Can Inhibiting 15-PGDH Enzyme Protect Against Cognitive Decline in TBI Patients?

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[Dr. Daniel Simon] Hello, everyone. My name is Dr. Dan Simon. I am your host of Science@UH podcast, sponsored by the University Hospitals Research and Education Institute. This podcast features University Hospitals' cutting-edge research and innovations. Thank you for listening to another episode. Today, I am happy to be joined by two guests, Dr. Sanford Markowitz and Dr. Andrew Pieper.

[Dr. Andrew Pieper] Great to be here.

[Dr. Sanford Markowitz] Thanks. Delighted to be part of the discussion.

[Dr. Daniel Simon] So little introductions. We are joined today by some real scientific stars of University Hospitals and Case Western. Sandy Markowitz holds the Markowitz Ingalls Professorship of Cancer Genetics at Case Western Reserve University School of Medicine with appointments in the Department of Medicine and in the Case Comprehensive Cancer Center. He is internationally recognized for his work identifying key genetic causes of colon cancer and developing molecular tests for early cancer detection. In clinical practice, he is an attending physician at the Seidman Cancer Center.

Dr. Pieper is a board-certified psychiatrist and neuroscientist in the Department of Psychiatry at Case Western Reserve University and University Hospital Cleveland Medical Center. He also serves as a psychiatrist at the Louis Stokes Cleveland VA Medical Center and is an investigator in the University Hospital's Harrington Discovery Institute, where he is the Director of the Center for Brain Health Medicines.

It's so nice to have both of you here today, and I want to dive right into this incredible topic, which is we have a colon cancer doctor and a psychiatrist collaborating on ways to protect the brain from Alzheimer's disease and traumatic brain injury by targeting a very interesting enzyme, 15-prostaglandin dehydrogenase, abbreviated as 15-PGDH. This breakthrough, as we said, comes from the combined expertuse of two very different specialties. So, before we dive into this project, Sandy, maybe you could just give us a little background on your favorite enzyme, 15-PGDH, how you got there, and how you went from colon cancer to Alzheimer's with that enzyme?

[Dr. Sanford Markowitz] Well, Dan, 15-PGDH is an enzyme, meaning it runs a chemical reaction that chews up a bunch of molecules that are involved in inflammation. And we had discovered it because we were interested in colitis and discovered that this enzyme promoted inflammation in the colon. And that if we took away the gene for it, we could protect the colon from colitis. That set us off with the idea if it's an enzyme, we ought to be able to poison it, find a drug for it. And so, we set off with a common collaborator of Andrew's and mine over a decade ago now at UT Southwestern. We looked at a corridor of a million different small molecules. We got very lucky and found one that could effectively turn this enzyme off and protect the colon. And then that collaborator connected Andrew and I, and we thought, well, if this thing protects from inflammation in the colon, maybe it should do it in the brain. Now, that was an absolutely wild and crazy idea, because based on what we knew then, it really shouldn't have worked. But Andrew was as much tickled by the idea as we were, and so agreed to take a flyer with us, and it did work. And so now we have to figure out how and why.

[Dr. Daniel Simon] Well, that's really interesting. And so, I guess immediately, Andrew, we got to ask you, I mean, you can't turn on the television now without ads for amyloid clearing antibodies, right, that are going to slow the progression of people with dementia. So, this is a completely different approach than targeting amyloid and clearing amyloid. Tell us how does inhibiting 15-PGDH somehow play a role in cognitive decline? Where did you come up with this idea?

[Dr. Andrew Pieper] Yeah, well, as Sandy mentioned, we started working together to see how it might impact the brain. And what we found was that it was actually really highly enriched at a part of the brain called the blood-brain barrier. And within the blood-brain barrier, it was really highly enriched in a certain population of cells that produce, that damage the blood-brain barrier during the process of neurodegenerative disease. And so in a nutshell, what we found is that it works not by the more traditional ways that you might have heard about, which are directly attacking the amyloid, which in many cases can drive certain aspects of the disease, but it actually protects the blood-brain barrier by lowering that amount of damage that can happen. And when the blood-brain barrier is functioning better, the brain can better withstand the amyloid problem that it has, and it can fight it off better. So essentially, we're helping the brain function better for a longer period of time.

[Dr. Daniel Simon] It's obviously really exciting because this is a devastating disease. It affects almost all of our families from some relative or very close friend. And so, knowing that we potentially have more arrows in the quiver, hitting more targets is potentially very interesting.

What I wanted to do was to hit on another slightly different area than Alzheimer's. And Andrew, you mentioned that you have a very strong interest, obviously, in cognitive decline after traumatic brain injury. And so, we think of vascular dementia, small strokes in the brain, potentially leading to dementia, but we think a lot of Alzheimer's. How many people have cognitive decline from traumatic brain injury? And how is this drug working in those patients?

[Dr. Andrew Pieper] Well, the problem is massive worldwide, millions of people and it's not just what happens acutely after the brain injury, but it's the fact that in many cases, sustaining a brain injury creates a chronic neurodegenerative process that can go on for a lifetime. And people don't really understand why that is. And what we found in this study together was that the same mechanism that was protecting the brain in Alzheimer's disease by just helping the brain function better to do what it should normally be able to do, that that same mechanism also protects in traumatic brain injury. And we have a pretty rigorous model of traumatic brain injury in our lab that faithfully recapitulates the complexity and a lot of the acute and chronic effects that happen with TBI in people. And what we found was that if we administer this injury to animals and then we wait 24 hours and then start inhibiting this enzyme, that that process of preserving the blood-brain barrier is also protective and prevents the animals from experiencing any of the problems they would otherwise have had after the injury.

[Dr. Daniel Simon] So, I guess the question here for both of you, given your experience with both the compound and then obviously you, Andrew, and the brain health space, would this be something that you would give to patients with a family history of Alzheimer's? Would you wait until they had mental status assessments of tests that show mild cognitive decline? How do you envision that this drug would actually be used clinically? Andrew, maybe to start.

[Dr. Andrew Pieper] Yeah, I mean, that's a really good question. Obviously, I think that the field thinks that as soon as somebody might be suffering from Alzheimer's disease in any capacity, that you would want to start a treatment if there's a treatment that's available because it's a progressive condition and the earlier you start treating, better success you're likely to have. Since our particular angle here approaches the blood-brain barrier, if you knew you were at risk for Alzheimer's disease, there are ways that you can image the blood-brain barrier and that could be something that could be monitored in people who, for example, knew they were at risk, and if they were having a problem, perhaps this treatment could be started then.

[Dr. Daniel Simon] Well, it's very exciting because I think in our families, it starts with grandparents that you know who've had cognitive decline, and then you obviously develop concerns for your parents and then obviously for yourself. And so, it's very exciting to think that there's something that is fundamentally targeting one of the causal pathways.

Sandy, you've had a lot of experience with this compound for other indications. Tell us a little bit about that journey, because this has obviously been licensed for different indications, and you've been down a very interesting path. Tell us a little bit about the early stages and other indications for 15-PGDH inhibition.

[Dr. Sanford Markowitz] Well, as we chatted about a moment ago, Dan, originally, we discovered that this compound was protective in mouse models of ulcerative colitis. And what we focused on there was the discovery that inhibiting PGDH was targeting stem cells in the colon to allow them to proliferate and re-line the colon so that it didn't become ulcerated. That's why the experiment that Andrew and I did really shouldn't have worked, because the brain's not a rapidly proliferating organ. But we've come to understand that this is a very ancient pathway and that it's really designed to help tissues withstand injury. So, the next step we took was the finding that in a model of lung fibrosis, idiopathic pulmonary fibrosis, to use the medical name, that we could stop the damage and protect mice from dying from lung failure. And that was eye-opening because that's a much more complicated disease than colitis. We still don't totally understand all of the ways in which the compound protects the lung, but it sort of allowed us to then jump into the brain. And in the brain, what we realized we were doing was turning off a key reaction that's involved in inflammation and brain damage. So, the inflammatory cells in the brain produce what's called reactive oxygen, which is basically chemically household bleach, right? They do this because it's a good way to kill bacteria and other pathogens. But when it's produced in excess and gets out of the cells, it also starts bleaching your brain, which you definitely don't want. So, what we're really doing here is allowing you to live with your amyloid by shutting off the toxic development of this bleach-like chemical that can damage the blood cells of the blood-brain barrier. So, it's been an iterative process of adding one brick to another and understanding how this pathway works.

[Dr. Daniel Simon] It's really exciting. And I think this is the power of having research collaboration and multidisciplinary teams. And it reminds me of countless times where you have a scientific symposium, and someone presents their own work. And after their talk, you go up and you start saying, you know what, this might be relevant to my disease, let's get together. And it's that those almost magical moments of having you and Andrew, even if introduced by a matchmaker friend, to say, hey, maybe you guys should get together is really amazing. So, help us understand for all of our listeners who aren't as experienced in drug development as both of you are...so what's the path now? You have mice that are protected in traumatic brain injury. You have mice that are protected in models of Alzheimer's and amyloid accumulation. What's the next step and how do you get into a patient? So, Andrew, why don't you start with that? What is the IND that you will need to do first in man with this compound?

[Dr. Andrew Pieper] Yeah. Well, actually, if it's okay, I think I would like to have Sandy start with that because he's been involved in the process of this for a peripheral indication so far so maybe he could tell us where that is and the next one.

[Dr. Daniel Simon] Sure, Sandy.

[Dr. Sanford Markowitz] Well, the process was an interesting and educational one. It started with our creating a biotech spin-off with the support of University Hospitals and Case Western Reserve. We found an incubator, and it was sponsored by Johnson & Johnson and AbbVie, a couple of other large drug companies, created a company called Rodeo. And Rodeo's job was to find a way to make the original compound that we discovered something that you could take as a pill. Something that you could swallow, be absorbed, give you good blood levels, because we were injecting it into mice in their belly, not definitely a user-friendly approach. And Rodeo worked for about four years and then one day, Amgen, another large pharmaceutical company, came knocking on the door and said, we know what you're doing - we want to buy it. So right now, Amgen has purchased the program, and it's in their hands for clinical development and to bring it forward to human patients. And we are in the midst of an interesting discussion with them of exactly what would they need to see to make neurodegeneration one of the areas that they would bring this compound forward for. Obviously, when they bought it, Andrew and I hadn't yet published our work, so this is new to them as well, but we very much want to make the case that this is one of the disease indications for which they should be advancing this program.

[Dr. Daniel Simon] So, under your combined pharma experience, we know the time from phase one to phase three typically could span five to seven years by the time you have all the results. What do you think it's going to take on a timetable, just a range of when you think you might be able to do a phase one in humans for dementia? Andrew.

[Dr. Andrew Pieper] I think that's going to depend on how things proceed with Amgen, et cetera and I'm not trying to punt the question. I just don't quite know the answer. In theory, it shouldn't take that long. We just need to identify our lead molecule that goes through two species toxicity testing and then put it into phase one clinical trials, and that could conceivably be done within one to two years. But it will be complicated, I think, by whether or not this is an indication, for example, that Amgen is interested in pursuing.

[Dr. Daniel Simon] Got it. And Sandy, what do you think from your experience with this drug and others?

[Dr. Daniel Simon] So, I would concur with Andrew's assessment. This could happen tomorrow if somebody would push the button. What we have to do is really make the case to the folks who are shepherding this program now at Amgen that this is such a high impact for human health, that understanding that this wasn't the reason they originally bought it, they should be prioritizing making this the reason now that we advance it.

[Dr. Daniel Simon] Well, it's really very exciting. And I want to thank both of you for, first of all, seeing the possibilities of working together, a colon cancer specialist, a neurodegeneration specialist coming together for an enzyme that prevents superoxide development in macrophages to save the blood-brain barrier. So, thank you so much for doing that.

And I want to thank you all for listening today and for taking the time to speak with me, Dr. Markowitz and Dr. Pieper.

To learn more about research at University Hospitals, please visit UHhospitals.org/UHResearch.

Thank you, Sandy and Andrew.

[Dr. Andrew Pieper] Thank you, Dan.

[Dr. Sanford Markowitz] Thank you, Dan, and thank you, University Hospitals, for giving us a home together.