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On January 22, 2021, Glaucoma Research Foundation presented an Innovations in Glaucoma Webinar: "Understanding Vision Restoration."
Watch the recorded webinar:
The 40-minute webinar features a presentation from Derek Welsbie, MD, PhD, a principal investigator in the Catalyst for a Cure Vision Restoration Initiative. The webinar is moderated by David Calkins, PhD, the Chair of GRF’s Research Committee and Chair of the Catalyst for a Cure Vision Restoration Scientific Advisory Board.
Derek Welsbie, MD, PhD
Assistant Professor of Ophthalmology, San Diego Shiley Eye Institute
University of California, San Diego
San Diego, CA
David J. Calkins, PhD
Vice-Chairman and Director for Research for the Vanderbilt Eye Institute and the Denis M. O’Day Professor of Ophthalmology and Visual Sciences at the Vanderbilt University School of Medicine
Director of the Vanderbilt Vision Research Center
Chair, GRF Research Committee
Chair, Catalyst for a Cure Vision Restoration Scientific Advisory Board
David Calkins, PhD: Good afternoon everyone, and welcome to our webinar, Understanding Vision Restoration. For those of you who are familiar with Glaucoma Research Foundation, you already know this, and that is that glaucoma is a devastating, blinding eye disease. For those of you who are less familiar, glaucoma is the number one cause of irreversible vision loss worldwide, and that's a lot of people. With some estimates, over a hundred million in the next decade or so.
And so, what we're going to talk about today, Understanding Vision Restoration, is focused on treatments that address the underlying causes of vision loss which are largely neurological in their origins. And so, welcome, and I'd like to tell you just a little bit about me before we continue. My name is David Calkins. I'm going to be the moderator today. I am the chair of the Catalyst for a Cure Scientific Advisory Board. And I have the privilege of overseeing these amazing scientists who are involved in Catalyst for a Cure, one of which, Dr. Derek Welsbie, you're going to hear from today.
I'm also the chair of the research committee for Glaucoma Research Foundation. When I'm not doing that, I am the assistant vice president for research at Vanderbilt University Medical Center, and the vice chairman and director for research of the Vanderbilt Eye Institute. I also direct the Vanderbilt Vision Research Center. And I'm a trained neuroscientist. And that's how our focus began with Catalyst for a Cure many, many years ago, by focusing on the underlying roots of vision loss in the retina and in the optic nerve.
And now what I'd like to do is introduce our speaker, Dr. Derek Welsbie, who is not only a talented scientist, but a glaucoma specialist as well. Derek is one of the members of the Catalyst for a Cure right now and has trained in glaucoma for a long time. He was the chief resident and also did a glaucoma fellowship at the Johns Hopkins University, and then moved from Baltimore to the University of California at San Diego. He is very, very, very active in both medical ophthalmology and also surgical ophthalmology. He specializes, once again, in glaucoma. And in his spare time, which I imagine is not much at all, he happens to have a wonderful laboratory where he uses something called high-throughput genetics to search for new therapies for glaucoma. So Derek, welcome, and the floor is yours.
Derek Welsbie, MD, PhD: Thank you very much. Thank you to Dr. Calkins and the GRF for inviting me here to speak on behalf of the entire Catalyst for the Cure team. So, this is the location where my lab does research, but there are three other team members for the Catalyst for the Cure. And the work you're going to hear about today is the collaboration of all four of us. Even though it's me presenting, this is really work done as a team. And that team consists of Xin Duan at UCSF, Anna La Torre at UC Davis, and Yang Hu at Stanford.
First let's start with some background. Here is a cartoon of an eyeball, and you're seeing it visualizing light. As people might know, the eye focuses the light onto a tissue in the back of the eyeball called the retina. The retina is made up of many different types of cells, but the one in particular that's relevant to glaucoma is called an optic nerve cell. And you'll sometimes hear me slip and call it a retinal ganglion cell, which is the terminology we use in science, but it's the same idea.
Now I'm showing you one optic nerve cell. In reality, there are about a million optic nerve cells lining the retina, with each one responsible for about one pixel of your vision. And each optic nerve cell has a long fiber that connects that point on the retina to a corresponding point on the brain. If we looked in the optic nerve, all the optic nerve is, is a collection of those fibers.
If we looked inside, we would see about a million of those fibers, one for each of those optic nerve cells. So, what happens? Light is focused by the eye onto the retina. That information is processed by the retina, and then transmitted via the optic nerve cell, via that long fiber, back up to the optic nerve, back to the brain where we experience that as vision.
So, what happens in glaucoma? What I'm showing you now is a photograph of a retina. This is what your ophthalmologist sees when they dilate your eye and they look in. We can't see individual optic nerve cells, but we can see where their fibers coalesce at the optic nerve as shown here. So, just to make things easier, I've overlaid a cartoon showing 12 optic nerve cells. And of course, there are a million here, but I'm only showing you 12. So, what happens in glaucoma? So first, I'm going to show you also the visual field. This is what the patient sees when we test them with the perimeter. And this little area right here, that is your optic nerve. That's normal. I's called the physiologic blind spot. So, everyone has this dark area. Also, remember that optics of the eye invert the image so that things are flipped. So, what happens is you have injury at the optic nerve head. That leads to degeneration of the fiber of the optic nerve cell. And after that, you get death of the optic nerve cell. And that sequence of injury, fiber degeneration and cell death, was actually discovered by Dr. Calkins and his collaborators in the first Catalyst for the Cure.
Well, once those optic nerve cells die, that point on the retina is no longer connected to the brain. And so, that disconnected area forms a visual field defect. As the disease progresses, more and more cells die, and more and more areas become disconnected leading to enlargement of the blind spot, as shown here. Eventually, this continues, and patients, unfortunately, can lose all their optic nerve cells, which means no part of the retina is connected to the brain, and the patient can have total darkness in the eye.
So, what do we do to treat this? All of our treatments, whether you've heard about the various eyedrops, or laser therapies, or surgical interventions where we take you to the OR and we do cutting and sewing surgery, all of them work by lowering eye pressure. In fact, we've been lowering eye pressure for 150 years for glaucoma, and that's the only treatment available.
What's interesting, if you look at glaucoma patients as a population, only about half have ever even had an elevated eye pressure. And this speaks to the idea that Dr. Calkins talked about, which is that glaucoma is a neurologic disease. It's a neurodegenerative disease characterized by the death of these neurons, these nerve cells called optic nerve cells. It's not an eye pressure disease. But eye pressure is the major risk factor. And so, we can do a good job of controlling the disease in some patients by lowering eye pressure. But the disease at its crux is really a neurologic disease.
Another thing to keep in mind is that when you look at patients who are followed by glaucoma specialists at major academic centers, one will find that patients continue to go blind despite pressure lowering some years after their diagnosis. In other words, pressure lowering is good, but it is not a perfect therapy. So, for both of these reasons, we need to understand what's actually going on with these nerve cells and come up with ways to block that and to allow these cells to regenerate.
In 2021, for patients who have lost all of their optic nerve cells, or a majority of their optic nerve cells, and who have loss of vision, we have no treatments to restore vision. In fact, for those that are totally blind, we can offer them only the cane or the [guide] dog. So, what are our challenges at the Catalyst for the Cure? Well, I think it's really two things. One, to protect the cells you already have, and two, replace the cells that have been lost.
It was discovered by my lab and others several years ago that there were certain genes in these optic nerve cells that were really important for this death and degeneration process. This is actually work done by Trent Watkins in Joe Lewcock's lab. And this is a mouse, and what you're looking at in this mouse is a picture of the retina. If you have this gene called DLK, and you injure the optic nerve like in glaucoma, optic nerve cells die just like in glaucoma. And that's what's shown here. There's no retinal ganglion cells, no optic nerve cells left. This branching tree here is actually just the remaining blood vessels.
In contrast, if you have the same mouse, you do the same injury, but it's missing just that one gene, you find that the optic nerve cells survive, and they survive for months and months and months in the mouse, which is a long time for a mouse. So, that was exciting. But we also want to restore vision, not just keep the cells you have.
So, it turns out there was a flip side to this story. There are ways to make optic nerve cells regenerate their fiber. So, if they have their fiber going back to the brain, we can cut that fiber, and there are things we can do to cause that to regenerate. And that's what shown at the top. However, if we remove that one gene, DLK, we find that we no longer get that regeneration, which is unfortunate. It means there's this fundamental opposition. Right? You can keep cells alive, but we can't get them to regenerate. Or there are interventions that can get them to regenerate, but they don't live very long. And this is true for DLK and for other genes.
So, we needed to find a way, for a meaningful vision restoration strategy, to be able to get these new optic nerve cells to survive and to regenerate their fiber. So, how do we do that? Well, ideally, I would do this by studying human optic nerve cells. Except I can't do that without blinding a patient and removing their optic nerve cells, so that's not possible.
So, a postdoc in my lab did the following experiment. This is work done by Amit Patel for my lab in collaboration with the rest of the Catalyst for the Cure team. We took blood from a patient at the Shiley Eye Center here at UC San Diego. From that blood, by putting in just these four genes, we can turn those blood cells into stem cells that have the ability to grow into any tissue of the body. We then genetically modified those stem cells so that if they become optic nerve cells, they'll turn red. We then give the stem cells the instructions to become retinas.
That ball you're looking at there is not an eyeball. That is a retina grown in a dish. And in red, you're seeing the optic nerve cells. Now, what I can do is I can purify the optic nerve cells, which means I can study optic nerve cells from that very patient without ever having to go into their eyeball to get the cells.
Then what do we do? This is the high-throughput genetics that Dr. Calkins referred to. We take those purified optic nerve cells, and we injure their fiber. Why do we do that? Because again, we're trying to mimic glaucoma, and that's how glaucoma happens. The fiber gets injured, the cell dies in response. So, we take those injured human optic nerve cells, and we put them into these multi-well dishes with thousands of little wells as shown here.
Now, if I don't do anything, what's going to happen? Well, just like in glaucoma, an injured optic nerve cell will eventually die. And so, all of the cells will die, so that's not useful. So, what I have to do then is use our robotic infrastructure here to add different chemicals to each of the wells. So, for instance, the first well might get this drug, the second well this one, third well, et cetera, et cetera. And we've done large libraries. We've done tens of thousands of interventions.
Then what we do is we would give the cells time to die like they normally will. And then we have a robotic microscope which goes through and takes pictures of each of the wells. And we have image analysis software that can automatically look at the picture, and it can count the number of surviving nerve cells, and it can count the number of nerve cells that are regrowing their fibers.
And so, we do this. And obviously the question then becomes, well, most of these wells died like they should, which means whatever drugs I added there didn't do anything. But whatever I added to this well here obviously is doing something pretty important because all these cells are surviving. So, we know what we add to every well so we can go back and say, "Gee, what was it that drug?"
And one might ask the question, "Well, why not just use that drug? It looks like you've discovered a treatment." But a lot of the drugs we're using are not actually therapies, they're not FDA approved, but they can teach us something. And the reason they can teach us something is you have to think about how a drug works. All of our cells have DNA, that code for various proteins. And what drugs do, they're like a key for a lock. They will go and bind to certain proteins and block their function, and they won't affect others.
So, for many of the drugs that we use, we know all the genes that they inhibit. In the cartoon I showed, I showed just that one well and that one active drug. In reality, we get many active drugs. So, what we can do then is use artificial intelligence and machine learning. If you know the pattern of all the drugs and all the things that the drugs work on, you can start to figure out what genes are actually responsible for this effect. And so, we did that. And we found that a set of genes called the GCK-IV kinases were very important.
So, we did this experiment with the human optic nerve cells. We asked what genes are important for survival? What genes are important for regeneration? And remember, those typically were different genes before. Are there any genes that are overlapped in the middle? And that was this group of three genes which we call GCK-IV kinases. For the purpose of this talk it's not important. Just that there is a set of genes that we can block that give us survival and improve regeneration.
So, this is actually what it looks like. These are human optic nerve cells. And on the left is what happens to human optic nerve cells if I injure them, if I injure their fibers. So, watch each of the cells and watch the fibers degenerate over time such that by the end of the time-lapse photography, there's really no fibers left. In contrast, by inhibiting the genes that we discovered through this high-throughput genetic approach, watch what happens to these human optic nerve cells. They're injured just like in the left, but now at the end of the time-lapse photography you see many of them continue to look healthy with healthy fibers.
This is obviously very exciting for us because we had found a set of genes that could give you survival and regeneration. But in all fairness, this is just on plastic. We wanted to make sure this was true in an actual animal. So, working with Yang Hu and Xin Duan, we tried to translate this to an animal model. And to do that, we used CRISPR gene editing. You may have heard about this. It's got a lot of good popular press recently. CRISPRs are like molecular scissors. Using this CRISPR technology, I can go in and selectively delete whatever gene I want.
Well, obviously we had discovered these three genes that we thought were important for survival and regeneration, so those are the ones that we use this CRISPR technology to target. And we did this in a mouse model of optic nerve injury or a mouse model of glaucoma. So, what happens is we go into the mouse, we use our CRISPR technology to delete those three genes. We then injure the optic nerve. And just like I've told you multiple times, when you injure the optic nerve, if you don't do anything, lots of optic nerve cells will die. And so, after two weeks, we can then look at the retinas of the mice, and we can count how many optic nerve cells are left, and how many are regenerating.
So, this is what it typically looks like. A healthy retina should have lots of green dots, but two weeks after injury, you just see a few green dots here. Each green dot is an optic nerve cell. And if you look, optic nerve cells, they try ... This is the optic nerve here in red. This is the site of the injury. These optic nerve cells, they try to regenerate their fibers, but they don't get very far. Obviously, if we could regenerate optic nerve fibers, that would be vision restoration, and this is the problem.
So, now let's go back to that first therapy I told you about before: DLK. If I inhibit DLK, the protection is profound. I get lots of surviving optic nerve cells. But if you look at their regeneration, just like I showed you before, it's actually worse. It's gone the wrong direction. So, this first-generation therapy was very good at keeping cells alive, but couldn't get you the regeneration. And in fact, it made regeneration worse.
These new genes that we discovered through this high-throughput genetic approach, we could get the same level of survival, but now we get massive optic nerve regeneration. And one of the things that the Catalyst for the Cure team is working on is now taking these three genes that give you this regeneration, and combining with other interventions that have been discovered by other scientists to see if we can really get long-distance regeneration of the optic nerve and restoration of function.
So, one thing that we were very excited about is that we basically demonstrated that regeneration and protection are not always in opposition. There are ways to get both, and that's critical. Well, what's an application of this? As I mentioned, we want to restore vision. And to restore vision, it's going to take replacing optic nerve cells. And those optic nerve cells are ultimately going to come probably from stem cells. We're going to take stem cells from a patient, we're going to make them into optic nerve cells, and that's going to be the substrate of what we try to use to restore vision.
Anna La Torre is a developmental biologist and works on these stem cell derived retinas. And it's been known for a long time that if you make these stem cell derived retinas in a dish, you can make optic nerve cells just like the red dots I showed you before. But if you try and wait, if you just wait long enough, they die. So, we thought, well, maybe our therapy here could be used to improve the transplanted optic nerve cells, the stem cell derived retinal ganglion cells.
So, she did an experiment which is very busy. And I'm just going to tell you like the take-home point. And the take-home points is if you look at the number of green dots here in one of those retinal balls, one of those retinas grown in a dish, you see very few surviving bright green dots. But if you inhibit those three genes, you see many, many more surviving optic nerve cells, and they're each regrowing fibers which is what you would want from your transplanted optic nerve cell. We were very fortunate. This work was actually just recently published in the Proceedings of the National Academy of Science with all of the members of the Catalysts for the Cure team.
In conclusion, stem cells have been very useful. In one way, the stem cell actually is the substrate. It is what we are going to use to restore vision by turning it into optic nerve cells. But then I've also demonstrated it can be used as a model of the disease to search for genes, which are basically drug targets, to improve the efficacy of transplantation, to improve the survival of optic nerve cells, and to improve regeneration.
Of course, I always want to acknowledge the people in the lab who actually do all the work, including especially Amit Patel, Cassidy, Shirley and Mai, and the support that we get from Tom Brunner, David Calkins, our scientific advisory board, and the Glaucoma Research Foundation. Thank you very much.
David Calkins: Thank you so much, Dr. Welsbie. We appreciate that. This was really, really tremendous. Congratulations on all of your hard work beginning to pay off. It's gratifying to watch. We've got quite a number of questions, Derek. And what I want to do right now is answer a very popular question, which is, these things are happening in the laboratory. When can we move these into the clinic?
Derek Welsbie: Okay. So, my patients ask me this all the time, and I think there is a two-part answer. So, as I told you, there are two challenges, and both are profound and both would have huge impact. The first challenge is, can we keep your cells alive that you already have? And second, can we replace the ones that have been lost?
For that first one, we call that neuroprotection. And my feeling is that interventions like drugs that are neuroprotective and help you keep the cells you have, that would basically cooperate with pressure lowering to maintain the disease, for preventing the disease from getting worse, I think that's short term. I think that's the next five years(-ish) before we're seeing clinical trials on neuroprotection. In fact, there are compounds I know right now that are gearing up for clinical trials in the next year. So, that's clearly short term.
The longer term goal is the second challenge, actually replacing the cells you've lost. And I would say that's not the next five years. Realistically I wish it were, but it's probably something where we're doing clinical trials in the end of this decade or beginning of the 2030s to actually have something that really works to restore vision for patients. But honestly, 10 years is not that long. If we could do 10 years, I think we'll be very pleased with that outcome.
David Calkins: Well, Derek, I think I speak for many people in the audience when I say 10 years may not be long for you (laughter), but it is long for others. So, what I'm hearing you say, Derek, is that these are experimental compounds that you're working with in the laboratory. They're not yet ready for use in patients, and therefore have not been approved by the FDA or any other health agency in the world.
Derek Welsbie: Correct.
David Calkins: Right. And folks, this is why supporting Glaucoma Research Foundation is so critical, because there are many, many hurdles that Derek and his team need to go through in order to bring these experimental treatments to the clinic. And so, Derek, along those lines, how long or when would you say we are going to be able to try in human beings a stem cell replacement therapy as we are trying with some other diseases?
Derek Welsbie: Right. So, again, I think that you're looking at probably the end of the 2020s. I want to make sure everyone understands what the challenge is. Because it is unsatisfying to hear someone say, "Oh, it's 10 years away," but there's a reason for that. Okay?
So, think about what has to happen. We take this optic nerve cell. We put it into the eye, into the vitreous, which is the center, the big cavity in the middle of the eye. It's got to make its way into the retina, connect to all the retinal cells, regrow its fiber, grow the fiber back to the brain and connect appropriately. That's a lot of challenges. And I'll tell you, people who've been working on this for 50 or 60 years to try to get this to happen. There has probably been more progress in the last five years than the preceding 45 years combined. There has been tremendous advance in terms of being able to achieve each of those steps.
I would say that the first step is going to be, to try this in a non-human primate, models of which, for instance, Dr. Calkins is working on. And once we start to see evidence that we can get this to work in a non-human primate, then I think we're looking at clinical trials in humans probably at the end of this decade. Understand that there's a lot of safety considerations you want to make sure you've hammered out before you go to a human clinical trial. Stem cells are great, but stem cells can turn into anything. And so, you've got to make sure you have a very controlled process, you really understand what you're doing.
David Calkins: Derek, our hope is that these neuroprotective and neuroregenerative therapies are going to work in all kinds of optic nerve injury and disease. So, would you anticipate that regardless of the form of glaucoma, these therapies would be useful?
Derek Welsbie: That's a great question. And I would say here's where we're most confident. All of our animal models that we use for glaucoma, we raise the eye pressure of the animal, we produce glaucoma, and we showed that our interventions are protective. So, for those patients who have high eye pressure glaucoma, honestly from my point of view as a glaucoma specialist, I would say it's probably not going to matter what caused your high eye pressure, those compounds will be protective.
Now, I think there's a little bit more equipoise about whether these will be active in patients who have glaucoma with low eye pressure. I would imagine yes. I don't think the disease is actually that different when it happens at lower eye pressure versus higher eye pressure. But in all fairness, that's not what the animal models study. And so, again, it will just take clinical trials to demonstrate that that's true.
But what's also exciting is, these neuroprotective interventions, while they'll work across a spectrum of glaucoma types, I think it's going to extend beyond that. There are other ways, although this group is probably focused on glaucoma, there's other ways to kill these optic nerve cells. Some patients have strokes of their optic nerves. Others inherited genetic diseases of their optic nerves. Others have mechanical damage to their optic nerve. And they all do the same thing as glaucoma which has they lead to that irreversible disconnection of the retina, and these neuroprotective interventions and these vision restoration strategies will be equally applicable to that group.
David Calkins: That's awesome. So, Derek, you and I both know that most glaucoma patients will go through a regimen of applying eye drops, then applying more eye drops, maybe a surgery or two, then a surgery plus eye drops. We're all hopeful that these treatments will arrive soon. And that begs the question, are there current treatments now that might preclude someone from receiving a regenerative therapy later, or do you recommend that everyone stay the course according to what their physicians recommend?
Derek Welsbie: Yeah, I would say like right now we should use 2021 technology to treat our patients. And so, we do the best with what we have available today. So, what do I have in my toolkit as a glaucoma specialist? Just like what you said, I've got essentially five different classes of medications. I've got one laser and I've got a whole toolkit of surgical interventions. And depending on the patient, I can do whatever I need to [in order] to lower the eye pressure.
Now I'll tell you, for some patients, I've got to work pretty hard to get that pressure lower. And in some people, there are consequences to trying to do that. So, that's why we need these neuroprotective interventions. My guess, without knowing what the therapy will be, the neuroprotection in the future, it's hard to answer this. But I'll just say it is probable that it won't matter what a patient has done up till now to be eligible for a future therapy. So, again, that's not an absolute, but it's probably the case. So, do whatever you've got to do to control your disease today. And my guess is if something great emerges, and we're very optimistic, you'll probably be just as eligible as if you had chosen some other therapy.
David Calkins: That's right. And Derek, they will hear me scream from Nashville, Tennessee, in joy when that day arrives. And so, what I'm hearing you say is that right now in 2021, you've got a certain toolkit that you're able to use of FDA-approved treatments. And chances are, those are the treatments that your patients and other patients are already receiving.
So Derek, you and I both know a famous scientist named David Sinclair at Harvard, and David studies the aging brain. We talk a lot about pressure in glaucoma, but in fact, age is one of the leading risk factors. This is an age-related neurodegenerative disorder. Would you please comment on the genetics work that David Sinclair is doing and how that might be applicable to our glaucoma patients today?
Derek Welsbie: It's very exciting work and very interesting work. So, let's take a step back. If you remember from my presentation, I said that we would get blood from a patient here at the UC San Diego Eye Center, Shiley Eye Center, we would take those blood cells, and we would put in these four genes. And by putting in those four genes, I can turn that patient's blood cell into a stem cell that could turn into anything. What the Sinclair lab and Zhigang He's lab did is they took three of those genes, not the fourth one, and they put three of those genes into optic nerve cells.
Now, why would you not want to put the fourth one in? Well, if you put the fourth one in, you turn the optic nerve cell into a stem cell, and then it's not an optic nerve cell anymore. So, that's too much. But by putting in three of those genes, the idea was you could potentially de-age the optic nerve cell. You could reverse aging.
And think about that. That's essentially what happens in a stem cell. If I take someone's skin cell or their blood cell and I put in those four factors called the Yamanaka factors what I'm essentially doing is ... It's the same cell, it's the same genes, but I'm changing what's called the epigenetics. I'm changing the environment of the cell to set back the clock and make that cell 'young again.'
So, the idea was that they could use that same approach, by putting in three of those factors into the optic nerve cell. And it was exciting. What they showed was a couple things. When they did a mouse model of glaucoma, they let the mouse have glaucoma, damage was done. And after the damage was done, they triggered those three genes. And what they showed was improved fiber regeneration and restoration of vision.
Now, in all fairness, this is a mouse model. It was short term. And I think the field would love to see this reproduced by multiple labs because this is such an exciting finding. But I think it's exciting, and I think it's just something that the field is going to, it's going to learn from.
David Calkins: That's great, Derek. Thank you very much. Derek, you and I have discussed the following, and that is that even though those fibers die in the optic nerve over many, many, many years, it seems that the cell bodies of the nerve cells and the retina can remain for a while longer. Would you anticipate, that being the case, that some of our therapies are going to help those stagnant or quiescent cell bodies pop back to life and sprout an axon into the optic nerve? If that's the case, are there any kinds of dietary or other home remedies that patients can do to enhance their chances of regaining vision?
Derek Welsbie: Right. So, I'm going to take those as two separate questions. So, the first question in my mind is: for a given patient with glaucoma that they've had for years, obviously there's the cells that have not died yet that are fine, there's the population of cells that are totally dead. And then the question you ask is, well, how many are in the middle? How many have been injured by the glaucoma process, but they haven't dropped off yet, that we could rescue them. In the stroke world that's called the penumbra. And so, I think the answer is we don't know how large that population is, but at least there is some cells in that population. I think that's clear.
And so, for a therapy, like for instance, the one that we described with the GCK-IV kinases, we would hope that by both keeping those cells alive and improving their ability to regenerate that we might be able to actually improve vision without putting in any new cells. By just causing those quiescent cells to reconnect. But I would say the jury is out on how big of an effect that would be.
David Calkins: Derek, how do you feel about exercise and diets rich in antioxidants?
Derek Welsbie: Yeah. So, I would say, my patients often ask me, besides the pressure lowering, what else can they do to control their disease? And truthfully, in terms of large clinical studies and our best evidence, look, we know pressure lowering works. And if I could de-age you, I'm sure that would work, too, but de-aging is hard.
David Calkins: Good luck with that, Derek. I'm waiting for that day.
Derek Welsbie: So am I. And so, the other thing, the other recommendation I make to patients, and I tell them, look, the evidence for this is not as good. Instead of randomized controlled trials where we give some patient A and some patient B and we follow them, we have what are called retrospective studies. But we just look back and we say, "You know what? The patients who exercise, who get their heart rate up through cardiovascular exercise, they seem to do better. And patients who eat green, leafy vegetables like kale seem to do better." So, I tell my patients exercise and eat healthy, which I figure even if I'm wrong, it's good for other parts of the body.
David Calkins: That's great. And so, Derek, our patients also wonder. Suppose tomorrow this wonderful treatment becomes available and is approved by the FDA. Will a person who is 75 years old have an equivalent chance for regeneration versus a person who is 15 or 16 years old.
Derek Welsbie: I think it's a great question. And there is work to show that regeneration is probably a little bit harder the older the optic nerve cell gets. But my guess is that that's not going to be a major factor. When we come up with a therapy that reconnects the eyeball to the brain, it's going to be such a robust intervention in that optic nerve cell that I am imagining that the effective age will be rather small, but we just don't know the answer.
David Calkins: Sure. We don't know the answer. And so, Derek, to summarize, many patients will be stable if they follow their doctor's instructions to keep their pressure low. For them, we're going to continue the course. For those patients who don't respond so well to lowering IOP, we're very, very hopeful that the experimental therapies that you're developing in the laboratory in the near future will make their way to the clinic.
And with that, Derek, I want to thank you on behalf of everyone who's participating today for the efforts that you're putting into this terrible disease. Keep up the great work, and we hope to hear from you real soon with some more positive results. Thanks, Derek.
Derek Welsbie: Thank you.
David Calkins: All right, friends. What I'd like to do now is remind everyone that the Glaucoma Research Foundation is always there for glaucoma patients. This is a tremendous resource, both on the web and in printed versions that you'll find in your mailbox. This is a small team, I know every single one of them very, very well, and I can tell you that there is no better group of dedicated people working to cure this disease. And each one of them that you see in your Hollywood Squares box there is working hard on a daily basis to keep you up-to-date on the latest results and define for you the resources that are necessary to answer your questions.
And so, what I'd like to do is encourage you all to continue to check the Glaucoma Research Foundation website, www.glaucoma.org. And often if you've got a very, very specific question, the friends at Glaucoma Research Foundation will be able to forward that question to one of the many, many experts who are involved with this terrific organization. So, keep checking the website and look for the future for some wonderful, wonderful results.
And so, on that positive note, what I'd like to do now is simply extend my thanks personally to all of you for your attention today, for your interest in Glaucoma Research Foundation, for your interest in Catalyst for a Cure, and all of the support that I know that you are providing both GRF and Catalyst for a Cure. Finally, what I want to say is stay healthy, stay happy, and keep the faith, and we'll see you all real soon. Thank you.
Last reviewed on February 11, 2021