just happen much like most cases of Alzheimer's disease and Parkinson's, about 10 to 15% are due to a genetic mutation. So, we know that there are some elements of the population that may be at risk of developing the elements later on, and I think that’s probably the group that we're most excited for possible future therapeutics, is if we can delay or stop the onset. It's very hard when you have the average time from diagnosis to the death of a month to get someone at a potential treatment and preserve quality of life, right.

Daniel Simon, MD: So, tell us a little bit, what is the nature of this first trial and the treatment.

Brian Appleby, MD: So this trial is very interesting. There have been other, smaller clinical trials in prion disease. They all looked at preventing the conversion of the normal prion protein into the abnormal form. Suffice it to say, none of them were successful. This is a first in many ways. It's the first clinical trial looking at reducing the production of the normal prion protein. You need to have the normal prion protein to have prion disease. It's kind of the fuel to the fire of the illness. So presumably, if you can reduce its production, you remove that fuel to the fire, slow down the illness, or maybe even prevent it in someone who's at risk. And the way that this particular agent is doing that is something called an antisense oligonucleotide, which interacts at the mRNA level but ultimately reduces the production of the normal prion protein. Of course, nowadays with biotechnology, there are a variety of ways to go about doing that, but that's how this study does it. It's also the first industry-sponsored clinical trial in prion disease, something I would have never thought would have ever happened in this disease because it's so rare. Who would care to invest so much money? But there are actually other pharmaceutical companies that are also interested in this, so that's very exciting. And then it's also really the first truly international prion disease study. We have clinical sites in the U.S., and Europe, and Japan, and Australia. Regardless of the outcome of the actual study itself, I think its very presence—and it's actually already closed enrollment, so it very easily enrolled, actually—but it's a success just in the fact that it existed and was able to complete enrollment.

Daniel Simon, MD: So, you told us that in some ways, prion disease is like other neurodegenerative diseases. Alzheimer's has amyloid plaques, it's got amyloid protein, it's got Tau and other things. Are there lessons that you can take from prion disease to help us treat more common dementia syndromes?

Brian Appleby, MD: Yeah, absolutely. Prion diseases are actually in their nature quite simplistic. You need to have the abnormal form to have the disease and you need to have the normal form to have the disease. So back in the early 1990s they made animal models where they knocked out the prion protein gene and then they inoculated them with prions. They never got ill. So, if you can remove that prion protein, you can't have disease. So, and there's actually natural animal models of this, right? We talked about bovine spongiform encephalopathy, chronic wasting disease, there's also scrapie. There's no animal equivalent of Alzheimer's disease or Parkinson's or frontal temporal dementia. These are all kind of made in the lab. They're not truly authentic to what a disease and a human would be. So, there's a lot of different ways that we can use prion disease. It's also because it's a rapidly progressive illness, even in animals, iIt allows us to do more high throughput bio assays for potential treatment. And we've seen this. Now we know that there are other genetic modifying therapies that are looking at changing the expression of normal proteins for these other illnesses, whether it be Alzheimer's or Parkinson's. But just the pure simplicity of prion disease, I think really allows it to be kind of the ideal model for how we approach these other illness.

Daniel Simon, MD: So future treatments, you talked about ASO's that I assume are delivered intrathecally into the cerebral spinal fluid. What are future treatments that you think could be coming down the line?

Brian Appleby, MD: So, I mean that's one of the drawbacks, right? It’s kind of hard to administer, but you know these are early days. You have to start somewhere. Eventually we'll probably get around the intrathecal requirement and be able to administer in some other way, but again because the premise of rational design for these therapeutics is to reduce the production of the normal prion protein, we can use any genetic modifying therapy to do that. So, you can use things like zinc finger repressors, like Sangamo is proposing. You can use molecular gait models that shuttle out particular proteins like Gate Biosciences, or you can even interact at the DNA level. Of course, CRISPR is not quite ready for something like this in a human, but you know similar approaches, silencing RNA for example. So, there's a variety of different currently available biotech that can go about doing this and it may be that we do a multi-pronged approach.

Daniel Simon, MD: So final question for you. So, with your very interesting and diverse training in three disciplines, how do you spend your week? How much time do you spend seeing patients with dementia that have both brain health and psychiatric issues, and how much is spent on prion disease or prion research?

Brian Appleby, MD: Search probably much like yourself, I tell my staff I start at the top of the schedule and I just work my way down wherever they want me to go. But I'm a clinician at heart. I love seeing patients, so most of what I do is seeing patients, whether it's in clinic, which is not as much as it used to be, but clinical trials such as the Alzheimer's Disease Research Center in Cleveland and a couple of other natural history studies, some clinical trials like the IONIS study. And then the prion center involves me in things I would have never thought I'd ever be in before, such as dealing with agricultural government relations. Couple weeks ago, I actually attended a conference that was just dealing with deer carcass disposal. Again, not something I would have thought I would have done in my life. So, I like to have a very interesting job. I never quite know what I'm going to be doing in a day or what might come across as an urgent thing, so it's very diverse, but I think it's all interconnected. Back in the early days of medicine, all neuropsychiatrists kind of had this phenotype. They did psychiatry. They did neurology and they did pathology. And you think of Arnold Pick, Alois Alzheimer, Kraepelin; they all kind of had this phenotype, but we gotten away from that and now we have these super specialists that only do this or that. So, I think there's a lot of utility in doing this, I do think pathology is very informative, especially for neurodegenerative disease. They have an understanding of that. I also run a fellowship program at UH and we try to emphasize that cross disciplinary approach, but it is difficult to do that in medicine. Thanks.

Daniel Simon, MD: Well, I have to tell you, it's been just an honor and a privilege to talk to you today. You are certainly one of the crown jewels of UH leading national programs and bringing hope to people with the fatal disease. Thank you so much for participating today in our podcast.

And to learn more about research at University Hospitals please visit Uhhospitals.org/UHresearch.

Thank you, Brian.

Brian Appleby, MD: Thank you, Dan. I appreciate it.

The Science@UH Podcast (the Podcast) is intended for informational and educational purposes only. It should not be used as a replacement for medical advice. The statements about devices, drugs, software, or other products may not have been reviewed by the Food and Drug Administration (FDA). The effectiveness of these products may not have been verified by FDA-approved studies. These products are not designed to diagnose, treat, cure, or prevent any disease. University Hospitals (UH) or a guest on the Podcast may have ownership of licensed intellectual property of this research study. As such, UH or a guest could receive financial gain from the outcomes of this research.