Protecting Memory After TBI and in Alzheimer’s – New Hope from 15-PGDH

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Daniel I. Simon, MD: Thank you for listening to another episode. Today, I am happy to be joined by two very special guests, Dr. Sanford Markowitz and Dr. Andrew Peiper.

Welcome, Sandy and Andrew.

Sanford Markowitz, MD, PhD: Thank you, Dan.

Andrew Pieper, MD, PhD: Thanks, Dan.

Daniel I. Simon, MD: Dr. Markowitz holds the Markowitz-Engels Professorship of Cancer Genetics at the 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 his clinical practice, he is an attending physician at the UH Seidman Cancer Center. Dr. Pieper is a board-certified psychiatrist and neuroscientist in the Department of Psychiatry at Case Western and University Hospitals, where he serves as a professor in the Morley Mather Chair in Neuropsychiatry. He is also the Director of the Center for Brain Health Medicines in the University Hospitals Harrington Discovery Institute.

As you can see, I'm joined by two superstars, and we're going to have a very special talk today. Before we get started, our listeners always like to hear your personal story. Maybe Sandy, we could start with you. Tell us a little bit about how you got into medicine, where you grew up, where you went to school, maybe your key mentors, and how did you get to Cleveland?

Sanford Markowitz, MD, PhD: I grew up in Pittsburgh, Pennsylvania. Went to the Pittsburgh Public Schools, got a scholarship to go off to Harvard, and then did the MD-PhD program at Yale, internal medicine training at the University of Chicago, and then oncology fellowship at the National Cancer Institute. Cleveland was my first job out of training, and it proved to be a wonderful place to build a scientific and medical career, and so there was never any reason to accept any offer to leave.

Daniel I. Simon, MD: Wow, it's a great path and very similar to a lot of us who've touched Boston at some point in our career, so that's really great. Andrew, how about you?

Andrew Pieper, MD, PhD: I grew up in the Midwest in Evansville, Indiana, and I went to Earlham College in Richmond, Indiana, where I majored in biology and chemistry. And then I did my MD-PhD training at Johns Hopkins University in Baltimore. And then I bounced around a little bit, Texas and then Iowa for a while, and then eventually landed in Cleveland, to work here at the Harrington Discovery Institute.

Daniel I. Simon, MD: Wow, that's great. So, we're getting the products of a lot of great institutions who've come here. What's really interesting here is that you might be wondering how do a cancer biologist and a psychiatrist get together for a totally different approach for Alzheimer's disease and for dementia following traumatic brain injury?

So maybe, you know, tell us, how did you guys…how did you hook up for potentially a whole new target in, degenerative neurology?

Sanford Markowitz, MD, PhD: I think the big picture, Dan, is that we're actually asking the same question. Cancer is about cells that are supposed to die and won't, and neurodegenerative disease is about cells that are supposed to live and won't. So, the big insight was to realize we were talking about the same pathways, and we just had to control the way they were behaving.

Andrew and I had the good fortune to have a great mutual friend in common, Joe Reedy, a wonderful medicinal chemist at the University of Texas Southwestern, where Andrew had been. It was Joe who introduced us.

Daniel I. Simon, MD: Wow. So, Sandy, we're going to get to an enzyme, your favorite enzyme, 15-PGDH, and that was something that you played a fundamental role in discovering in colitis, so inflammation in the colon and in bone marrow physiology. So, tell us a little bit about that enzyme, and then why was it natural for you and Andrew to get together?

Sanford Markowitz, MD, PhD: The enzyme came onto our target screen because we discovered that it was one of the key effectors to a pathway called TGF-beta that we had shown was a major pathway inactivated in the development of colon cancer. And as we understood the role of this enzyme, 15-PGDH, what we originally saw was that it was shutting off stem cells in the colon.

That's why it was shutting off tumors. We wondered whether perhaps it might be useful to shut it off for medicinal purposes, particularly after an injury like the destruction of the colon by colitis. We hooked up with Jim Wilson, my former partner here at UH, who was down at UT Southwestern, to go on a drug discovery hunt and try to find a drug that could shut PGDH down in people who had had an injury like colitis.

And we were able to show that we could find a small molecule. It was incredibly potent. We could dilute it down to one part in a billion. It would still protect the mouse from colitis, and then working together with Stan Gerson, who was head of the cancer center at the time, and a hematologist, we showed it had the same ability to protect the bone marrow that it had in the colon.

So, we had two very different tissues, bone marrow and colon, where this was protective. And Andrew, to his great credit, was willing to jump off the diving board with a what if question, which was, "We can't explain why it would work in the brain, but what if it did?" so Andrew was at Iowa at the time, and he liked the what if question, and we sent him some of our compound to try in his models of brain injury. We got this wonderful email back one day saying, "Guess what? It works." And that was ten years ago. It's only taken us all that time to figure out how it works and how you would use it.

Daniel I. Simon, MD: So, you know, Andrew, for a lot of our listeners, we know that amyloid and tau is really important, but there's so much more to the brain. There are 100 billion neurons, but there are 100 billion astrocytes, oligodendrocytes, and microglia, and there's this thing called the blood-brain barrier. So, tell us from a brain science standpoint, is Alzheimer's an inflammatory disease?  Are there common mechanisms where you would think something that worked in colitis could work in Alzheimer's? Tell us about new ideas of the pathogenesis of Alzheimer's - that this thing could actually work.

Andrew Pieper, MD, PhD: Well, in terms of new ideas about the pathogenesis of Alzheimer's, it's becoming pretty well recognized that there are a number of different secondary processes that really drive the disease forward, particularly at the stages where people start to have symptoms.  And some of those processes are things like neuroinflammation. Another one is decreased neurogenesis in a region of the brain called the hippocampus. The hippocampus is really important for learning and memory and emotional…assigning an emotional value to the things that we learn and for navigating our day-to-day experiences over the course of our lifetime.

And Sandy's work had shown that inhibiting this enzyme helped support the health of stem cells in the colon, and that was what made us wonder, "Well, what if this could also help support stem cells in the brain?" And the hippocampus is one of the few regions of the brain that makes new cells from stem cells that reside.

And so that was really the, the flyer, if you will, that we took was we wondered, well, if it's helping in this other part of the body with this type of cell might it also be helpful in the brain? And so that was a pretty straightforward thing to test. We administered Sandy's compound to mice and showed that it got into the brain, and then we saw that it was increasing not the proliferation of those stem cells, but it was actually increasing their survival.

So normally they're made, and they die at a certain rate, and when we gave the mice Sandy's compound, they were surviving at a much higher rate, and so that was one of the most exciting things that we found early on that gave us a clue that this could have an important role in the brain.

Daniel I. Simon, MD: That's really incredible. So, I think it's really important that in the last four to six weeks, social media platforms have been lighting up with the notion that these amyloid clearing antibodies have what are described as clinically marginal benefits. So yes, slowing progression, but if you really look at patient reported outcomes, meaningful reductions or improvements in quality of life, they're quite marginal.

So, it's always very exciting when we hear about new targets and new pathways that are independent of this primary amyloid hypothesis. So, of course, it's not what we think about it, but it's what the scientific community thinks about it. And we're sitting in front of two rock stars who won the Cozzarelli Prize from PNAS, which means, you know, top paper of the year.

So, maybe you could tell us…I'm sure your phones and your computers lit up with all your friends calling you. What does it mean to win a prize like that? Obviously, an impactful paper, but tell us about that. What was it like?

Sanford Markowitz, MD, PhD: It sort of makes your day for more than a, more than a month, that's for sure. It was a bolt out of the blue. It was unexpected and it was delightful. Everybody always welcomes the recognition of their peers, and this is a decision of the National Academy of Sciences, who are, you know, among the most distinguished medical-scientists in the country.

So, I think for Andrew and I, it was, it was wonderful validation, of an idea that when we began was pretty much outside the bounds of what people thought was, you know, real. It's fun to see it happen. And what I think Andrew and I both hope is that the bright light that it shines on this work will help bring us the resources to advance it forward for our patients.

Daniel I. Simon, MD: How about you, Andrew?

Andrew Pieper, MD, PhD: Yeah, first of all, I'll echo what Sandy said, which was that it was just a wonderful surprise - I just opened up your email and wow, we weren't expecting this at all. So, it was really nice to know that people were paying attention to our work and that they found value in it. I think one of the main reasons that it got so much attention was not only that it's new biology about the brain, but that in the Alzheimer's model, we protected the mice completely from developing Alzheimer's without interfering with the amyloid cascade at all.

So even though the mice still had plaques throughout their entire brain, we prevented the Alzheimer's disease from taking effect. And at a time when, as you say, the antibodies that are being used to try to treat Alzheimer's disease have been somewhat disappointing, so far. I think it got a lot of attention, and it made me very happy to know that the world is paying attention to other ways to treat the disease and that they're not just becoming or feeling like there's no hope.

Daniel I. Simon, MD: Right. So, in addition to the mouse models of Alzheimer, you use traumatic brain injury. Tell us a little bit about dementia following traumatic brain injury. Obviously, we know a lot about that from football players who have repetitive concussive injuries and the big concern over that, but in your paper, you actually administered the drug even after the brain injury, which gives even more promise because you know, you want to take this after you've been injured, and yet it was protective.

So, Andrew, I know that's a model that you use commonly. Tell us about dementia following traumatic brain injury.

Andrew Pieper, MD, PhD: I'm glad you asked that. Not that many people-- or it's not that well-recognized that a traumatic brain injury is the third leading risk factor for developing, aging-related neurodegenerative disease, especially Alzheimer's disease. The most significant factor is age. The second one is if you have a genetic predisposition that makes your brain less resilient in some way, and then the third one is have you undergone a brain injury? And it's now becoming increasingly appreciated that even after just a single, sometimes a mild TBI, some people suffer from a chronic neurodegenerative process that can persist for months, if not years. And that in some cases, that can trigger the advancement and the worsened severity of conditions like Alzheimer's disease.

Daniel I. Simon, MD: Wow. So that's a really impressive finding, in the paper as well. So, I think our, you know, our listeners want to know what are the next steps. So, both of you are part of the Harrington Discovery Institute. We're all about commercializing and getting drugs, as we say, into the clinic, into phase one clinical trials for first demand.

So, what are the steps that typically take, what kind of trials need to be done, and I guess most importantly, how many years does it take potentially to go through phase one, two, and three testing where this might get into routine use?

Sanford Markowitz, MD, PhD: Drug development's a rollercoaster, as, as you know well, Danm, it's easily an eight to 10-year process. We've licensed the original drug family that my lab developed to a large pharmaceutical company. The spotlight that Andrew's work and my work has shown on this pathway has now encouraged other companies to jump into the pool, and there's at least one biotechnology company, spun out of Stanford that also has developed drugs that'll inhibit this enzyme and has taken them into and successfully concluded phase one human trials.

So, the exciting thing is that we've put this class of drugs on the map. They are being developed. And now Andrew and I need to make the case to the companies that are interested in this target that a major disease that we should be targeting is neurodegeneration. Alzheimer's certainly being one of those.

We have to convince companies to optimize these drugs so that they'll penetrate the brain well. I would make the case may be here in the Harrington and at University Hospitals, we should say, "What the heck? We've done this successfully once. Let's do it again and optimize it for the brain."

Daniel I. Simon, MD: That's really great. So, Andrew, how about you? You think it's still about an eight to 10-year journey

Andrew Pieper, MD, PhD: Through phase three? Yes.

Daniel I. Simon, MD: Yeah. Yeah, I think the, you know, the really hard part with Alzheimer's has been the uncertainty that the mouse models predict human disease responses, and then just the very, very high bar because the trial endpoints, right, traditionally have been behavioral endpoints, not surrogate biomarker endpoints or imaging endpoints. And so, these are large trials, and with large trials comes, you know, a great expense. And so, yes, it is an uphill battle. However, all of our families are affected by dementia illness. I think there isn't a single person who doesn't have a relative or a close friend who's been affected by this. So, I'm really hopeful that you'll be able to cross into that.

Now, Andrew, I think we have to ask one more question because you've had a, a remarkable year in that you've not only shown that 15-PGDH changes cognitive decline in mouse models of Alzheimer's and traumatic brain injury, but your lab has independently and separately reported that you have one of the first Alzheimer reversal drugs targeting a whole different pathway.

Maybe just to tantalize our listeners…maybe we can invite you back...tell us about this exciting finding of really the first pathway that shows that you can actually reverse the disease.

Andrew Pieper, MD, PhD: We have a, a different agent, it's, it's called P7C3-A20, and it's been something that we've been working on in our lab for, well over a decade as well. And it works to optimize and stabilize mitochondrial function under times of cellular stress. And this is a vulnerability that is especially prominent in the brain because the brain is so energetically needy.

And what we showed was that when mitochondria are put under too much strain that coincides with the onset of disease, Alzheimer's disease. We showed that in human brain, and then we showed that it happens in our mouse models. And then we showed that if we wait until the animals are pretty sick, they have learning impairment, memory impairment, they have a lot of pathology in their brain, and we restabilize their energy levels by reestablishing their normal mitochondrial function that the brain can actually start to repair itself.

And over time, over the course of a few months in this study that we just published that you mentioned, the mice were able to learn and remember things just as if they never had the disease in the first place. And I think this study got a lot of attention because Alzheimer's has always been considered to be irreversible.

In fact, that's what we're taught in medical school, that it's the most common, most prevalent irreversible form of dementia. And, of course, we don't know what will happen in people, but in two different mouse models, an amyloid-based model and a tau-based model, we showed that the disease was reversible and that we could recover function simply by stopping the active degenerative processes from going on, even after a lot of neurons had died.

I don't think that our discovery of our molecule is going to be the only agent that's able to accomplish that, but I think what our study did show was that this is something that can be accomplished. And so, there are just… it opens up new ways to consider the disease and new ways to look for ways to help patients.

Daniel I. Simon, MD: Well, you know, we're so lucky to have both of you. I think, you know, I've learned a lot from both of you. One is that stem cells in the hippocampus are alive every day- keeping our, you know, involved in neurogenesis to keep us young. So that's good for us. And then the second thing, as you point out - that this is not an all-or-none thing.

These neurons, if you take care of their energy balance and you make them healthy, they'll keep their synaptic connections, and we'll keep our memories. So, I'm so glad to be joined by both of you. It's really an honor and a privilege to follow what you're doing and to bring you to our listeners.

Sanford Markowitz, MD, PhD: Dan, if I can just add one small thing. You asked a key question, which is, "will this work in people or is it just a story in mice?" And Andrew and I have tremendous optimism that it will work in people. And there's three reasons for that. First, Andrew has shown that the target, this 15-PGDH enzyme, is increased in patients - humans with Alzheimer's.

Second, the mechanism by which it works, which again is one of Andrew's key insights of protecting the blood-brain barrier, is well understood to be an important liability that drives Alzheimer's forward in people.

And third, the really fun scientific piece of this was that we realized that we were protecting the mouse brains not just by protecting stem cells, but also by turning off the inflammation. Andrew touched on this when he pointed out we weren't treating the amyloid. What we're allowing the mouse brain is to live happily with its amyloid by shutting off the inflammation that the amyloid normally engenders. And that too is understood to be a key facet of the human Alzheimer's disease. And we know that the cells that we're targeting, the inflammatory cells in the brain, have the same hardwiring in mice and in people with respect to this enzyme. So, for one, I am hugely hopeful this is going help people and not just mice.

Daniel I. Simon, MD: Well, Sandy, I think it's appropriate that we gave you the last word. It was about hope, and we will end now with saying let's bring hope to patients who really need it.

Sanford Markowitz, MD, PhD: Thank you, Dan.

Daniel I. Simon, MD: Thank you

Andrew Pieper, MD, PhD: Thanks, Dan

Daniel I. Simon, MD: To learn more about research at University Hospitals, please visit UHhospitals.org/UHResearch.

Conflicts of Interest: University Hospitals, Dr. Andrew Pieper and Dr. Sanford Markowitz could benefit financially from the outcome of this study.

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.