 Everybody we want to go ahead and get started. So please let's grab what you have for food and let's sit down. It's just a real honor to have Paul Sternberg here with us. He is really one of the luminaries in ophthalmology, a dear friend, amazing leader. He's had his impact on just so many areas of our field. He's also has a very long close relationship with Amy Hartnett. It goes way back and so I thought it would be only appropriate to have Amy give a few details but not too many and too long. We want to hear from Paul. Paul, thank you for making the trek to be here with us. Thank you, Randy. It's a great honor for me to have the opportunity to introduce Paul Sternberg who has been a mentor and a friend of mine for many years. Besides being the GW Hale professor and chair at Vanderbilt, he's also the associate dean of clinical affairs and the chief medical officer and assistant vice chancellor for adult health affairs. Paul received his BA from Harvard College and his MD from University of Chicago where he also did an internal medicine internship. He did his residency at Wilmer Eye Institute and Johns Hopkins and Retina Fellowship at Duke University. He's been president of the American Academy of Ophthalmology, vice president of Arvo and he's also been president of Macula Society. His research interests have been long-standing in antioxidants and age-related macular degeneration and now in regenerative medicine as it pertains to the RPE. He's really been a tremendous leader, a dear friend and a great mentor for me and to many others and so it's with my great pleasure that I introduce Paul Sternberg. Well thank you, Randy and Amy. It is a real privilege to be here. This is an amazing eye institution. Your chairman, Dr. Olson, has been one of my role models and when I became, I know we're about the same age but he's been chair for about twice as long as I have so and when I became a chair, you know truly I tried to emulate what we did at Vanderbilt with what has been accomplished here in terms of building an institution that truly valued all three priorities of our mission, providing clinical care, extending it to the community, making trainees feel like they were important, not just people to do refractions and having research be ingrained in the culture of the institution where whether you're a clinician or an educator you still think about research as being a priority where the clinicians who know that part of their job is to generate some margin to support the academic missions and that's not viewed as a crutch but viewed as a privilege and you've done that here. The culture here is remarkable and you can feel it when you walk in the doors and talk to everyone which I had the privilege of doing yesterday. So I want to congratulate you and let you know that this place really has incredible esteem across the nation and around the world and when we look at the US news rankings, we know they do not reflect the true quality of certain institutions around the country and so don't buy the journal. So this morning I'm going to give a talk that I first prepared about six months ago when I was asked to give a lecture at the Retina Society and they wanted me to reflect on my career as a vision researcher and I'll be honest. I closed my lab about ten years ago when I became chief medical officer that I just didn't have the bandwidth to be a clinician, to be a scientist and to do all the administrative responsibilities for the Vanderbilt Medical Group which is a 2000 doctor practice similar to your faculty practice here in Salt Lake. But like Randy who also doesn't have a lab, it doesn't mean that we aren't interested in science and that we don't read about it and talk about it and try very hard to partner with our faculty to push them to identify and solve the key problems that continue to face us in our profession and I think those of us who have been it for a while can look back and remark on the incredible advances that we've made. I mean I was telling the residents that you know there's very little I do in my clinical practice that I learned in my fellowship because of all the advances that have come along but there still are incredible gaps in where we need to go and where we can go and I think that's what drives us to have chosen to be in an academic institution and to practice here. So the area that's gotten the most interest for me is regenerative vision and because there still are so many patients that for whom we can't do enough to help them see. So we're going to talk a little bit about why this has become a priority for me and what challenges it creates, where we stand in our current clinical care for patients with these problems, what sort of approaches I think we should consider and then just a few reflections on what things might look like down the road. So despite all of our advances there still is an incredible amount of irreversible vision loss. Whether it's nationally or worldwide there are millions of patients that are blind. Glaucoma, macular degeneration and diabetic retinopathy are the three leading causes of irreversible vision loss in this country. Akela trauma is another where we still have half a million patients lose some level of sight from trauma each year. The tissues affected are neural tissue. The neural tissue of the macula in macular degeneration, the RPE and photoreceptor neurons, and glaucoma, the retinal ganglion cells, and the axons in the optic nerve, diabetic retinopathy, both the outer and inner retina, and in trauma it's the whole eye that can be affected. And the limiting factors for irreversible vision loss is that that we're really talking about the brain. The brain is an extension of the eye. That was a joke. It's an ophthalmic perspective of the neural central nervous system and the central nervous system as we know does not naturally regenerate. So the problems that we're seeing in glaucoma and ocular trauma are really similar to why we see irreversible damage from stroke or spinal cord injury and epilepsy and Parkinson's. In fact, one of the things that really drove my interest in this was we have a pediatric ophthalmologist who shortly after I joined the faculty, one evening developed a spontaneous spinal cord infarction and became paraplegic just suddenly. And she has really been interested in regenerative neuroscience as a result. And being an ophthalmologist, she has pushed me to make this something that we focus on at our institution. And in fact, she is part of our external review panel for the work we're doing. One of the conditions that I see most in my practice and in fact has been an interest of mine as Emmy reflected in her introduction literally since I was a resident in the 1980s has been dry macular degeneration. A number of you in the room who do retina research, I see Paul and Greg who have been by my side for many of these years will remember that it was hard enough to get any funding for macular degeneration research in the 80s. It was just considered a non, it was a disease that wasn't worth investment because there was nothing we could do. But particularly for dry AMD, there was very little interest in study. So the few of us that have been beating our heads against this wall have been persistent and but we still have a long way to go. Current treatments. Well, if you call it a treatment, are the red supplements, the age related eye disease study was designed in the late 1980s. I was one of the people that sat in a conference room at the National Eye Institute in I think it was 1988. When we were designing a natural history study for cataracts and macular degeneration age related eye disease study was designed as a natural history study, not an interventional study. While we were doing this, a retina specialist in New Orleans named David Newsom published a very small paper with less than 100 patients followed for six months who were treated with Zinc and showed remarkable improvement in their visual acuity with a six month treatment. The AARP and everyone else went crazy about the important that this wonderful new advance had been developed and everyone was taking Zinc and we decided that we would put a treatment arm in the age related eye disease study to do a national a properly powered study to disprove the benefit of Zinc in the treatment of age related macular degeneration. At the same time, we thought we should look at some other antioxidants and the dosages that we picked were not too dissimilar to putting your finger in your mouth, wetting it, holding it up in the air and deciding what the dosages should be. It was the closest thing to guesswork that I've ever done. We did the study. It was about eight years later, 10 years later that we had the results. We sat in a conference room bigger than this because there were about 100 centers. We were asked to put on a sheet of paper whether we thought it was effective or not. They collected the cards. They read the results. 80% said they thought it was ineffective. And then they shared the results that it showed a benefit. So this is not this was not a clinical trial like anti VEGF where we knew within a few months of the study that there was a benefit from the treatment. This was one word not only did not think there was a benefit from the treatment. We thought there was no benefit from the treatment. So the fact that we were able to demonstrate the statistical benefit of a 25% reduction in progression to advanced AMD was important and has been our only treatment now for 40 years 30 years 30 years. A Reds to similar trial that most amazing A Reds to was that the data from A Reds one was replicated almost exactly. There are a lot of the question the statistics of A Reds one, A Reds to affirm it. So there are things, you know, people that are working on this, you know, you should know that this good looking guy is has been at the forefront of our study of dry AMD, understanding the role of xanthophyll carotenoids omega three fatty acids, and both in terms of non invasive methods to measure it, but also using those to help combine genetics with interventions to advance it. And then this other even better looking guy, as always has been instrumental in identifying the role of different complement related proteins, activators, proteins and drusen, and then looking at genetics related to that, and trying to leverage those discoveries to develop some innovative strategies to prevent or slow the progression of macular generation, combining it with genotypes, am I accurately reflecting that word? And then this is another familiar face to you, Sabina Furman, who we were successful in stealing away from Randy a few years ago. And I did that because I wanted to move her a little more into translational research, and be part of this regenerative vision initiative for us. And she is trying to see if there are ways that we can restimulate dying RPE cells to by genetic manipulation, to repopulate the areas where they're dying for a trophic using some important signal transduction pathways as a mechanism to increase regeneration of dying RPE cells. Glaucoma is the other big neurodegenerative disease and good work has shown that it truly is a neurodegenerative disease. It's not a disease just of the eye. The retinal ganglion cells are challenged through IOP related stress. They're biochemical, biomechanical, and bio energetic mechanisms by which we can hypothesize the damage to the ganglion cells and the axons and lead to loss of function from glaucoma. And lowering intracular pressure is probably a little bit more effective than the AREDS vitamins in the treatment of glaucoma, but it doesn't work for all patients. And I think we all know that that visual field loss can't will proceed in a significant subgroup of patients. And we also know that compliance with this treatment is certainly not ideal. And although we search for better pressure lowering drops, and we search for more effective ways to deliver those drugs that are easier for the elderly patients afflicted with it, glaucoma still remains a significant cause of irreversible vision loss in our population. Gene therapy is something that we're starting to think about as as a potential way to treat all of these conditions. And you're familiar with the work with the adenososciitis virus, which can be used to replace the damaged genetic material with with a therapeutic gene. And the proof of principle has been the wonderful work being done with labors congenital amaurosis, the gene therapy for mutations in RPE 65, the development of a drugs subretinally delivered Luxterna that now has got FDA approval, the first FDA approved gene therapy for any genetic disease, not just an ophthalmic genetic disease. And I was fortunate to be in Lisbon, when this group of investigators from around the world were honored. And one of the lovely things about the shampoo alone ward is that they they also honored the basic science work that was done, not not just those people that did the more glitzy gene therapy work. But unfortunately, this isn't doesn't work for everyone. And the improvement is is not permanent. Unfortunately, the a lot of these patients, although they see improvement in their visual function after the gene therapy from the subretinal injection will start to see some deterioration in that function over time. But this is really remarkable. And I think that it provides an opportunity for us to see a window into the potential benefits of gene therapy for so many of these diseases. And it's not limited to gene therapy for photoreceptor diseases. But there's work being done for glaucoma that Tonya Rex, who's another member of our regenerative vision team is using a associated delivery of modified earth or poison, has been able to show that it slows optic nerve degeneration in an experimental model of glaucoma. It's a microbead model that that was developed microbead or injecting the entered chamber, they block the outflow pathways. And if you give these patients the AAV Epo vector, their vision loss is reduced. There's also later labors hereditary optic neuropathy. And there are two ongoing clinical trials using an AAV mediated gene delivery of the subunit of complex one that can be administered with simply intravitural injection. And there have been several reports of both safety and efficacy for these patients. We've been treating a number of them. We're one of the clinical centers. These are kids that are getting intravitural injections. So we have to take from the operating room to do this. But you can see in this image here, the improvement in visual fields that these patients experience. And this is held up to 36 months. So some remarkable benefit from this treatment. And we anticipate that this will probably be the next ophthalmic gene therapy treatment that we'll receive FDA approvals and take a little while longer to get before that happens. But we anticipate that. But despite these advances, you know, these are the ones that are clinically beneficial are ones that I've had very specific gene changes that can be treated. I think we all know that the conditions like macular and generation, or I was talking with Dr. Bernstein about MacTel, these are not simple genetic conditions. They're very complicated. And so the 40 foot questions are, you know, how do we prevent diseases of the CNS? Because that's what these become. And when we can't prevent them, how do we replace lost tissue? And that's the field of regenerative medicine. And the approaches we feel vary with the stage of the disease. So if you can identify early, you can have protective mechanisms, identify the vulnerable tissue. Before there's loss of function, I think that's what Greg Hageman is trying to do in some of his work. The repair of the stress or damage neural tissue to regain function. That's what Sabina is the area that she's working on. And then the restoring lost tissue or nerve tissue to regain connectivity with the brain. We'll talk about that a little bit. I feel that the work there, which is a lot of it stem cell therapy or these artificial vision. I guess my bias is that we need to work more the first two, that that's really where our opportunities are. So in optic nerve degeneration or optic neuropathy, glaucoma being an optic neuropathy, you know, we can, you know, how and when do we intervene. So there's a point in the disease where the axons are still intact. So we want to protect those axons from stress. There's a point where they develop early axonopathy where there are functional deficits that are associated with remodeling of the astrocyte reorganization. And this is where we really need to focus on repair. When we get to this point where there's really loss of tissue and glial scarring, you know, the cause left barn and our efforts there are going to be much more complicated. One project that has been very promising has been gene therapy using mTOR, you know, which is we know about from work with autophagy and very important pathway. And there's been work that has been done about Huberman and his associates that have shown that increasing the activity of ganglion cells through boosting mTOR activity through a AB gene therapy can facilitate the repair of degenerating axons in the optic nerve. And mTOR is really the key to helping those neural tissues remodel after injury. And this work has shown that when animals are treated with this, that they can demonstrate re-innovation into the central brain, that they also, using sophisticated testing, have improvement in their contrast sensitivity. It's not ideal. It's a proof of principle, but it shows that there is the potential. If you identify the right pathway, upregulating that pathway can potentially improve the ability to repair damaged axons and ganglion cells and improve visual performance. Dave Calkins at our institution has been focusing on this as well. He's been able to demonstrate that he can enhance retinal ganglion cell excitability through an axogenic associated mechanism. And again, using the animal model have shown that this is a very promising therapeutic target for not just glaucoma, but other age related neurodegenerate disorders, you know, like Alzheimer's and Parkinson's. Let's look more at the different stages and where we could intervene. Here's a model where Larry Benowitz used a crush injury to the optic nerve. And he was able to find actually that using zinc chelation promoted axon regeneration in the nerve and was able to show improvement in axonal function through this mechanism. But the cells when the cells are gone, you know, there's not a lot that can be done. And I think we just like there's work that's being done to explore the potential benefit of RPE or photoreceptor transplantation. We may need to think about retinal ganglion cell transplantation for some of these more advanced stages. And we've been fortunate to have received two recent audacious goal grants to look at ways that we can address both glaucoma and optic neuropathy to using stem cells derived to move into regenerating retinal ganglion cells. Moving back to photoreceptors, which is more where us retina guys work. We know that photoreceptors are critically damaged in macular degeneration. And there are a number of different conditions that lead to this, whether it's retinitis pigmentosa or make potential all sorts of retinal generations. And the model that has been most helpful has been zebrafish. In zebrafish, we've been able to demonstrate that mular cells that in the retina can actually become stem cell like. So when there's an injury, you can using some external manipulations stimulate the mular cells to become stem cells and actually transform the mular glial cells into photoreceptors and have regeneration of damaged photoreceptors. Really remarkable. And zebrafish have become a great model for studying this. But you know, we're not zebrafish. And our ability to regenerate has not been shown in mammals until recently. Bo Chen at Yale did a remarkable study where he again using AAV based re programming was able to demonstrate that he could generate a rod photoreceptor following injury. That it was, you know, a multiple stage process, where first he stimulated the mular glial cell proliferation. And then with a second treatment, able to get them to transform into photoreceptors. And so you can see this set of slides, you first get the stem increase in the mular cells. And then over time, they evolve into a rod phenotype. And so as a result, over time, there was an increase in the number of rod photoreceptors and all four retina quadrants in the mice that were studied. First time that's really been shown in a mammalian model. But more importantly, he was able to show improvement in the VEP from this. Not only was restoration of rod photoreceptors in these animals, but there also was improvement in visual function. And this nature paper that came out this summer, I think it gives us extraordinary hope that that we have direction as to how we can potentially deal with these devastating blinding diseases. Another familiar face to some people here. Ed is working more along this line. And so the work that we're pushing Ed to do is to use his knowledge and background in developmental retinal biology to get mular cells to evolve into a pluripotent state with a regenerative capacity. Ed has been working with zebrafish as well. And we're now having him move from zebrafish into mice with the promise that this will be an effective approach to treating retinal degenerations and macular degeneration. What we hear about a lot more often is stem cells, RPE transplantation, photoreceptor transplantation. And I haven't really talked about that at all here. And I could show you slides from some of the clinical trials for Stargardt or for dry AMD, small numbers from Steve Schwartz, paper in Lancet with, I think, 10 Is, was it, where you could demonstrate that that they stuck under the retina they survived. But there's nothing really physiologic that these were able to demonstrate in the work. And I think that we can say they carry promise but the challenges of getting, you know, the I guess I have a lot of problem with the idea that you inject a slurry of cells into the sub retinal space and they're going to magically integrate with the complex circuitry of the retina. It to me, it just doesn't pass the sniff test. I can I can I mean, I can understand that they will survive. But the fact that they're actually going to help people see again. I think we're just really far from that. And and so I don't want to be dismissive because the last thing any of us know who've done this for a while is, you know, if you have, you know, I don't know how these venture capital guys do it. But that's because they do 20 they invest in 20 things at once, you know, because they know that only one or two of them might hit. And so I'm not saying to be dismissive of it. But I just for me, I find it very challenging. And there's also the whole issue of the rejection from immunologic response and that these eyes patients will need to to have treatment with any, you know, with like they have transplants and be on medications and you know, I know they'll do it if it restores their vision. That's not the issue. But it's a big deal. And then we've also heard lots about artificial vision, retinal prostheses, brain implants. And I know there was a group here that did a lot of work. Are they still active here? So we just had our first human implantation. We're kind of keeping a little bit quiet. And there's also been very, very interesting, as I'll say, and we hope to get publication out relatively soon. But you know, I think it'll be a huge improvement over over trying to take that that grossly aberrated retina after these that remodeling that Brian Jones and Robert Market pointed out, I think, I think the brain could could be a better way. That's it's still long ways from what we would call a good functional vision. But I think it's going to be a lot, a lot better. I am, you know, the Argus two has been approved, approved. It provides some level of what you could call in quotes regenerative vision. There, there certainly are patients that get the Argus two, who are, you know, black blind, and who afterwards, you know, can function. And, you know, it's remarkable. And, but I, again, like you, I worry about the ability to take it much farther. And the idea of bypassing the damaged retina is, this is something that has we think about. So and it's, this is also very expensive technology. I mean, I have to think about that, of course, so is gene therapy, you know, was $750,000 for the looks turn on. So, so my reflections on how regenerative visual neuroscience will transform eye care. I really feel that the work should be focused more on better ways to delay degeneration. I think that the earlier we can treat these patients, the better that and we don't have effective ways to really do that. I also feel that our repair should be focused on activating intrinsic mechanisms rather than transplanting. I think the focus on stem cells and transplanting is gotten a lot of glitz and a lot of coverage. But I don't think it's as physiologically got the same physiologic potential as trying to take advantage of the innate structures and wiring and work with that rather than trying to re institute or re implant new tissue. Gene therapy, I think needs to be part of it. So many of these conditions do have genetic underlying. And I think that certainly the AAV vectors are great ways to whether it's to change the genetics or whether it's just to put a new repair mechanism in place. Right now it's a very valuable way to stimulate transformation of diseased cells into more normal cells. This is our investigators that are interested in this at our program. It's become the primary focus for our research. One of the things that that when I became chair, I decided was that we weren't going to be a research program that did everything that there just was we weren't going to do cornea research. We weren't going to do lens biochemistry. We weren't going to do amblyopia. We were going to focus on basically post your segment disease. And and it rather than being, you know, that, you know, a mile wide and an inch deep, we try to be narrower and and build strength in a few areas. And this is where we're focused. And I hope that it proves to be effective. I want to thank Randy for helping support my program with two of his scientists. And thank you all for the opportunity to come and speak here this morning and to visit with your your scientists and your trainees and your faculty. It's really a remarkable place that I know you're proud of and you should be. So thank you for this opportunity. Yes. So great summary of the field, Paul. And we very much agree with the issues that you talked about before. Just a little historical thing yet that a lot of people may not realize. So David Newsom was a very controversial fellow, as you remember. And it was controversial enough that he couldn't get anybody to consider doing this zinc thing that he thought maybe could could have impact. He had tried it on a few patients that he thought maybe be important. So he called up Mano Swartz who was here with me and Mano came to me and David and said, and I remember David, this is a long shot. I realized that this really needs to have a prospective randomized clinical trial. And I don't really have any money to do this. And so I put a little bit of money into the kitty so we could get that study done. Mano agreed to essentially do it for nothing. And it was a decent randomized clinical trial of which, frankly, my reaction at Manos was there's almost zero chance this is going to do anything. And so lo and behold, we were surprised as everybody else. Well, we showed a small but definitely significant of this just to be significant. There's no question. And so the question was, you know, and I said, go for it. You got to publish it. David said, well, because of me, it's going to be controversial. So we knew when a red started, it was essentially they answered that question. This is ridiculous. We're going to prove that the question was not how can we help AMD? It's how can we just prove how we prove that this zinc thing is a joke. Right. Yeah. We failed. Just which is the way science should work. Yeah. Right. You're right. Yes. The stem cells of the sort of Alibaba's cable reaches these days. See all these habits. I when I was visiting my own hospital more fields, they were doing this sub retinal RPE patch under the retinal pigment epithelial layer, which was fascinating to see. And the theory was purely because, well, these patients are down to counting fingers. There's nothing we can do. There are no more introvert to the injections that work. And you saw that report last year, they came up with two patients. It was very small. Any views about the patch, the stem cell patch? Well, the question becomes, if you put in healthy RPE cells, the patient still is macular degeneration. And so you have a geriatric atrophy, you probably have damaged Brooks membrane, you probably damaged coreo capillaris. You know, I just it's hard for me. I'd be curious, you know, what, what me Paul, you know, Greg think I, I, it seems to me a stretch. I mean, I can show you slides that I created for my job talk in 1984 was recruited to Emory of RPE transplantation. What my talk was was taking an RPE patch and putting in geographic atrophy. That's what I wanted to do. Now, those days, there had been no submacular surgery, the instrumentation to do it was just didn't exist. And my efforts to do that in rabbits. In my first few years, we're entertaining, I wish I had videos of some of those animal surgeries that I did, because they were pretty ugly. So the idea is not, you know, an original idea, you see this patch of GA, like you want to put something there, you know, you want, you know, it's just, you know, all of us who see those patients every day, why can't we just, you know, plug plug a gap. But it is an incredibly sophisticated organ. And the idea of just putting in a layer of cells and expecting it to repair it. I think it's just too naive. I don't think it'll work. Paul, what do you think? It's it's been a big challenge in there. The hype has has far exceeded the actual reality. We clinicians have to kind of back that, you know, we have to explain this to patients all the time. They have to be patient and that science doesn't, you know, it doesn't move as fast sometimes as we would like. We have to do it right. It's a hot area, though. I was at a meeting and next door, they had it and there are people out there with these clinics that are charging huge amounts of money using their patients own stem cells and they're injecting them everywhere. And this one paper I went to and it was it was a foreign medical graduate in internal medicine who was claiming that he was doing retro bull bar stem cells and helping people with macular degeneration. And so I mean, it's just it's just got absolutely crazy. And then a lot of us the business side, how if you take somebody's fat derived, you avoid the FDA issues, because you're injecting their own cells. And they were getting $25,000 of pop and they were doing, you know, 20 patients a day with this. It was just mind boggling. But there were a handful of patients that developed horrible goals and those intraocular injections. I also had some trying intraocular. And so he said that was a mistake, you do retro bull bar. And I went out after I said, How do you think that's possibly how could possibly stem cells or some magic potion? It's crazy. I think if you have AI and stem cells in your company, yes, your little money at you. So Paul great. I really enjoyed this. One of the areas that I think we've worked on is is regarding reactive oxygen species. And many times, you know, antioxidants are also seen as this magic bullet. But the complexity of their effects as signaling, secondary signaling compounds can can make it really hard to sort of piece it parse it all together. But I was wondering what your philosophy philosophy was about that field now, you know, recognizing that we have a lot more information than we did, you know, initially, we did. And as any point on the introduction, that really has has been my was my focus of research for 25 years. And we were able to identify some important mechanisms of injury. And I think we were we were much better at identifying how oxidative stress played a role in that lost in the damage in AMD than we were. And being able to show that repair through antioxidant mechanisms could be effective in treating it. And I think that's where the where, you know, where the next steps are. I mean, you know, Paul, I know you're this is where you're trying to take this, I think. What are your thoughts? You know, I think regenerative medicine is, you know, we do need the basic science behind this. I think it's gonna signaling pathways are really going to be more important than just any oxidative species. Very good. Well, thank you over. Thank you.