Tasneem Putliwala Sharma, PhD, Assistant Professor of Ophthalmology at IU School of Medicine, talks about discovering new ways to treat glaucoma.
Interview conducted by Ivanhoe Broadcast News in 2024.
Tell me a little bit about the work you do in your areas of expertise.
Sharma: I’m actually a glaucoma researcher. I work with human eye research organ models, as well as stem cell technologies. We basically take control and patient lines. We get human donor eyes in the lab, and then we take the cells from the cornea, and then reprogram them into stem cells. Using these control and patient lines, we go downstream and test therapeutics, we look at different strategies of pressure, because pressure is a major risk factor in glaucoma. When you go to the eye doctor and you get that puff of air in your eye, that’s what they’re measuring. They’re measuring pressure within your eye, and so we can test that using our human eye model system as well.
What is glaucoma?
Sharma: In Glaucoma, around 70% of primary open-angle glaucoma, is a disease of pressure within the eye. This pressure within the eye, is called intraocular pressure and is elevated in these high tension glaucoma patients. When this pressure is elevated, what it does is it impacts the nerve that connects the eye to the visual centers in the brain. As more and more time passes and you have more pressure that is built up over time in the eye, it stays sustained and maintained, it damages the eye neurons that connect the eye to the brain. Basically, you see peripheral vision loss and you start getting tunnel vision within the eye. Then that tunnel vision affects downstream and you basically lose vision.
Are there different stages of it? What is the progression from when you start noticing it to it gets really bad? How long does it typically take?
Sharma: It is an age related neurodegeneration. It does include other types of glaucoma, there’s congenital glaucoma and other types that happen earlier on in life, but in most of them, age is a risk factor for glaucoma, and it starts in later decades of life. As it progresses, basically during early stage of disease when you will have high pressure but no other discernible symptoms, you go to the eye doctor, your optometrist, and you go there you get your eyes checked, you have high pressure, they check the back of your eye, which is your retina or the fundus, and they see that your optic nerve or the nerve that connects the eye to the brain is starting to get affected. That means there’s early retinal neuron loss. That’s early stage disease. The clinicians, or the health professionals come in and they lower the pressure within your eye. That happens pharmaceutically with drugs or different pharmaceutical strategies. But then if you keep having high pressures, they’ll go surgically and modulate that pressure. The way we can do that is through the front of the eye by surgically targeting the trabecular meshwork which is a tissue within the eye which controls fluid outflow. The way the pressure is maintained is there’s inflow of aqueous humor or fluid within the eye, and then that fluid exits the eye through the trabecular meshwork. So there’s a constant perfusion of the eye and exiting of that perfusion media but in glaucoma, that trabecular meshwork does not act the way it should. So the fluid keeps staying in the eye, and that’s what is building up the pressure. It’s like a balloon. As you fill more air into the balloon, there is a capacity for that balloon to burst. Except in the eye, the scleral tissue protects the eye really well. But that pressure then goes to the nerve which is the most sensitive part of the eye. That’s where you have cupping, or classically called cupping of the optic nerve head, which is where the retinal neurons are and that starts dying. The retinal ganglion cells are the terminal or eye neurons that connect to the visual centers of the brain.
For someone who has glaucoma, is there pain associated with it, or is it just the vision loss? What does a patient with glaucoma experience?
Sharma: It is actually known as a silent disease, because when the vision loss happens, it starts happening from the peripheral region of the eye and you don’t have pain with it. You have high pressure, but unless the pressure is really high and that’s like something acute, but most stages of glaucoma are chronic, so it’s a slow progression of this high pressure and you don’t even feel it because one of the most unique parts of our human body is adaptation and flexibility and plasticity. As little by little the neurons start dying from the periphery, your brain starts adapting. Till the end stage of disease in a lot of times, unless you’re getting regular eye checkups, you don’t even realize you have vision loss, which is why we say please get your eyes checked, especially for glaucoma. Go get that pressure test done so that we can actually identify disease at early stages of life.
How common is it? Do you have any statistics or numbers that you know of?
Tasneem Sharma: Yes, so it is one of the most highly prevalent neurodegenerative diseases. Why is it neurodegenerative? It is because the eye is part of the central nervous system and connects to the brain. So the eye and the brain have similar type of central nervous system neurons. The progression and the prevalence of the disease is almost 70 million people worldwide. Just in the United States alone, it’s three million people and 10% of these patients go blind with the disease as well. It’s a pretty significant neurodegenerative disease and vision, or sight, is something that’s very important to us. This basic quality of life is affected. You can’t drive, you can’t read, you can’t do every day activities and that makes it really important. For me, it’s what I’m passionate about. It’s what really makes me feel like I want to do this every day.
You talked a little bit about this, about how it’s currently treated. You talked about some medication options earlier on in the surgery. Can you explain a little bit more about the current treatment options for someone with glaucoma and the different stages?
Sharma: In early stage disease, you’re trying to maintain that pressure, you’re trying to lower that pressure, get it to normal stages. There are patients who are also called normal tension glaucoma or low tension glaucoma as well, where the pressure never goes up. Those are more of hard to diagnose patients because you don’t have high pressures. Even in those cases, lowering the pressure has done wonders, but it just slows the progression of disease. It doesn’t halt it, it doesn’t reverse it or any of those things. When we’re thinking about glaucoma, we are thinking about how do we surgically go and manipulate it. The trabecular meshwork, which is the tissue that I was talking about, you can go in and take out pieces of that tissue to make sure the flow is happening well. There’s a lot of therapeutics right now in the market that relax the tissue in that region, so more flow happens. Even the production of the fluid, so you can attack the disease at both stages of pharmaceutical options where not only the flow is decreased, but also the outflow or the outflow facility is increased so that you can maintain that pressure. Then obviously, none of that works, you have combination therapies with the pharmaceuticals and the surgical options where you go in and manipulate the tissue around the eye so that there is more outflow facility as well. That is the main ways, because the thing we are trying to attack is the intraocular pressure. That is one of the main risk factors in glaucoma, and the only modifiable risk factor. So age is one, race is one, where, African Americans, Hispanic populations are more at higher prevalence or have the disease at earlier stages as well sometimes. So those are other risk factors, but even though health disparities is one of the things that we talk about in glaucoma, race, age, myopia, but they are all non modifiable. The only major risk factor that’s modifiable is intraocular pressure. As I mentioned, controlling it does not prevent the disease from progressing. What we need to find out, or what most labs around the country are doing for glaucoma research is how do we make sure that the sick and dying neurons or retinal neurons, which is the retinal ganglion cells, how do we protect them, keep them alive, or even do transplantation strategies? At early stage disease, we’re trying to protect those neurons. And so one way is the pressure modulation. But what my lab focuses in neuroprotection strategies is how do we protect these neurons. But at any stage of disease, when most of those neurons are lost and the disease has progressed really drastically, how do we come in and replace those neurons? And that’s where my background in stem cell biology comes in, where I can actually reprogram skin cells, I can reprogram corneal cells, I can reprogram blood or different things to make stem cells, and then we can make retinal neurons in the lab. Then we can in a way do a little bit of precision medicine, so test different drugs or therapeutics, and also look at transplantation strategies. That’s where our human eye model comes in. So I actually can acquire post-mortem donor eyes from patients who have disease and kindly donated their eyes to research. We can put that human eye actually in a model like this. This is called the Translaminar Autonomous System. As you can see, we can take that human eye and put it in here. We can seal it and pressurize it. So now we can build a pressure within that eye globe. Once we do that, we can seal it completely and keep it in the incubator and generally, our experiments runs for 10 days, we can now modulate the pressure within a human eye and this model, we just recently got it patented as well. This is the only human eye model in the country that allows us to do that, once we pressurize it, then we can actually go in and test therapeutics, we can put fluid in there, we can do gene therapy, and we can look at the health of the retina and how it affects the ganglion cells in glaucoma. We can also get donor eyes, transplant them with the stem cell-derived retinal neurons that we have generated in the lab, assess integration, and look at transplantation strategies. The decision is when do we need to transplant. If there was a patient that had high pressure and came in when most of the neurons are dead, but when we do transplantation at that stage then the neurons may not even survive because the microenvironment could be very unhealthy for that patient. Maybe those neurons don’t survive. So maybe we need to target early stages of disease or moderate stages of disease and do transplantations there. But would that be something a patient would really like doing? So there’s also ethical considerations on that stage as well, but that’s the thing where and at what stage of disease do we go in for intervention? How should we target neuroprotection strategies; at early-stage or moderate-stage disease, and then come in at end-stage disease and do transplantation strategies? Our lab looks at the whole spectrum of disease stages. Basically, a neuroprotection drug at early stages and transplantation strategies at end-stage disease, or even a combination therapy with neuroprotection and transplantation.
Do the donor eyes have to be an eye that has glaucoma or it doesn’t have to have that, but this is going to simulate that pressure?
Sharma: Yes. We do it in both strategies. We get donor eyes that are from control individuals who do not have ocular history. Then we set it up and then emulate that pressure paradigm. That’s one. The other part is if you didn’t emulate the pressure, I mentioned the normal tension glaucoma where they don’t have pressure but they have glaucoma, which is the retinal neurons have started progressively dying. When we do get a glaucoma donor pair, we can put in normal pressure and see how the glaucomatous, retinal neurons that have died. How do they get more survival with therapies or treatments or how can we actually treat those eyes as well? In addition, sometimes our preference is to do studies with control eyes and emulate the pressure to start with a common baseline with both eyes. What is the pattern of vision loss, or what is the pattern of retinal ganglion cell death? The other aspect is that could we treat with the therapeutic is neuritin, which is what I got my R01 for, is a neuroprotective and regenerative agent that allows us to not only protect the sick and dying neurons but also still keep the connections or regenerate some of the deteriorated axons that connect the eye to the brain. So keep the remaining neurons alive but also regenerate the ones that have are sick or dying, because the donor eyes that we get, they’re axotomized, the neurons have been cut. Now, we would like to see a strategy on how do we not only protect the neurons once axotomy has happened, but could we regenerate? Because even in glaucoma, the way the disease progresses is when there’s pressure at that back of the eye, the nerve starts degenerating. For us, it is more acute when those donor eyes come but if we can help the patients at acute stages of disease, for those chronic patients, that would be really a great strategy as well.
You were talking about something you’re looking into is possibly doing transplants earlier because maybe it’s early on in the progression, but it might have a long-term better outcome. But then you were saying people might not want to do that.
Sharma: Sometimes when you do have vision loss, getting an injection of transplanted stem cell-derived retinal ganglion cells, that may be a little bit more scary to a patient, but they don’t want to do it at that stage. But they may sometimes want to if they’re still progressing and there’s a lot of vision loss happening, maybe on the periphery, we could go in and do that and say, you know, that could help you and protect you long term, especially if somebody in the 50s or the 60s comes into the clinics and they have the progression of disease through their life. Around 78 is like what is the average age a person lives? That’s almost two decades of life that they could have vision loss. Maybe that is an effective strategy at that moderate stage of disease where we can help them long term, but obviously, it is something that a patient decides and what they want from their therapy or from the way they would like to see their therapeutics or their clinical management going, what they’re comfortable with in the long run.
Is that something that’s currently happening or is that something that’s part of your research?
Sharma: That is something that is part of my research. We got an R01, which is a 1.9 million dollar grant to study this neuroprotection drug that is not only neuroprotective but regenerative as well. So we’re trying to see if we do these different paradigms of high pressure or low pressure, how do we go in and use this drug to protect these neurons? Then obviously a future extension of that grant would be, is to not only make this drug more marketable, basically have a slow drug release formulation, put it in the retina and also in the future, pairing it with a transplantation strategy with those stem cell-derived retinal neurons as well.
Tell me a little bit about the grants that you received to make this happen. You were talking to me earlier, a little bit about how competitive it was, and tell me about the grant itself.
Sharma: So, we use an NIH, or National Institute of Health mechanism to apply for this grant. We go to particular institutes within the NIH, and so we go to the National Eye Institute or NEI. Funding range 14-20-25% It depends if your early stage investigator or late stage or you’ve already passed that early stage and so it’s really competitive, seeing 14% of grants funded, you know, we do a lot of advocacy for increasing version research also. To make sure that we can have these drugs to the market. Funding rates historically from the 1980s have not increased much. But expenses, costs, everything else has increased in terms of research. So whatever we can do with that small pot of money is to make sure that we can save patients’ lives.
Do you have a timeline, like one year or two or five years that you’re kind of working on this or how does that work?
Sharma: Our proposal is for five years. That 1.9 million dollar gets divided over five years. That helps us pay for not only the facility costs, you know, researchers that are working in my lab, doing the work that they can but also paying for reagents, materials and supplies. Our main cost is human eyes obviously, we appreciate not only forthe precious donation of these donors but also because of the cost of research that is related with human donor eyes. So that’s what it pays for, for the five years and to make sure that the drug is, is effective, it’s safe, allowing us to do viable studies, on the patient retinal ganglion cells or the retinal neurons, they’re actually getting protected. So we can use even the translaminar autonomous system that I was talking about. We’re going to be using this system and pressurize the eyes and look at the different strategies and how we can protect these neurons.
What’s your main goal with this research? What are you hoping is the end result after maybe five years? What are you hoping is the huge takeaway from this?
Sharma: The huge takeaway would be is can we take this drug and formulate it and test it? So one of the other aspects of that grant is also the diversity aspect of it. Because we have more than 50 control and patient lines in the lab that are coming from African American, Caucasian, Hispanic populations. So we can test not only the diversity and how this drug would be targeting different populations, but also if we can actually look at it in terms of age, race, gender, we are also looking at male and female, and is it affecting most populations similarly, because sometimes you, for lack of better word, you want the miracle pill but the miracle pill cannot target all the populations. One of the things we want to do is, can we target different populations? Can we make this drug work, and do we need different dosing and paradigms? And then once it is, and we’ve tested all of that, we want to make it into a formulation that could be a slow drug release nanoparticle that we could implant in the retina, and it would slowly release the drug over time and help protect these neurons and make sure that the regenerative capacity of these neurons is also maintained for the sick and dying ones that have those axotomized neurons.
If I’m understanding it right, currently, it’s just treating the pressure and treating things as they progress, but you’re hoping to get in there and treat it more of a longer-term. Is that what you’re hoping?
Sharma: Yes. We are trying to get to the root cause of the problem. The root cause of the problem is the pressure is the problem, so we are trying to maintain the pressure, but the root cause is that these neurons are dying. So how do we protect them? How do we make sure that these neurons stay alive and healthy even with high pressure or even in normal tension or low tension glaucoma patients when pressure is not a factor? Can we go in there and still protect these neurons? Because the neurons are what is giving you the vision or helps with the vision. So if you can maintain them and protect them, that is our root cause of the problem. Can we get to the root cause of the problem and help maintain that vision for long-term?
Would you say that your work is going to be a game changer for people with glaucoma?
Sharma: As a researcher, I’m more of a cynic than anything else. I would say I would want that to be my dream job, my dream goal in my life. That is what I want to do is protect vision obviously, and I hope that this is the therapeutic that will do it. But obviously everything comes with nuances. And being a scientist myself, I have to always look at the data. I always help my students also follow the data. If that is the data, that’s what it says, that the data and this drug will help protect it, that’s what my goal is obviously. And yes, I do want it to be the game changer. That’s my goal.
Do you want to touch on the NASA thing real quick?
Sharma: So one of the things that we do is pressure within the eye for glaucoma, and so our model allows us to do that. But one other aspect that we also do is space biology research. Approximately 70 percent of astronauts that stay more than six months in microgravity environments, they start having this syndrome, which is known as spaceflight associated neuro-ocular syndrome. What that happens is that one of the hypothesis is that there is a cephalad fluid shift or high pressure within the brain because there is a lack of microgravity. So the fluid cannot be pulled down due to gravity. When there’s high pressure within the brain, and as I mentioned, the eye is an extension of the brain. There is pressure at the back of the eye as well and that changes the whole shape of the eye and there’s flattening of the globe. One of the findings with spaceflight associated neuro-ocular syndrome is that it causes globe flattening and changes within the optic nerve. Basically it is called hyperopic shifts, but in layman’s terms you need higher powered reading glasses because you can’t see and your vision changes. So for short-term missions, it doesn’t matter. And it is reversible when they come back over a year or progress of year but when you have long-term missions, like the mission to Mars or Artemis missions, it’s a high risk for NASA. Because the operational capacity of the astronaut is to make sure that everything on that space flight is working and they can do the research and all the things that they’re doing. So if the missions’ operational capacity is affected, that becomes a high risk for NASA. And so we do dabble in some of the research that we do for space biology.
Are you working on getting a grant for this, too?
Sharma: Yes. So we are. We just recently got approved for the feasibility form. So these are letter of intents that you write to different kinds of agencies. But for the International Space Station, if we can take our human eye model as a research payload and study some of the effects for not only radiation, but also microgravity in those environments and how we can test the human eye in these harsh space environments- we’re testing antioxidant drugs to protect these eyes. So we have been invited for the full proposal. So hopefully it goes in and we do get selected. They do select between two to four proposals a year. So hopefully we have fingers crossed for that. So that’s our hope. But yes, that’s what our thought process is if we can take this model to that research environment. We are working with Redwire, who’s our implementation partner on that, and we can get this research payload into the International Space Station and study the antioxidant therapeutic, which is what we’re trying to do.
That’s so fascinating and you don’t really think about.
Sharma: Yes, I know. There’s a lot of changes that happen to the astronauts. Bone loss and cardiovascular changes and muscle strength and all of that stuff. Muscle tone, everything changes. But sight is something that’s so important because if you’re not able to see properly, how are you going to actually accomplish all the things that you would like to accomplish, especially for those long duration missions as well.
I feel like, in the movies, you see the muscle loss and things like that but you don’t ever hear of eye.
Sharma: Yes definitely. The show, “For all mankind”, I think, one of the astronauts, I think she is exposed to radiation or the actor astronaut obviously in that show. She in fact gets normal tension glaucoma. So obviously, it’s not related, but it was really interesting to see that they brought that aspect into it. So whenever I watch any of those shows, it’s like really cool to see some of the things and how I think sometimes movies like that can actually broaden your horizons and make you think of things that you normally don’t think about. Some of the research, and that’s the fun part about being a scientist, is I think one of my greatest things about being a scientist is the world is my venue and I can do any research I want. It’s things that nobody has discovered. And that’s the fun part about discovery and research, and finding therapeutics basically to help slow any disease progression. And so most of us scientists, that’s what we’re trying to do. Help our community, our environment or the people we are trying to change. Or whether you’re a bioengineer or whatever. As a researcher, you’re trying to help people. So that’s what really helps me and gets me excited every day.
END OF INTERVIEW
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