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Dr. Clardy: Hi, I'm Stacey Clardy, Associate Professor of Neurology at the University of Utah. I'm excited today to talk with Stefan Pulst for our series on where cures for brain diseases begin.

Stefan is the Chair of Neurology here at the University of Utah and has accomplished a tremendous amount in that role. But today I want to focus our discussion on his role as a very successful researcher in neurodegenerative diseases.

Specifically, Stefan, you are quite well known internationally for your work on a group of conditions called spinocerebellar ataxias. How did you find yourself focusing on this group of diseases? They are rare diseases. Did you seek out that area based on a lecture you heard early in your career or a patient you had seen? Was there some sort of existing project? How did you settle on the spinocerebellar ataxias for your particular research questions?

Dr. Pulst: Well, it was a typical L.A. story. I was Chair of Neurology at Cedars-Sinai at that time, and I got a phone call, a phone call from a colleague at UCLA, who recalled that, as a resident at Columbia University, he had seen a family that had a very unique distribution of age of onset of a particular neurodegenerative disease. It appeared to happen earlier and earlier in each subsequent generation.

And it's hard to believe today, but in the late '80s, I was one of the few neurology geneticists in Los Angeles. So that's why he called me. And I said to him, "I've never seen a genetic disease that I don't like," and we decided to fly out to New York State and examine that family, obtain DNA samples. And then my search began to find the actual mutated gene that caused this disease that we now call SCA2 or spinocerebellar ataxia type 2.

Dr. Clardy: And this is sort of unique and really, I think, drives home the point of the value of a clinician scientist, right, because you're both a scientist but also were able to come see the patients. You're a physician. You're able to examine them and get a sense of what was different about this, highlighting, I think, what's unique about academic medicine is that you serve in both those roles. And, of course, that was pre-Zoom era, so you had to fly out there.

Dr. Pulst: We had to fly out there. And we learned a lot from the patients. Part of cerebellar disease is that you are uncoordinated in your gait. And so one of our measures was to ask people to basically walk a line, like a police officer would do when they pull you over. And we had one young woman who we asked to come back and do the test again. And she was very concerned that she might actually have inherited the disease. And we later found out that she did. She was just a bit clumsier than some of her other family members. So when one learns a lot, and I think that, you know, I've been in this business now for 40 years, what I enjoy about it, going back and forth between lab and the patient and then back from the patient back to the lab, asking the questions.

Dr. Clardy: And you just hinted at what I was going to ask you next, which is how long have you been studying this condition? I think we somehow read a news release about an exciting research finding and we think that it happened in the last six months. So tell us when you started. How long has it really been?

Dr. Pulst: So we flew out to Syracuse, New York, in the late '80s and collected DNA samples. And then, for the next six years, we tried to identify this gene. And although this can be much faster today, this was a time where the genome was not mapped. We made different kinds of maps, maps based on distance and on location. And finally, in March 1996, we identified the disease gene that is now called ATXN2. All the ataxia-causing genes have numbers now. And we found out that it was a very unusual mutation, actually a mutation that was dynamic. It did not remain stable, and in the end that explained this phenomenon of having earlier and earlier disease onset in subsequent generations.

Dr. Clardy: And so what I heard you say was it took a long time to find the mutation. So what have you been doing on that mutation in that ensuing 25 years? Right? You get to discover what the problem is, and then what's next?

Dr. Pulst: Yes, and quite right. We thought climbing the Everest was finding the gene. That there was a lot of glory to be had to find the gene, and then somehow the therapy would just fall into our lab. And now we just know that we were in the hills leading up to Everest. Everest was really finding therapies. And for really a decade, maybe even two decades we and others spent our time trying to understand what this disease gene actually normally does, assuming that, when it's mutated, it has something like a deranged normal function.

And really, for me, the change came with moving to Utah in 2007. We decided to completely refocus and target the mutated gene itself. After all, that's the first cause, the primary reason why patients develop this particular disease, a DNA change happens. And we thought, if we can somehow quiet this disease gene down, then we would have a path forward. And that's what we have been doing since 2007. And you're quite right, that is still 13 or 14 years ago, and it has taken us that long to develop a gene-directed therapy.

Dr. Clardy: Wow, that's incredible. And I want to back up a little bit before we get to talking about the therapy that you're working on. The mutation you found, tell us more about this class of conditions, the spinocerebellar ataxias. What do all the patients look like? Are they similar? Are they different? How many different types are there?

Dr. Pulst: Yes. So the patients with ataxia share a certain presentation. Most of them present with gait instability that then progresses to affecting their speech, their reaching movements, their stance, their eye movements, and sometimes also their thinking. So these are really neurodegenerative diseases. They share some features with other diseases, such as Huntington's disease, but also with diseases like Lou Gehrig's disease or motor neurone disease. So they really fall into the larger group of neurodegenerative diseases.

We have about 50 SCAs, spinocerebellar ataxia, so at least 50 genes or gene locations that cause dominantly-inherited ataxias. These diseases are called polyglutamine diseases because a repeat that normally codes for the amino acid glutamine, it now expands and causes very large stretches of glutamine that misshape the protein, misform it. It tends to aggregate and cause disease.

Dr. Clardy: So unlike some other neurologic diseases that are caused by, say, missing a piece of a chromosome or a deletion, in these spinocerebellar ataxias, most of them, it's really all the DNA is there, but there's extra and it's repeated. Is that right?

Dr. Pulst: That is correct. It's repeated and it's repeated in a part of the gene that directly codes for a protein, so it has a direct effect on the way this protein is formed, the way it behaves. And as we now know, these repeat expansions cause the proteins to aggregate and really cause havoc in the cell.

Dr. Clardy: And I think what you're not saying is that a lot of this was not known. And certainly 50 different types were not known when you started this area of research. And you're saying that family had SCA number what?

Dr. Pulst: Number 2.

Dr. Clardy: Wow, so early on.

Dr. Pulst: Yeah, actually, in Utah, we are working on finding the mutation for a disease that is very common in Utah. It's called SCA4. So it was mapped to a chromosome a long time ago, but it has been very difficult to find the actual mutation causing that disease.

Dr. Clardy: So SCA4, the fourth spinocerebellar ataxia to be discovered is actually common in Utah. I didn't know that. Can you tell me more?

Dr. Pulst: Yes. So this disease was originally described and mapped to chromosome 16 by a former faculty member here at the University of Utah, Dr. Kevin Flanigan. And when we came, we took this off and we realized it is a family, a gigantic family, with more than 1,000 members actually. And we traced them back. The individuals were early pioneers. Actually we know that they were born in the 19th century, came from Scandinavia to Utah. And it's a disease with late onset, so people have a normal number of children. And we have now mapped the disease more precisely to chromosome 16.

What we have also found out, that other families, that we became aware of, there's a smaller family in the U.S. state of Georgia, and we were able to map them genetically but also by family records back to southern Sweden. And we actually found out that the family in Georgia and the family here in Utah come from two villages in southern Sweden that are about 10 miles apart. And there appears to be even a link between them, a man who was an oiler, he oiled machines and he may have had relationships in these two villages.

Again, it's a neurodegenerative disease that affects mainly the cerebellum, so patients have uncoordinated gait. But, interestingly, it has other effects as well. They develop a very significant sensory neuropathy. So what that means is they cannot quite sense where their toes and ankle and their fingers are. So they really have to deal with double damage. Both the feedback from the joints is not correct, and then the part of the brain that should coordinate all this information, the cerebellum is also defective. We are now pretty certain that it's not a simple mutation. It is likely a complex rearrangement on chromosome 16 that has made it difficult to pinpoint down what the precise mutation is.

Dr. Clardy: Wow. So just one of the other . . . I know we only touched on a couple areas of research in your lab, but this is obviously another one. And I love so much of what was in that story. One, the power of genetics, that we can trace back history now. But, two, I think you and I talk about this frequently, both being sort of transplants who came here to work at the University of Utah, but just the power of the recordkeeping and the ancestral records and the Utah population database, how the original settlers continue to give us information to push the science forward. It's such a fun part of working here in Utah.

Dr. Pulst: Yeah. And to give our listeners a bit of a visual image, usually, when you draw a family tree, a pedigree, you know, it fits on a sheet of paper quite easily. In this SCA4 family, we have like a papyrus scroll because it is so enormous. And actually, when we unroll it, it goes across my office. It's quite remarkable. And it was really thanks to one particular patient who contacted family members and made this pedigree. And it extends from Idaho and Wyoming all the way to Arizona through Utah and to California.

Dr. Clardy: That's fantastic. And we have so many of those patients here who are really driving their own science. It's wonderful, right?

Dr. Pulst: Yes, it's great. And the family is very involved, and we owe it to them to find the genes. So we are trying to work as hard as we can on using some of the most modern gene-sequencing technologies. And at this point, as of today, we have not found the mutation. So we still need to examine more patients and hopefully narrow also the location on chromosome 16 even further.

Dr. Clardy: Wow. So a lot of areas of research going on in your lab. I want to switch back a little bit though. You started to allude to this. Your lab has developed what's called an antisense oligonucleotide as a therapy, potentially, for one of these types of spinocerebellar ataxia. And, as I understand it, this has actually also led into a potential treatment for Lou Gehrig's disease or amyotrophic lateral sclerosis. But can you tell us what is an antisense oligonucleotide and how might it work in this disease?

Dr. Pulst: So this goes back to the refocus on targeting the actual cause of the disease, the primary cause. And that's the faulty gene that then leads to a faulty molecule that we call "messenger RNA." It's a molecule that takes the message of how to make proteins from the nucleus into the cell body, into the cytoplasm, and then specifies how a protein is made.

So, as I said, there's an expansion of a DNA repeat, which means the mRNA, the messenger RNA is expanded and the protein has an expanded polyglutamine domain. So we thought, "Why don't we try to attack the faulty messenger RNA and make a molecule that is complementary to this messenger RNA, it binds to it?" And then, what the cell does is actually, when it sees a new molecule made out of a messenger RNA and a piece of DNA, it actually targets this new artificial molecule and destroys it. And that's really the basis of these antisense oligonucleotides. They're called antisense because they are complementary antisense to the messenger RNA. And the oligonucleotide just means they have between 18 and 22 base pairs, so they're much shorter than a long messenger RNA.

And then, when this happens, an enzyme comes in, chops up the messenger RNA, so it's not present anymore. The antisense oligonucleotide is released and can undergo another round of binding to messenger RNA. So, with modifications, these new molecules are very stable and can be effective for therapy.

Dr. Clardy: And if I'm understanding what you're explaining correctly about this mRNA approach, this could really potentially be used in people who are known to have inherited the mutation but aren't yet having symptoms. Is that right?

Dr. Pulst: Yes. Yes, that's actually our hope for genetic disease to target diseases as early as we can. It just makes the point for our listeners that it's important to ask your neurologist to really get to the basis of a disease, to get to the correct name of the disease. And sometimes that means being referred to a specialist who really lives with these diseases and knows a lot about them.

Dr. Clardy: You make a really great point there, which is it's one thing to treat the symptoms, but perhaps the strength of the University of Utah or other academic medical centers too is that while we're treating the symptoms, while we're addressing where the patient's at, we also want to know what caused it in the first place. And your lab is, obviously, one of the extreme examples of that where you've actually found the mutation. So what phase of trial or study is this antisense oligonucleotide in right now?

Dr. Pulst: Okay, let me step one step back because it's important to realize, when I said that these ataxia sometimes are really neurodegenerative diseases that affect other nerve cells as well, and we recognized, just by seeing patients, that some of them had characteristics of Lou Gehrig's disease or amyotrophic lateral sclerosis. So, clinically, we saw that there appeared to be a connection between SCA2 and ALS. A colleague and friend of mine at Stanford, Dr. Gitler, then discovered molecularly a link between SCA2 and ALS.

So when we drove the development of this antisense oligonucleotide to ATXN2 forward, we partnered with a pharmaceutical company called Ionis and developed this initially in mouse models of ataxia but also in mouse models of ALS. And this molecule, the best one we identified in mouse studies and in studies in non-human primates, has now gone into a Phase I trial in ALS patients. And the reason it's in ALS patients, this is a more dramatic disease, very often, unfortunately, leading to death in three to five years, in some patients even earlier. And there are more ALS patients than SCA2 patients. So the dose finding study, knowing how much of this ASO to inject, is done in ALS patients. And a few patients have been injected so far with this new compound.

Dr. Clardy: It is very exciting, and it is really . . . you know, the neurodegenerative diseases are sort of the last frontier in neurology, right? They have, historically, hit a wall when it came to trials. And it sounds like your work and obviously the work done in other conditions and using antisense oligonucleotides is really the most exciting thing to come around in our entire generation.

Dr. Pulst: I agree. I think it's remarkable that really this dream of finding the genetic causes of disease actually now is leading to therapy. And I think another point is that even if you work on rare diseases or very rare diseases, if you pursue it, you may obtain insights into more common neurodegenerative diseases, as this connection between ALS and spinocerebellar ataxia type 2 shows.

Dr. Clardy: Well, I know certainly when I see patients in our shared clinics who have a neurodegenerative disease, I really love telling them that, just down the hall, you're doing work on this and you're making progress. But I want to know what advice do you have for patients who are diagnosed with neurodegenerative diseases?

Dr. Pulst: I think the first line of advice is try to really find out what your neurodegenerative disease is. Does it have a name? Does it have a genetic cause? And that often requires to go to specialists or sometimes, as I call them, sub-specialists or sub-sub-specialists who really know about the disease. It is still true that there are actually very few ataxia specialists in the nation. And patients fly to Utah as they do to other ataxia centers to find the right diagnosis.

Genetic testing these days is less expensive than getting an imaging study. And insurance companies are slowly learning that it's the right way to go and to support these tests.

The other general piece of advice is be part of clinical trials. I think we know that patients do better when they're in clinical trials, even if they just "get the placebo." So you get to see specialists. You get followed up. People take great care of you. So I think that's the other one.

Dr. Clardy: Well, thank you, Stefan. Again, I've been speaking with Stefan Pulst, our Chair of Neurology here at the University of Utah, on his groundbreaking work on spinocerebellar ataxia and the possible translation over to amyotrophic lateral sclerosis as well. To learn more about his research, to support the lab, or any of the many, many research projects and labs here at the University of Utah, you can just go ahead and google "University of Utah neurology" where you'll find links about all of the ongoing departmental activities and information on how you can become involved.