Barbara Slusher, PhD, Professor of Neurology, Pharmacology, Neuroscience, Psychiatry, Medicine, and Oncology and Director of Johns Hopkins Drug Discovery talks about treating IBD with something new.
Interview conducted by Ivanhoe Broadcast News in 2024.
This is such an interesting and exciting issue to people because they either suffer from it or they know someone who does. Can you tell us what you found with this protein and then the connection between neuro and tummy?
Slusher: This is a very exciting project. This is an enzyme called GCP2, or glutamate carboxypeptidase 2. This is an enzyme that I’ve been studying for, like, three decades. It exists in the brain and we’ve been studying it as a way to regulate neurological disease. The problem has been that we’ve developed all these potent drugs that don’t get to the brain very well. It’s hard to get drugs across the blood-brain barrier. And so a couple of years ago, we almost gave up on this project. But about that same time, there was a group of scientists working in gastroenterology that found that this same enzyme, which is typically not in your gut, increases dramatically if the patient had inflammatory bowel disease (IBD). And when I say increased, I mean up to 30-fold. This is a huge increase. So given that we had drugs that inhibit the enzyme, we asked the question, if we gave our drugs – which we can’t get to the brain, but we can get to the gut – to animals that had an IBD syndrome would they get better? We ran this experiment and found that the animals’ IBD symptoms improved dramatically, which was very exciting.
Did you start targeting the brain and then found out it was here, or what was the chronological process?
Slusher: We started studying this enzyme in the brain, for sure. We initially identified this enzyme in the brain and for over 20 years have been synthesizing drugs to inhibit its activity in the brain. The problem is that designing a drug that gets across the blood brain barrier is really tough. The GCP2 inhibitors we made were very charged and polar so they didn’t penetrate the brain very well.
The drugs that you made were what? And what were they going for?
Slusher: The drugs that we made inhibit the GCP2 enzyme. This is an enzyme, a glutamate carboxypeptidase, that clips glutamates off of peptides and proteins, and we designed drugs to inhibit that activity.
Because that’s a bad actor, right?
Slusher: Its increased activity in disease can be a bad actor in neurological disease, and now we’re finding its dusregulation could also be a bad actor in IBD.
That initial discovery was the “aha” moment for the whole thing, right?
Slusher: The synthesis of the GCP2 drugs was a definite “aha” moment and led to many different publications. I have over 100 publications on GCPII and its inhibitors showing that these drugs are useful for neurological disease. The sad thing is that we were never able to take this to the clinic because these drugs don’t adequately penetrate the blood-brain barrier.
But they will if you hit here?
Slusher: No, the point is that in IBD, GCP2 is overexpressed in your gut. If you take a pill, it can get to your gut. That’s a much easier tissue to target. And so we took our potent drugs that we had made that we couldn’t get into the brain, and administered them orally, and they got to the gut. That’s when we saw the efficacy of IBD symptoms in preclinical models.
So all of this work, all of these years that you’ve been working on this enzyme in the brain since grad school was targeting this?
Slusher: Unsuccessfully.
You kept going and then you discovered that It’s going to work in the gut right?
Slusher: So the same enzyme target in the brain is upregulated in patients that have IBD. And when we give our drugs to animals that have an IBD syndrome, their symptoms get better. So we are excited by this finding — this is a man-to-mouse story. We saw this abnormality in people who have IBD. We were able to recreate it in an animal, and then show in animals that our drugs could cure the disease.
The first time you saw that in the lab, were you just jumping?
Slusher: So when we first started this in the lab, we didn’t have expertise in IBD animal models, and so we worked with a gastroenterology group here at Hopkins. And the first model we tried worked perfectly. So it was so exciting to think that we had spent all these years unsuccessfully making drugs for the brain that now looked like they were finally going to have a therapeutic benefit in IBD that we could take to the clinic.
And a purpose for getting it into the human body. But if you had found out prior to this that you couldn’t penetrate that blood brain barrier, why did you just keep going at that point? Because you had to have known for some time.
Slusher: We made thousands of drugs trying to get them to cross the blood-brain barrier better. It has been an iterative learning process, with some small successes along the way, but not ever successful enough to take them into patients. The fact that inhibiting this enzyme in the brain is likely to have a huge beneficial effect on several neurological diseases, made us never give up.
What is that feeling like to you as a researcher?
Slusher: People ask me all the time, “You’ve been working on this for 30 years. Aren’t you bored? Don’t you want to do something else?” The truth is that I feel so privileged to have a job that pays me to do research. It is motivating to think that if we’re lucky enough, smart enough, and work hard enough, we could develop a medicine that helps people. There’s nothing else more rewarding than that.
What do you anticipate that’s going to look like for people who suffer from the disease?
Slusher: So people that suffer from inflammatory bowel disease have either ulcerative colitis or Crohn’s disease. Those are the two main categories. And currently, there are several medications that people can take, biologics and small molecule oral medications. But about 30% of patients are refractory to those treatments. And because this is a brand new treatment with a new mechanism of action, we hope that our drug would benefit hose patients that are refractory to current therapies.
Am I hearing that because it’s new, sometimes the body’s like, “what’s that?”
Slusher: Yeah. But these are questions that will only be answered through clinical trials. But the hope is that, given this medicine works in a different way than medicines currently available, it may be beneficial for IBD patients where current drugs don’t work.
People who currently have it or may not have yet been diagnosed or I don’t know, this is going to be drastically different. In what way can you describe that?
Slusher: Actually, no. So I can tell you how it makes a mouse better, but how that correlates to humans, honestly, that’s what clinical trials will teach us. And so I think to guess at this point would be just that.
So what did it do to the mice?
Slusher: In mice, our GCP2 inhibitor drugs have an effect on inflammation. In inflammatory bowel disease, there’s a large amount of inflammation in the gut. And so again, if you’re a mouse and we treat you, that inflammation is dramatically dampened.
Does that impact their appetite, their way of life, everything?
Slusher: Yes. Laboratory mice that have an IBD syndrome have issues with stool consistency, with body weight, and with blood in the stool. Again, we give our drugs to these mice and those three things are relieved.
That statement alone is incredible. Right now, this is such a huge area, not only in medicine but in advertising and more smart toilets. AI in computer algorithms and software, is that going to eventually get into the human usage aspect like this?
Slusher: I’m not sure, at this point, how AI will be able to contribute to how the drugs are used. But one thing that is happening in medicine is combinatorial treatments. One drug may not cure you, and several drugs may be necessary, and so I think in the IBD world, this may be used with other medications to get the best benefit. Perhaps AI, in the future, will be able to predict which patients will have the best benefit from what therapy.
So there’s a whole road ahead of trying other recombinants or covenants initially to see how well they work with this drug?
Slusher: Yes.
So you have all of that rolling out ahead of you. If you had to look at a chronological timeline of how long this is going to be, what does it look like?
Slusher: I lectured on this this morning. The average timeline from when one identifies a new drug to getting that drug into clinical trials, is usually a couple of years. And then getting the drug through phase 1, phase 2, and phase 3 clinical trials is another five to six years. If all that goes perfectly, then one has to file an NDA with the FDA and it is reviewed, which is another year or two. So the entire period is about 8-10 years.
So you still got that ahead of us.
Slusher: Agree. We still have that ahead of us. And there will be learnings that we’ll have throughout that process, like who benefits, and what combinations work the best.
But ultimately, the goal is to make people feel better that have this dreadful disease. And what is that going to look like in your mind right now?
Slusher: Well, yeah, There is tremendous gratification to think that my lab and colleagues were able to create a drug that could benefit people with IBD. There’s no bigger reward that one can get.
You injected this to the mice, is that correct? Is that how it got in?
Slusher: So the way we give it to mice is just like what we plan to do in people. We give the pill orally.
When you send it into the animal, into the mouse’s stomach, describe to us, physically, what’s happening with that.
Slusher: So what happens when you give it orally, just like when you take a medicine orally, it’s going through the mouth, pharynx (throat), esophagus, stomach and then to the small intestine which contains the duodenum, jejunum, and ileum. In Crohn’s disease patients, the ileum is where we see a large increase in the enzyme. So in that case, we would expect the enzyme inhibitor, this GCP2 drug, to be able to bind to this dysregulated elevated enzyme and control its activity.
What triggers this thing?
Slusher: That’s a great question that we’re actually in the lab trying to figure out why it goes up in the first place.
How does it go up?
Slusher: Yeah. So again, what we see in patient biopsies in Crohn’s disease where we see the highest GCP2 elevation, is anything from three-fold to 30-fold increase in the activity of this enzyme. So it’s not a little increase. This is a very large increase.
And how long does that take? Let’s say at the beginning, some of these perfectly normal and then all of a sudden, it starts?
Slusher: That’s a great question. So the way that we’ve answered the question is to study biopsies from patients that go into the clinic for exploratory colonoscopy. That’s how we found that this enzyme activity is upregulated in the first place. If we look at normal ilium versus ilium from a patient that has Crohn’s disease, we see a very large increase.
Do you get rid of the colon?
Slusher: You’d have to take your colon out. This is an intricate part of your intestines, so that is probably not feasible.
Do you think it’s partially the Western diet or what are the triggers that set this all?
Slusher: It’s a great question that we really don’t have an answer to. One of the things the lab is trying to study right now is the regulation of the expression of this enzyme. What causes it to go up? What causes it to stay elevated? What causes it to go down? We don’t have answers, but it’s an area of investigation for the group.
Do you put some artificial thing in there to try to trigger it?
Slusher: You can addreess those types of mechanistic questions in cellular systems in a culture dish. We can give the cell various stressors like oxidative stress, cytokine stress, things that we know will activate these cells and then see if the enzyme is abnormally regulated in those conditions.
You mentioned cytokines. Did you learn anything through the pandemic?
Slusher: We learned that it’s really hard to do laboratory work during the pandemic. It was very difficult to keep experiments going during COVID. We ran the lab almost on a 24 hour basis. Our labs typically have eight people working in one lab, and during COVID we are allowed one or two. So we devised a round-the-clock rotation system. It was very difficult.
Initially, what causes the disease of IBD to just get on the roll, if you will, because surely everybody’s got the same material inside but something goes away?
Slusher: Just like many other diseases, some of this is genetic. There are some known genetic causes where IBD will run in families. But the other triggers can be environmental triggers such as stress, smoking, medication use, and depression. Others, we don’t know what causes the flare-up.
Not organic foods, anything. You just don’t know. There’s a lot of mystery surrounding this.
Slusher: There is a lot of mystery as to why and when a patient gets a flare-up and when it subsides and goes into remission.
And from your investigatory research, are you trying to determine if it’s trigger a, let’s just say it’s pesticide. Then we’re going to make this tweak here. Is that what you’re talking about with recombinant of medications?
Slusher: No, not at all. What I do is I make drugs. We figure out what could be causing the disease, and then we try to design drugs to cure that, or to alter that, or to normalize the process. And we do that by modeling the disease in animals. Once we’re successful, we hand off the project to a commercial entity that would move the drug from the laboratory into clinical trials. So really, our focus is to understand the disease, understand the targets that might be causative or involved in the disease., try to make drugs that normalize it., and then move those out of academia, out of our lab, into clinical trials.
Describe to us what you have discovered.
Slusher: In our elevator pitch, I say that I’ve worked on this enzyme target in the brain for 30 years. We’ve successfully made very potent and selective drugs that inhibit this enzyme. But we’ve been unsuccessful moving these into patients because we can’t adequately get the drugs into the brain. But now that we know the same enzyme is abnormally regulated in patients who have IBD. Our drugs can get to the gut and can normalize this abnormal enzymatic activity and have therapeutic benefit, and at least if your mouse. Now we’re excited to take this into the clinic to see if we’ll have the same effect in patients that have IBD.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
If you would like more information, please contact:
Caslon Hatch
Sign up for a free weekly e-mail on Medical Breakthroughs called First to Know by clicking here
