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The 2022 Weston Lecture: Ahmara Gibbons Ross, MD, PhD

"Neuroprotection: A New Path for Glaucoma Patients" was the topic of the 2022 Weston Family Lecture presented virtually on October 27, 2022.

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Photo of Dr. Ahmara Gibbons Ross looking into the camera
Photo of Dr. Ahmara Gibbons Ross looking into the camera

The 2022 Weston Lecture: Ahmara Gibbons Ross, MD, PhD

"Neuroprotection: A New Path for Glaucoma Patients" was the topic of the 2022 Weston Family Lecture presented virtually on October 27, 2022.

The 2022 Weston Family Lecture featured Ahmara Gibbons Ross, MD, PhD, Assistant Professor of Ophthalmology and Neurology at the University of Pennsylvania. “Neuroprotection: A New Path for Glaucoma Patients” is an informative and inspiring update on innovative research seeking new and better glaucoma treatments. The virtual lecture is introduced and moderated by Thomas M. Brunner, President and CEO of the Glaucoma Research Foundation in San Francisco, CA.

The Weston Family Lectureship was established in 2007 with a grant from Gladys and George Weston, DDS, in memory of their son Daniel. Each year the lectureship showcases a clinician or scientist whose work is significantly advancing our knowledge of glaucoma, particularly in new therapies and progress toward a cure.

Watch the video recording:

Read the video transcript

Tom Brunner:

My name is Tom Brunner, and I’m the president and CEO of Glaucoma Research Foundation. Now it is my privilege to introduce Dr. Ahmara Gibbons Ross. Ahmara is an assistant professor of ophthalmology and neurology at the hospital of the University of Pennsylvania. She completed her ophthalmology residency at the University of Pittsburgh and her fellowship in neuro-ophthalmology in glaucoma at the Scheie Eye Institute of the University of Pennsylvania. She also has a PhD in molecular pharmacology and structural biology from Thomas Jefferson University. In addition to caring for patients with glaucoma and neuro ophthalmological disorders, Dr. Ross conducts research on the neuroprotective potential of gene therapy directed at retinal ganglion cells and neighboring cells to treat chronic glaucoma. Dr. Ross has received numerous awards and has published prestigious peer reviewed papers in both neuro-ophthalmology and glaucoma. It is my sincere pleasure to welcome Dr. Ahmara Gibbons Ross.

Ahmara Gibbons Ross:

Thank you very, very much. It’s truly an honor to be presenting for the Weston Lecture series on research that I’m doing, along with many of my colleagues all over the country, to provide a new path of treatment for glaucoma patients. I want to first thank the Weston family for the opportunity to present this to you today. It is through philanthropic support that a lot of this research is, or the pendulum of research is pushed forward, and hopefully I can give patients and clinicians more hope about new and innovative treatments that are in the pipeline for the treatment of patients with glaucoma. And so an overview of what this lecture’s going to look at are really nailing down, what is neuroprotection? And what is neuro restoration? How are these two things different? And what kinds of patients are these two are therapies going to be for?

I’m going to show some advances in my own lab that are really quickly moving into beyond preclinical to clinical studies for gene therapy to treat glaucoma with neuroprotection, but I’m always cognizant, as I practice glaucoma and neuro-ophthalmology, to give real life examples and to introduce how the research might provide real life solutions for patients. And so I always start by reminding everyone that glaucoma is the silent thief of sight. This is really a grab bag or a basket of disorders that leads to irreversible vision loss. And so most patients are walking around with vision that look very much like the left picture that says normal. But as glaucoma slowly starts to advance, you end up getting tunnel vision. And though the center may be clear, how you interact with the world is definitely not clear. And this is the second leading cause of blindness worldwide.

I like to tell patients that high intraocular pressure is a risk factor for glaucoma. It’s not necessarily the cause, though it is the thing that we treat at the moment. And what happens is that we think the pressure inside of the eye causes damage to the optic nerve, which you can see all the way to the right of this cartoon eye. And so if you’ve ever been to the ophthalmology or ophthalmologist office, you’ll see they’ll show you pictures of the optic nerve as we’re looking at it in the eye, and you might even get several of the imaging studies we’re going to go over today. But at the top, highlighted as normal, this is a normal optic nerve. This is the cable that connects your eyeball to your brain. This is normal. We like… If you imagine the entirety of the nerve to be a circle, and then there’s a pale or circle in the middle, we like that circle to be maybe 30% of the entire circle.

We call that a cup because it is actually a cup inside of the optic nerve. These are where all of the arms from the cells inside of the retina are stretching to your brain so that you can process the images that you’re seeing. At the bottom, you can see a nerve where the cup is much, much larger than 30 to 40% of the circle. It’s taking up almost 80 to 90%. And this is what we see as one of the red flags or one of the diagnostic criteria for glaucoma. Clinically, what we know is that this is classified by distinct structural changes that happen at this optic nerve that we can test, both in function, as you can see in this middle picture where this patient has lost almost all of his visual feel at the bottom. And it correlates with changes in structure where we take a picture, not just the picture you’re seeing to the left, but we use optic coherence tomography to look and see what parts of the retina are thin or thinning.

And that corresponds to the loss of vision that we see in the visual field. But what we do know is that the loss of retinal ganglion cells really does correspond to the loss of vision that we see in these patients. And so when we talk about retinal ganglion cells, if you look to the left, we have a cartoon picture of an eyeball that we’ve cut in half. The front of the eye is the cornea, and the back of the eye is that optic nerve I was talking about. But really the cells that are going into the optic nerve are the retinal ganglion cells. And so if we blow up this box and able to label or highlight the cells that we’re talking about, you would see them in green. These are all the retinal ganglion cells. And so if you look at the green picture, there’s a hole or a black circle in the center that would be the optic nerve, and all of the green cells that are lighting up the entire view are those retinal ganglion cells.

And what they look like, if you were to look at them in cross section or as opening up half of a sandwich, you would see these pink cells that have their bodies in the retina, but their arms are stretching all the way from the retina to the brain. And so to date, even though we know the cells that are affected by the disease, the only treatment modality or risk factor we have to control the disease is medications. And so anyone that knows the medications that go on for the treatment of glaucoma know that this can be arduous, often, several drops a day, several times a day through the lifetime of a patient. We can also do laser surgery, but that again is to lower the pressure. And then of course there’s glaucoma surgery that can also go on to lower the pressure. But really, despite lowering the pressure, we all know that 10% of patients with the diagnosis of glaucoma are going to lose vision despite treatment, despite low intraocular pressures through any of these modalities.

And so let me introduce you to a real patient of mine. These are actual real patients that I’m introducing. And then I’m also introducing you and shamelessly using a picture of my children to drive home how a patient with glaucoma is interacting with the world, and more importantly, why pressure, intraocular pressure is not always the determinate for who is going to progress and who is not going to progress in the disease. So, this is a patient who I unfortunately did not know in 2013. These were her visual fields. And it’s important for you to know that her pressure was normal, with the normal pressures being between 15 to 21.

In 2016, the patient came into the system, into the Scheie system with these visual fields, and I was able to lower her pressure to single digits, from 16 to 15, all the while knowing that this patient had a normal pressure to begin with. And you can see that going from the middle visual field to the bottom visual fields to today, she still lost a significant amount of her vision, despite pressures in the single digits. And so up above is a pic… So, on the right hand side, you have her peripheral vision. And as her disease began to progress, her central vision did start to get affected, like that cartoon picture I showed you. So, this is the right and left eye. And anywhere there’s black is not black in the periphery, it’s black in the center. And so the patient’s unable to interact with the world in a normal way at this point, and they have multiple areas and visual field defects that are going to not just affect her peripheral vision, but her central vision. And so she’s unable to see the picture, unable to make out the completion of her grandchildren.

And so she’s significantly affected by this disease. I started to care about glaucoma because almost 2.7 million Americans have glaucoma, but only half of them know it. After cataracts, this is the leading cause of blindness in certain demographics. Only 61% of Americans are even receiving a dilated examination to diagnose glaucoma. And stunningly, only 30% of Americans have ever heard of glaucoma, which is why I am so appreciative to take the time to discuss this with you today. We know that prevention is the most effective tool that we have, and I’m really, really proud to be involved and to be showing you some of the research that’s underway to treat the disease regardless of intraocular pressure.

Glaucoma affects everyone. There are certainly high risk groups, but it is common enough that if you ask, I’m almost certain you have a dear friend or a relative that’s been affected by this disease. And the anxiety that patients have about losing their sight is ranked pretty high. It’s third after cancer and heart disease as people’s most major health fear. And what was stunning to me, even as a resident that the University of Pittsburgh, was that 10 to 15% of patients with glaucoma are going to go blind, despite adequate treatment, which means that the treatment was not adequate. There are no symptoms to warn you except for losing your vision, and in which case, this is really the later stages of the disease. And so my lab focuses not just on clinically managing glaucoma by managing intraocular pressure, but neuroprotection and neuro restoration as potential treatments for glaucoma in the future.

And so for neuroprotection, most of my lab has been using something called gene-based therapy. And the way I explain it is that every cell in our body contains genetic material, DNA, and almost every other organism has it as well. When we talk about genes, we’re talking about DNA that is making up the genes. These will eventually be made into proteins that build the body and help it to function. When gene mutations happen, they can occur over time, or they can be inherited or given to you by your parents. And anytime you get a mutation in a gene, sometimes this can result in abnormal proteins like you can see at the bottom right corner, this orange protein. That impacts the body and can cause human disease.

And so when we talk about gene therapy, we either are going to replace the new genes into the body, so we’ll replace the damaged genes with new genes by delivering that genetic material, or we can help preexisting pathways that exist that will help cells survive. And so the concept that my lab highlights is adding more of a gene to impact disease states, or I often explain it to you as using a viral vector or a gene therapy to deliver the therapy directly to the eye. But I think I always like to stop and really highlight that a lot of the research that I’m going to present to you in my lab in other labs are preclinical. And what this means is that the work is still actively under investigation in the laboratory, and it involves animals, not humans just yet. It might involve a mouse or a rat or a pig, a monkey, and it really needs to be deemed safe before it’s ready for prime time.

I will also mention some preclinical studies that have moved to the clinical realm. And this means that we are testing it in humans and that we are really getting ready to offer this therapy as a potential for treatment of glaucoma. And so at the top of the slides, I put preclinical and clinical just to drive home the fact that it’s all really, really exciting. It gets me up most days, really excites me during the clinic, but it’s still preclinical and there’s still more work to do. And so this is what my lab does. This is preclinical again, and we deliver genes to specific cells. Up at the top, right. This is sort of what the therapy that I deliver to the eyes looks like. It’s genetic material. And in this case, it’s not a therapy so much as a protein that’s going to glow and let me know that it’s going where it’s supposed to go.

I deliver this therapy in the posterior pole or as an intravitreal injection, a shot inside of the eye. And the middle picture is showing you that the animal is still alive. The retina looks nice and flat and healthy. But when I turn on a special light, it lets me know that my gene therapy is not only able to deliver genetic material to the cells of the mouse eye, but that the mouse eye is able to turn that genetic material into a protein that functions. And in this case, that function is turning green.

This is driving home just showing more pictures of how we’re able to deliver genetic material. Our cells become factories to turn that genetic material into proteins. In this case, the cells that we’ve been talking about today, the retinal ganglion cells are red. The cells that I’ve delivered, the vector two or the genetic material two are green. And where they lie together are the retinal ganglion cells that are able to receive the therapy and turn it into a protein. Here’s that cross section of the retina we looked in the first picture. And those are green too, so it lets me know that we can get our vector where we want it to, to the cells we want it to, and they too can turn green. So, now we want to have some end points for when we do make a therapy that they work. And so one of the things that my lab does is able to test vision in mice.

And the way we do that is with an optic kinetic response, or OKR. So on the left, a mouse with good vision is able to behave and track lines that are very thin and moving very fast, and that usually corresponds to good vision. And we watch the mouse’s behavior to make sure he’s, he or she is behaving well to the lines that are moving counterclockwise or clockwise. It’s a behavioral response. And we wait, and eventually the lines become thicker and slower. And when we finally get a response, we’ll give it a number, but it might represent poor vision in the animal.

The disease model that my lab uses is called the microbead occlusion model. We take tiny little beads, we inject them into the front of the eye, and we clog the drainage system so that the pressure goes up. You can kind of see them not necessarily that this is not a picture from my lab, this is a picture from Dr. Calkins lab, but these are highlighting the green beads in the drainage system of the mouse eye that are going to clog the system and make the pressure in the eye go up. This is from my lab. And now, note that it’s still preclinical, but on the top right, we have a therapy. Now, we’re delivering a protein called SIRT, which has been shown to help with cell survival in cell stress conditions. And so we delivered this as a gene therapy to mice, and then spiked their pressure, made their pressure go up.

And so here’s that vision endpoint that I just showed you. Everything in gray is normal vision. The bottom line are mice that have had glaucoma for a period of time, and you can see that their vision slowly starts to decline, just like we see in patients. But in the mice that have received our gene therapy, they’re able to preserve their vision, and that is independent of changing the intraocular pressure. You might ask me, what about those retinal ganglion cells? Well, when we cause the glaucoma in the animal, we kill about a third of the retinal ganglion cells. And what we found, and you can see that in the graph are the pie chart to the right in yellow, we are able to protect almost 25 to 24% of that 30% with the remaining black retinal ganglion cells that still die.

And so what this suggests to us is that this could potentially be a specific, cell specific neuroprotective treatment that we can take into the clinic. And that’s exactly what we are doing right now. We are still in the preclinical work. We’re looking at safety and hopefully moving towards safety studies in non-human primates. And then once we deem it safe and effective, then perhaps we might be ready to go into the clinical pipeline. But let me give you some hope for that research. With the CNTF story. This was a factor that had been shown in preclinical work to preserve retinal ganglion cells. So, you can see moving from left to right, these are animals that have been made to express that fluorescent protein I showed you. In this case, rather than cause glaucoma, they crushed the optic nerve and killed the retinal ganglion cells.

And mice that had received CNTF seemed to have been able to preserve some of the retinal ganglion cells. And this was preclinical work that was done in multiple labs between the times of 2006 and 2009. And so this is sort of the timeline for how research goes from animal and preclinical studies to phase one human studies, highlighted by the two asterisks here. So, we’ve got CNTF happening and being actively researched in 2009, and now in 2012… And in 2012 was able to be used to treat humans, and that clinical work is still being investigated today. So, it’s not that long, but I think it’s important to highlight the two different phases of scientific discovery.

I would be completely remiss if I didn’t mention the catalyst for the cure. This is an initiative by the Glaucoma Research Foundation. It’s not just me that are looking at neuroprotection, but also many, many scientists all over the world. And catalyst for the cure brings all of these scientists together to study the neurobiology, the ophthalmology, the physiology, and the genetics that go into protecting a retinal ganglion cell. But what about my patient? My patient obviously wants to protect the retinal ganglion shell she has, but she’s always giving me a hard way to go saying, “Dr. Ross, when are you going to bring the vision back that I’ve lost?” And so another arm of my lab looks at neuroprotection. And so it’s really important to underline the steps that are involved with needing to talk about stem cell transplantation in the retina. You need to develop a reliable source of transplantable retinal ganglion cells.

Do they come from the patient? Do they come from another person? You need to be able to deliver them safely to their area. You need to help them with survival. And this is something that my lab is looking at. How can we help transplanted retinal ganglion cells survive long enough so that they can, as in number four, establish integration, play nice with the other cells inside of the retina that they’re trying to work with? How do we make sure that they’re working well with the other cells? How do they promote growth, and how do they promote connection with the brain? This is not a recipe or a cookbook that I’ve come up with. There are many, many researchers all over the world looking at transplanting retinal ganglion cells into retina and how to make this a more reliable and more efficient process, such as the scientists for the catalyst for the cure for this year that are looking at the vision restoration initiative, replacing retinal ganglion cells in their axons in attempting to regrow them and reform those connections to the brain.

I was very fortunate to be involved with the Restore Consortium. This is yet another avenue and forum for scientists that are interested in doing the same. This was started by Dr. Tom Johnson at Hopkins. He brought scientists all over the country. Many of the organizing committees are from all over the country, myself included, that are interested in addressing the challenges and questions that are related to transplanting these retinal ganglion cell into retina, and potentially being able to bring site back that’s been lost from glaucoma.

There’s not enough time to talk about more that the catalyst for the cure has done. I haven’t really talked about prevention. It’s not necessarily an area that my lab is looking at, but many of the leaders in the field of glaucoma are also looking at more biomedical imaging or technology that we can use to see retinal ganglion cells, see what’s healthy, see what’s not healthy, so that when we start to bring some of these neuroprotective therapies to the forefront and to the field, that we’re able to decide if they’re working well and who they’re working, what cells they’re working well for. And so hopefully I’ve convinced you that there are many therapies on the horizon, both preclinical and clinical, to treat glaucoma that is more than just drops, lasers, and surgery, and that it’s just a matter of being patient, and these therapies will be ready when scientists and doctors have deemed them safe and effective.

Neuroprotection and restoration is really truly getting closer to the reality of treating patients with advanced glaucoma. And what’s making this a reality is that there’s many organizations and collaborative scientists that are trying to make sure that this is real, but safe to use in our patients. I don’t work alone. Certainly not alone at Scheie. I have collaborators all over the country, but this is my lab and my mentor, the many, many young scientists that are interested in continuing to push the pendulum forward. I’m always thankful for their support, and I am looking very much forward to questions from the audience.

Tom Brunner:

Well, thank you Ahmara. That was a great talk, very fascinating, and some really groundbreaking research. We do have a lot of questions for you from our attendees, and I’ve got some questions as well. One thing I just wanted to bring up before we start the questions, and you mentioned the hereditary aspect that there is for glaucoma. And it strikes me that people don’t often talk about it within their families. And so with the holidays coming up, it really is a good opportunity to mention a relative or a grandparent or a sibling, a sister or brother. If there’s glaucoma in the family, then one way to get early detection is to get a complete eye exam and to talk about it. And often, people just don’t want anyone to know they have glaucoma. And so I want to put that out there for our participants and just get your thoughts on that as well. How do you deal with families where there appears to be multi-generational glaucoma?

Ahmara Gibbons Ross:

Thank you so much for bringing this up, and I’m sorry I didn’t even get to touch on it in my talk. A lot of times, I have patients bringing their parents in because they are visually impaired. And again, it’s difficult. It’s not always the best… It’s not always the easiest to approach with them, but I say, “How are you related to the patient?” “Oh, this is my mother.” Have you had a dilated exam? And I’m always very stunned that eight times out of 10, they haven’t. They’ve been caring for their loved one. And I give them the riot act and I say, The next time that you come here, you make an appointment for yourself and your mom, and I’ll see you both together. So, there’s lots of patients that… I have lots of family members that I have gotten from patients that were bringing their parents or their grandparents in.

So, that’s number one. The other thing that I think forums like this are doing are really raising public awareness of the disease, and so making it more mainstream to talk about. People didn’t always talk about breast cancer and now it’s very mainstream. You’re wearing the bracelets, you’re talking about breast cancer, you’re talking about getting mammograms. And that’s kind of how I see glaucoma. The more we talk about it, the more we make it mainstream and make it something that doesn’t have to be uncomfortable to bring up At family holidays. I usually use barbecues because that’s when people have their family reunions and they might have more than just their immediate family. It’s going to be extended family. And I like to tell them to talk about their diagnosis with them. It’s really important.

Tom Brunner:

Well, it is. It really is important. And it’s not… Glaucoma isn’t just an old person’s disease. Young people get it, even college students. There’s juvenile glaucoma. And so if it’s in the family, I really encourage people to make sure that they talk about it and that they get their eyes examined.

Ahmara Gibbons Ross:

Absolutely.

Tom Brunner:

Now, some of the questions that have come up, and speaking about family, one question was about neuroprotection. Is this something that could also apply for children, for example?

Ahmara Gibbons Ross:

Yeah. So, one of one… I showed the lab, my whole lab at the end of my slideshow, and I always sort of smiled because part of what drove me to do neuro-ophthalmology and glaucoma was because I believed in the SIRT therapy. I believed that delivering these to the cells would be able to keep them alive under stressful environments. Glaucoma is one stressful environment, but we’ve looked at other animal models that kill retinal ganglion cells, such as optic neuritis, compressive tumors, trauma, and it seems to be effective at keeping them alive in general. It’s a longevity protein, so that’s what it’s designed for. And so our idea is, if it’s safe for humans, then it’s going to be applicable to any instance where retinal ganglion cells might be under a continuous stress. Maybe you have a tumor that you can’t operate on, but it’s not malignant, but it’s compressing the optic nerve and killing cells. This might be a way to protect them. Obviously glaucoma being the most common use for this, but there are many other neurologic diseases that kill retinal ganglion cells that we are hoping for this therapy to be applicable for.

Tom Brunner:

So, you did talk about the importance of the preclinical work. Well, first, the lab work, and then preclinical, and then the early human trials, phase one to really show that it’s safe, and then phase two, to start to show that it really works and has a benefit. But I guess the tough question is always when. And so if you had to put a number on it, and I think you did say that some of the neuroprotection trials are actually being tested in humans today in phase one, and now even a phase two, phase three trial. So, that’s pretty exciting, but do you have any feeling with the work you’re doing on when you might actually start to test it in humans?

Ahmara Gibbons Ross:

I think probably for the next two or three years, we’re going to go into non-human primates, and I’m hoping to have safety trials within the next seven years.

Tom Brunner:

Okay, well that’s good.

Ahmara Gibbons Ross:

That’s a lucky number. But I do want to highlight that a lot of these trials, the initial trials are going to be making sure that they’re safe. So, one of the neuroprotective agents that my mentor Ken Schindler studied in preclinical, we were able to take to the bedside to humans and see how it worked. And that was a safety trial. These aren’t patients that have glaucoma. These were patients that were willing to try the medication to make sure it’s safe. And it has not yet gone to the patients with the disease as of yet. One of the limitations, and I mentioned this in catalyst for the cure, are some of the biomarkers that we use. They’re not great in clinic. They really haven’t changed much. And so we really do need to push the pendulum.

And the Glaucoma Research Foundation, through the catalyst for the cure, is really helping to push that pendulum forward at developing biomarkers that will help us determine not just who’s going to get glaucoma early, but when we start to implement some of these neuroprotective diseases, that we don’t have to wait 10, 15 years to give them to a patient with a disease to see if they’re working, so that we’re able to kind of look at each individual retinal ganglion cell in a patient or look at some of the biofeedback of those retinal ganglion cells to see if our therapy is working, so that we might have results a little bit longer than some of the neuroprotective trials that have gone on in the past.

Tom Brunner:

Yes. Well, as you mentioned, the catalyst for a cure on biomarkers was specifically addressing that issue. And one of the things they’ve been able to do with adaptive optics scanning ophthalmoscopy is actually look at the health of a ganglion cell, if you will look at the axons and try to determine if the cell is benefiting from the treatment at a microscopic level. And so that again, is an important step, because you don’t want to have to strictly rely on visual fields as you’re measurement. You want to have some direct measurements. So, one thing I think it might also be interesting, which also I think came from work at the University of Pennsylvania, is that treatment, a gene therapy for LCA, leber congenital amaurosis. So, that’s a perfect example of exactly what you’re talking about, right? Could you speak to that just for a moment? Because I think it would give people confidence that these things aren’t just laboratory. They’re being used today to help children with a specific retinal disease to see.

Ahmara Gibbons Ross:

So, one of the draws for me to come to the University of Pennsylvania when I first started my career and this research was to have the opportunity to be mentored by, obviously Ken Schindler, but Gene Bennett and Al McGuire, who are the inventors. They’re married. They’re the inventors of LUXTURNA, which is the first FDA approved treatment, gene therapy treatment in the eye, and not just in the eye, in children, which to me, that’s a huge regulatory barrier to get over. This started, that the research… Gene started the research in her own lab with mice. And what? I guess in 2016, 2015, they went through all of the regulations that are needed to deliver the gene therapy. And now it’s being used right now. So, it’s not like this is going to be 20, 30 years, but there were regulatory… There were not barriers. There were hurdles, the necessary hurdles to jump to make sure that it’s ready for being safe in children.

The benefit of being at the University of Pennsylvania is Gene has already leveled some of those hurdles for us. And so because it was unprecedented, she had to invent a lot of the endpoints to make sure that it was safe. And I don’t have to do that. I’m not interested in reinventing the wheel. I’m interested in getting safe neuroprotective therapy to patients. And so that’s part of the allure of staying at Penn, but also some of the benefit that glaucoma gets from LUXTURNA and LCA, leber congenital amaurosis. So, we’re going to use a lot of those endpoints.

Tom Brunner:

So, tell me about who would benefit from… Let’s say that… Let’s talk first about neuroprotection, because I think it’s perhaps a little closer than replacing ganglion cells, right?

Ahmara Gibbons Ross:

Yes.

Tom Brunner:

So, with neuroprotection, you’re really… Can we save neurons? Maybe some… So, which patients? Who would benefit the most from neuroprotection?

Ahmara Gibbons Ross:

Really tough to justify an intraocular injection in a normal or a glaucoma suspect, someone who we suspect might have glaucoma that might later convert. How I’m imagining this being important is there are always a subset of patients in our clinic that, despite all of our attempts to slow progression with lower pressure, that we still see them progressing. These are probably some of the first patients we’re going to end up treating. And so people with moderate disease that are progressing to more moderate severe disease, despite normal pressures, are who I’m imagining this being available to. But I’m also seeing this available to patients… I know that this is a glaucoma talk, and I don’t want to commit any faux [inaudible 00:38:05] here, but patients that have debilitating relapsing and remitting optic neuritis, these are patients that constantly get inflammatory damage to their nerve. They slowly lose retinal ganglion cells from that disease, or patients that have optic nerve sheath meningiomas.

These are tumors that can compress the nerve that aren’t necessarily amenable to therapy. We might be able to preserve their vision a little bit longer, even though we can’t necessarily address the insult. And so the beauty of the SIRT story is that I collaborate with Dr. Ken Schindler who does a lot of the neuro ophthalmic disease models. And we think that this is a therapy for all of those, anytime a retinal ganglion cell is at risk of dying.

Tom Brunner:

Well, again, we’re interested in saving vision, so we’re not… And to your point, if a development in one area can help patients in another area or another disease, and even our most recent catalyst for a cure is really looking at, more broadly, neurogenerative disease as a type of disease. So, looking at Alzheimer’s for example, because there are things that you might treat in Alzheimer’s that might help glaucoma patients, or things that we might discover in treating glaucoma that could benefit other neurogenerative diseases. So, I think there’s a lot we can learn from other specialties and from other diseases. But in terms of neuroprotection, if the nerve is already damaged, do you think there could still be a potential maybe to throw at a life preserver or-

Ahmara Gibbons Ross:

I think there’s always a potential to throw in a life preserver. What’s interesting, you mentioned adaptive optics, and one of the things we’re learning is that you can have an insult, like a narrow angle glaucoma and still have vision loss, despite normalization of the pressure. And that’s because we always like to… We’re very binary. We like to say either their cell is alive or the cell is dead, and it turns out there are also sick retinal ganglion cells that are in the retina that sometimes are sending signals to other cells that might cause them to die or secreting what we call tropic factors to other cells. And it’s really not just one cells dead and one cells alive, but there are probably more sick cells that are causing the disease to progress. And so that’s kind of why I would answer yes to your question. I think if it’s a life preserver, throw the life preserver. And if it doesn’t work, well, it didn’t work. But if it does work, then the payoff is so much greater. It’s an inocular injection.

Tom Brunner:

Yeah. Well, another question that’s come up is, in the meantime, while we’re waiting seven years, or 10 years, whatever… And again, just to encourage people, there are some, as you said, some clinical trials today in humans. And if you want to learn about those, you can also look at the NEI [National Eye Institute] website, clinicaltrials.gov, and find out what’s going on in neuroprotection, for example, or in glaucoma clinical trials. But what about vitamin B3 nicotinamide is a way of improving vision, or other natural remedies. Are there things people can do to just help keep their retinal ganglion cells strong?

Ahmara Gibbons Ross:

Remember, I told you one of the barriers to neuroprotection, studying neuroprotection is that you have to study it for a really long time. Glaucoma is not… Thankfully, it’s a silent thief, but the thief is pretty slow. They’re not moving… It’s not like… They’re in stealth mode, but they’re not in speed mode. And so those studies tend to be expensive and take a long time to figure out if they’re going to work. And so I say this with a caveat, and I say this to patients with a caveat, I do sometimes recommend resveratrol, which has been shown to be… It actually activates SIRT and many other things. It’s a longevity. It’s the component of red wine, and they offer that as a pill for patients with glaucoma. And then ginkgo biloba also been shown, loosely associated with neuroprotection. And again, I think because these things are so hard to dose, they’re so hard to study, it’s always anecdotal.

But if you’re in a situation where you want a life vest, resveratrol is pretty benign, as is ginkgo biloba. And so those two entities, some people will recommend taking, in addition to the normal treatment, the standard treatment for glaucoma. I really cannot underscore the importance of, yes, there’s going to be neuroprotective things on the pipeline, yes, there might even be people that will recommend things like resveratrol or ginkgo biloba, but it does not replace the normal standard treatment for glaucoma, which are, as I mentioned, medications, lasers, and surgeries to lower the pressure. And that’s a decision that you’re going to make in conjunction with your ophthalmologist.

I think the most important drive home point is what you brought up first, which is prevention. Talk to your family members about glaucoma, make sure you have a dilated exam, and a complete exam by an ophthalmologist to identify you as a suspect. And then developing a normal routine of going to see the eye doctor with a lot of the tests I introduced today are the best modality we have now at combating the disease.

Tom Brunner:

Yeah, I think there’s a lot of evidence to show that early detection and treatment can preserve vision for life. And people who come in to the office having already lost a lot of vision are probably the worst candidates, because now you’ve already got serious problems and you’re trying to figure out how can we keep what’s left. So, I think you can’t emphasize that enough. One another question about gene therapy. Does it have to be injected into the eye, or could it be a vaccine or… Could you comment on that?

Ahmara Gibbons Ross:

Yeah, so the clinical trials for CNTF, it’s being delivered as an implant. So, it doesn’t always have to be injected into the eye. I mean, in our lab, it would be injected as an intravitreal injection because you really want it to get to the cell. Now, a lot of what my lab does is making it as targeted to retinal ganglion cells as possible. We don’t want to make other cells in the live long, particularly inflammatory cells that might be contributing to the disease. And so we believe we have generated a targeted therapy for retinal ganglia cells, but it would be delivered as a intravitreal injection. One of the allures of gene therapy, and I think makes gene therapy amenable, is the eye. It’s very privileged. It’s like a room that there’s not a lot of going in and not a lot of going out. And so could we deliver? Yes, there are gene therapies that are being used to treat diseases of the body system and they give it as a injection in the bloodstream.

But remember, then you can’t control where it goes. It’s going to go to the kidney, it’s going to go to the heart, it’s going to go to the liver. And those are when you start getting off target effects. And so our therapy is designed to go directly where we want it, and hopefully nowhere else that we don’t want it.

Tom Brunner:

Well, and injections in the eye today are quite routine, as you know. I mean, with macular degeneration generation, people are getting intraocular injections, and they’re safe and they’ve been doing it, I’m sure literally millions of patients and in many years now. So, part of gene therapy is getting enough of the virus close enough to the tissue to get enough cells treated, right? That’s the other key issue.

Ahmara Gibbons Ross:

That’s exactly it.

Tom Brunner:

So, the eye is really the perfect organ to do this as you pointed out, because you can put those viral vectors that are going to deliver the genes where you want them.

Ahmara Gibbons Ross:

That’s right.

Tom Brunner:

And have a high penetration level in a high success ratio.

Ahmara Gibbons Ross:

That’s right.

Tom Brunner:

Well, we’re nearing the end of our time here. I think we’ve covered a lot of ground, a lot of good questions. And the one other thing I might ask you about, and then we can wrap up, is, just good clean living for almost any disease, right? Exercise, eating right…

Ahmara Gibbons Ross:

Absolutely, absolutely.

Tom Brunner:

The famous green leafy vegetables.

Ahmara Gibbons Ross:

Carrots.

Tom Brunner:

And not smoking, for example.

Ahmara Gibbons Ross:

And not smoking, yeah.

Tom Brunner:

So, there are things we can all do that help for every disease, whether it’s glaucoma or any other condition. And even there’s data now even meditation can be useful because it can lower your IOP actually. But to your point, none of this is a substitute for working with your doctor and for using the medications or laser therapy or whatever is prescribed. They’re all additional things that you can do to try to keep your vision or stay healthy.

Ahmara Gibbons Ross:

Right. And you don’t have to come to my clinic to get fantastic glaucoma care from academic institutions, private practices, ophthalmologists in the community. I think the most important thing for glaucoma patients is establishing a relationship with the doctor that you trust and understanding that most of us that go into glaucoma, we want to be in the trenches with you. We know that this is a difficult disease. And finding somewhere that you trust that’s easy to get to, that you don’t miss appointments, that really is probably the most important treatment we have now.

Tom Brunner:

It really is a partnership between the doctor and the patient, and finding, from the doctor’s perspective, it is a chronic disease that can be a lifetime relationship, and patients become real friends. And the same from the patient side. Having someone you really trust and can confide in and can share concerns and reactions to medications, whatever, so that you can make sure you’re taking your eye drops or getting your laser treatment or whatever is needed to keep that pressure. Because today, as you say, it’s really the only thing we can do, and it does work and it does. So, I want to thank you for a really inspiring talk and for answering our questions. And thank you for your dedication to helping glaucoma patients.

Ahmara Gibbons Ross:

My pleasure.

Tom Brunner:

Well, thank you so much. If we were unable to answer your question today, please do visit our website, which is glaucoma.org, for more information about glaucoma and our research programs on vision restoration. All our activities focus on our important mission to cure glaucoma and restore vision through innovative research. We’re incredibly indebted to our donors for your ongoing investment in our work. It is generous gifts from you that help Glaucoma Research Foundation grow our research and our educational programs. Please know that every gift, no matter the size, makes a difference and brings us closer to our goal of a future free from glaucoma. Thank you for joining us, and see you next time.

-End Transcript-

Posted on November 8, 2022

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