 Good afternoon, everyone. I think we can get started. Before introducing our Benning speaker, I wish to thank the Benning Society, which sponsors the lecture series. The Benning Society is an honorary society of shareholders whose primary mission is to enhance biomedical research at the University of Utah and is charged with advocating and maintaining excellence in biomedical research, mentoring future researchers, and encouraging interdisciplinary coordination in clinical and laboratory research. The society was made possible by a very generous grant to the University of Utah Medical School from H.A. and Bending. And with that, it is a great honor to introduce to you our next Benning speaker, who is a dear and respected colleague and a consummate clinician-scientist. Dr. Joan Miller is the Henry Willard Williams Professor of Ophthalmology and Chair of Ophthalmology at Harvard Medical School. Dr. Miller also serves as Chief of Ophthalmology at Massachusetts I and Air and Massachusetts General Hospital. Joan graduated with high honors from MIT, undergrad, and Harvard Medical School. She is most known for her work in age-related macular degeneration, one of the leading causes of adult blindness worldwide. And we all likely know someone who's been afflicted with this condition. Joan and colleagues developed photodynamic therapy using group orphan, the first pharmacologic therapy for age-related macular degeneration, and identified the importance of vascular endothelial growth factor in ocular diseases. And this has formed the basis for our current anti-angiogenic therapies for many ocular diseases. As a well-respected clinician-scientist, Dr. Miller serves as consultant for a number of scientific advisory boards and maintains a practice as an explicit vitriol retinal clinician. She leads not only in her position as Chair of Ophthalmology at Harvard, but also nationally and internationally, and has paved the road for burgeoning clinician-scientists and surgeons as a strong mentor and supporter. Listing over 80 direct mentees, many of whom now hold academic positions around the world. She is a member of the National Academy of Medicine and a recipient of numerous awards, including along with colleagues, the 2014 Antonio Champalamar Vision Award, which is the highest distinction in ophthalmology and visual science. She will speak to us today regarding ongoing research to improve our consumptions with age-related macular degeneration. Joan. Thanks, Amy, for that very warm introduction. It's really wonderful to be here. I'm embarrassed to say I've never really spent any time in Salt Lake. I've just landed in Gunelsburg, so it's really a treat. And even more of a treat to be here at Ed Moran and seeing all the wonderful things that you're doing here. And it's an honor, of course, to give the bending lecture. First, just want to provide my financial disclosures. What I'm going to talk about today is not really relevant, because it's mostly today is all about speculation. And these are really related to the work I did in the Board of Perfect PET, as well as some consulting. I wanted to look up and learn a little more about the bending society. And the bending gift was coming to get the lecture. So I did that and was intrigued to learn about the bending family and the amalgamated sugar company. And then really seeing the connection between grateful patient and this wonderful endowment that was given to the institution and as a chair, we all aspire to leveraging these relationships and reminding clinicians and anybody involved in the patient care aspect, how important your interactions can be in terms of stimulating this great generosity and making possible the supports that really let us do the research and training that we view as our mission. So just kudos to the bendings. So age-related mech and degeneration remains an important public health problem. It is the third leading cause of blindness worldwide after cataract in glaucoma and the leading cause of blindness in industrialized countries. As clinicians, we still really categorize it based on what we see looking in the retina with the typical bruiser and the posits that you can see in that upper middle panel, some humanitarian posits all in the early or intermediate forms, and then the late stages characterized either by atrophy that you see on the bottom left or the neobascular form in the lower two panels, both of which lead to severe vision loss. We've had advances in treatment primarily directed at the advanced forms and really reserved for the late form, the neobascular forms of advanced AMD. And when I finished my training, really all we had was laser photo coagulation where you used a hot laser to try to coagulate the blood vessels, but of course damaged the retinob overlying those. It was really not a very rewarding treatment. We moved through photodynamic therapy, had some brief forays into surgical removal or translocation. People tried injecting steroids. Then really it was anti-vegeta therapy that has changed so much of what we do for patients with this condition. And I like to joke that retinob clinicians have this particular graphic imprinted in their brain that's sort of like the Halle Berry cell. This is the Renovizumab phase three data cell because this was such a change from what we'd been able to do for patients. So this is the vision outcomes from the Marina study, which was the Renovizumab or Mucentus trial and went back into generation where we showed where we cycled the first time really vision improvement over the course of two years compared to what our standard of care was. So with anti-vegeta therapy, more than 90% of patients can avoid moderate vision loss, a third achieved vision of 2040 or better, which is driving vision. And there have been a number of studies that have really compared the various ages that we have now really showing very similar outcomes for macular degeneration. But what happens beyond two years? And really the perspective randomized clinical trials that we'd like to rely on really go out to 24 months and that's about it. And given the cost of them, I don't think we will get more than that. There have been some extension studies where people have used the patient populations that are willing to come back and be studied longer afterwards that we've looked at. One of those is the 7F study. A number of us have done some retrospective studies from random practice groups. And these are all, of course, flawed because there's different protocols, there are a varied degree of follow-up and varied drug. And I think there's a move to use registries, things like the American Academy of Ophthalmology's Irish Registry where we'll have more realistic outcomes studies that at least give us some indication of how things really work sort of in the real world. But when you look at the studies that we have and you start looking out longer than the two years, you find that by the time you get up to four or seven or 10 years that most of these patients end up losing vision. So they don't maintain great vision. And what they seem to do is to progress to atrophy. And that's sort of the standard that you see throughout with either auto-plastic studies or imaging that you can see macular atrophy and a very large percentage of these patients. So what happens when you've controlled the Neovascular process and why are these patients losing vision? Well, I would argue, and I think that the most, the greatest underlying cause is really that you're unveiling what is after all of degenerative disease. And so that you really have controlled angiogenesis and permeability, but you are continuing to have a degenerative problem and patients end up with geographic atrophy. Of course, it's also possible that we end up with poor profusion there in part perhaps because of our anti-vegette treatment. And so you get progression of atrophy because you've wiped out the blood supply. And then of course there is a role potentially for anti-vegette since vegette is a neurotrophic agent. Well, if you look at some of the older studies, these are images from Annie Malam where she looked at what happened over Lyme bruisin and you can see that there is a degenerative process that occurs in the rosin combs and obviously more extensive loss by the time you get to geographic atrophy. But if you look even back in some of Green's old studies, you can see that same kind of process happening over in neobascular lesions. So you get abnormalities of the photoreceptors and eventually on loss of those cells. And in fact, even in the more recent studies, the CAT trial, Burnwell showed the geographic atrophy progression rates were really similar to treated neobascular AMD patients as they were to those with non-neobascular AMD. Then as I mentioned, it can also be that we are destroying the perfusion of the utter retina. I think that as C and D coronary evascularization develops that it replaces the normal coronary capillaris and that if that lesion regresses that you're really left without a way to refuse the utter retina. And strategies to really cause regression of the coronary evascularization may be detrimental. And finally, blocking the neurotrophic effect of VEGF has the potential. I don't know that there's great clinical evidence for that. Probably we're not completely effective at blocking VEGF and probably that's a good thing for the retina. So all of this sort of leads me to advocate for a role for neuro-protection. I think that intervening with neuro-protection as degenerative process can prevent vision loss and the atrophic changes that you see. So we would suggest combining neuro-protection adjuvant therapy along with ATVGF to prevent this photoreceptor cell death and improve vision outcomes both in the short term and long term. So far we've yet to convince a pharmaceutical company to go along with us on this. So I've been studying this for a while. A lot of this work is really led now by Dmitriy Zavavis at our location. And we first started actually with David Zax who's now Michigan looking at apoptosis in the death of photoreceptors. And that seemed to occur in the models that we used. We started off actually using a model of retinal detachment in the rat and then in the mouse. You could see caspases that were involved. But when you blocked the caspase inhibitors you really didn't prevent photoreceptor cell death. And so it turned out that we found that there was another cell death pathway that was involved which was programmed across this through the rip kinases. But that if you were able to block both the apoptosis pathway and the necrotosis pathway with two different agents you could actually really prevent photoreceptor cell death. And we've done that in a series of models, the retinal detachment certainly and then sort of a few with AMD-ish models including chemical injury models with sodium iodate and demonstrated RNA. And then one retinal degeneration model on the RD10 mouse. So we would argue that there are multiple cell death pathways that are somewhat redundant and complementary and that this combination therapy is really what one needs to go forward with to adequately protect the photoreceptors. And this just sort of goes through a few more of these pathways. What we found in terms of cell death in the models that we've been using really seem to be apoptosis and necrotosis. Pyrotosis will get into a little bit more in terms of inflammatory activation in AMD and then autophagy obviously is important in sort of normal cell function as well. So I would argue that neuro-protection may offer some broad-based treatment approaches to a variety of disorders including macular degeneration. We think it would be useful as an attribute therapy along with anti-vegif and then the abaster forms but ultimately you'd want to treat early and intermediate AMD but of course you'd need some long-term safe delivery strategies for that. So what about treating macular degeneration earlier in the process? One of my mentors chastised me for focusing so much on the abaster AMD in my career because he said you don't want to be starting on the end stage of the disease, that's stupid. You should be really working upstream. And of course, now that is the focus for many of us. I would argue that the severe vision loss at the time was really the neobaster form so it seems kind of logical to me. But now we and others are really trying to understand how we can treat earlier on in the disease process. And it's worth remembering that the successful treatment that we developed for neobaster AMD was really based on a therapy that was targeted to a key pathway. It turned out that vegif really was and had a key role in angiogenesis and permeability and macular degeneration and many other octo-ineobaster diseases. But if we're going to target early AMD we need to really understand AMD pathogenesis better to develop those targets. So in trying to understand AMD pathogenesis one needs to put together information from a whole series of investigations. So including clinical observation which we sometimes forget about these days. Imaging which is near and dear to the clinician's heart now. Epidemiology, histopathology and then more recently from genetics and molecular biology. And when you pull those together I've tried to categorize it. I think you end up with these six sort of different buckets or pathways as it were. Age and senescence, lipid and lipoprotein, metabolism and transport, inflammation and immunity, extracellular matrix and cell adhesion, angiogenesis and then cellular stress and toxicity. So in thinking about how the process occurs, this is really just your outer retina for a capillaris down below, broke some membrane with the sandwich of elastin between two layers of collagen and then RPE above that with age. You get lipofusion in the RPE, a lipid wall that occurs that develops and then the basal laminar deposits and ultimately a druse. With those lipoprotein deposits you get inflammatory activity that can be compliment mediated. You can also involve the inflammatory which haven't added to my cartoon yet. And then you can go in different directions. You can get breakthrough of Brooks and the angiogenesis and permeability with Neovascular AMD or you can end up with cell death, both the RPE and photoreceptors and geographic entropy. So what about targeting some of these? So first thinking about age and senescence and this is kind of still at a rudimentary stage but one aspect is alterations in autophagy and riznoid deposit formation. And there also appears to be alterations in energy sensor function which can lead to some synaptic dysfunction. So thinking about autophagy, this is a major catabolic system which is used to degrade unnecessary dysfunctional cellular components using the lysosome. And of course the RPE does this every morning when we wake up when it engulfs photoreceptor outer segments. And an important protein involved and this is the lysosome associated membrane protein two or LAMP two and it's key in autophagy. We found that and others have shown that LAMP two is expressed in the RPE that decreases with age and it decreases in AMD. And this is a work again by Bobbis looking at a LAMP two knockout mouse and it's interesting that it seems to recapitulate some of the aspects that we think of in AMD that it has these deposits that accumulate between six, 12 months. Of course mouse does not, as you know, have a macula. So you're just looking sort of at peripheral retina. When you look with autofluorescence you can see that these autofluoresce in these same mice over time you get a thickening of gross membrane and truzenoid deposits that occur that are seen at six months and then more impressed at 12 months. So it has some similar aspects to what we see in patients with macular degeneration. So there may be this age, both an age related and perhaps disease specific dysregulation of autophagy in the RP that may be part of the pathogenesis of AMD. And it seems that a paired LAMP two function is involved in the accumulation of this truzenoid material and that these LAMP two deficient mice recapitulate many of the features of AMD. So again, maybe not necessarily LAMP two itself but targeting autophagy dysregulation may be a strategy for early AMD. So another sort of target in aging and senescence is that there seems to be a role for controlling senescence through AMP kinase. And I've forgotten most of AMP kinase in my brain. I'm sure more of you remember that well but just as a refresher, when consumed AMP is produced, AMP kinase is activated and AMP kinase really functions as an energy sensor within the cell and a positive regulator of autophagy. You can regulate it by number of inputs, exercise, caloric restriction, never a popular one for any of us. LKV one, ACARP, which is an exercise of a medic and of course metformin which is kind of a target of interest to people these days. So let's just show some of the upstream and downstream aspects to AMP kinase. And what Josh Stainz and Dmitrios Vavas looked at were the role of AMP kinase in aging effects within the retina. And they found that there were age related changes in both neural and retinal function resulting in part from changes, alterations and synapses. And you can see that in the retina of young adults the synapse is really localized to a narrow band and the other plexiform layer and of course this is a neurology neuroscience view of the retina which I have trouble with. But really they're all limited within this range and with aging you start getting these aberrant outgrowths and it seems that so these processes are regulated by AMP kinase. And when you can cause similar changes in young animals if you have a conditional knockout of AMP kinase and you start to get this abnormal formation and if you can stitchily activate AMP kinase you can attenuate the synaptic aging changes as you can see down here. And you can activate AMP kinase either through gene delivery or caloric restriction which is what we've got in the middle or with high dose metformin. And all of those can restore this aging decline that you otherwise see. So again maybe the AMP kinase pathway could be another attractive target for interventions aimed at sort of mitigating this age-related synaptic decline. So the next pathway is lipid and lipoprotein metabolism and transport. And it's been long demonstrated by many including curcio and others that there were a lot of similarities between AMD and atherosclerosis and if you think of rote membrane being similar to the vascular ethylene. And lipoproteins like able lipoprotein B deliver cholesterol to the tissues and become retained in rote membrane and in the sub-RPE space. This retained lipid leads to the lipid wall and then to the basal lineal deposits and drusen. And the RPE plays a really key role in this process in that it both takes out lipoproteins from the circulation. It accumulates lipoproteins in the process of fetishizing the photoreceptor outer segments. And the RPE actually has significant lipoprotein synthesis. So again just sort of refreshing on our lipid wall accumulation and basal linear deposits. One can think about targeting different aspects so whether it's lipid transport or the RPE lipid metabolism itself or sort of going after the retained level proteins once they have occurred. There are of course various associated with AMD that have our genes in the lipid transport metabolism pathways which I've listed here. So there's sort of obviously genetic components suggesting that this pathway is important as well. Well one way to think about targeting lipids is to think about statins. And this is something that people have looked at really over the last couple of decades and it was sort of an easy thing to think of because of the lipid loading and also anti-inflammatory effects of statins. And the previous investigations really have been very mixed in terms of whether it can either affect the development of AMD or alter its progression in any way. And in fact in 2015 there was a Cochrane review that just concluded that statins really played no role in preventing or delaying the onset of AMD or its progression with ophthalmologists have not quite given up. So Geimer in Australia performed a prospective randomized placebo controlled study which suggested that semi-statin meant slow progression of non-advanced AMD especially in those with the CFH risk allele. And Van Der Beek who's now a pen showed that an increased serum LDL and triglycerides in more than a year of statin use led to an increased risk of Neobaster AMD. It made the argument that it wasn't that statins increased your risk of progression but that these folks were very resistant to statins. And the Eleanor study showed serum HDL perhaps increased AMD risk. And then again the clients with the Beaver Dam study and using a minute analysis of three cohorts once again said no association on either instance for progression. So why all this variability? Well one aspect may be that there's a real heterogeneity within AMD particularly what we characterize as intermediate AMD. So all of these images would classify as that from a few drusen in the macula to some not very much in the way of drusen but fumitary changes and even this very large drusen of deposit and it's possible that these really are not O1 category. Then it's also a lot of variable dosing and activity of the statins. 40 milligrams of cypostatin is equivalent to 20 milligrams of atorvastatin so you need to sort of know how to convert those. And of course there's a very wide use of statins in the population. So Bob is once again just kind of the energizer bunny in our AMD group was reading cardiovascular literature and read pretty old papers by the cardiologists where they used actually high dose atorvastatin to prevent restenosis. And a number of studies confirmed this and they actually can even get regression of plaque with these high dose statins. So you can see here there's a carotid artery so a lot bigger vessel than we're used to looking at with a plaque and with high dose atorvastatin or lipitor over the course of three years really showed a resorption of that plaque in a near normal vessel. So Bob is like well now that's a carotid now maybe I could do the same thing in the outer retina and maybe you could just sort of take that patient and make all this stuff dissolve them and put them back 20 years and give them 20 years of freedom from the risk of vision change from the AMD. So he had gave that some thought didn't really act on it. Had a 63 year old patient came in who's a photographer, very unhappy with his vision. All the vision measured quite good. It's 2025 with some distortion. He had large confluent drusen and some overlying disturbance in that area but Bob is sort of true to the recommendations just told the patient to go home and take his air as supplements. So a year later the patient came back more unhappy, visual acuties 2030 still good by retina standards. And at that point the patient was really wanted to try something and Bob described sort of his rationale and thinking why the atrocious statin might be useful. And described the patient had wanted the patient to work with his internist in order to go forward with this internist called up Bob saying what are you crazy? What are you using hydrostatins for the eye? You're out of your mind. But after some conversations they kind of came to an agreement and started the patient's mission and tell them it's milligrams and escalated up to 80. And within six months the patient was really happy. Vision was 2020 and there was improvement on the fundus photographs. So here is a baseline showing these large drusen and you're more pronounced on OCT. And just color fundus photos, again baseline and then one year after treatment. You notice that many of the drusen disappeared not all of them sort of regular flavored drusen are not disappearing but these large sort of fat juicy ones are. And sort of more pronounced on the OCT that these deposits really resolved. And what's more intriguing is it really didn't seem to be atrophic changes. So we sometimes see when those drusenoid deposits do go away you're usually left with geographic entropy. So this was intriguing and based on this we went forward with a smallish pilot study with Demetrius Bavis and a colleague in Crete, Multiautocelumbaris. Enrolling patients who are over 50 years of age with those large soft confluent drusen. So not everybody with intermediate A and D. Really avoiding those with geographic atrophy and avoiding those with anemia vascular A and D. We had 26 subjects enrolled and three discontinued. One piece of some cramps, one from some muscle aches. It's worth noting, which I didn't know before we did the study that the really severe muscle cramps that you know about with statins are not dose dependent, they're idiosyncratic. So patients either get them or they don't and it's not a question of the dose in that case. You do need to be careful of their liver enzymes and those have to be monitored when you're on this high of a dose. One patient stopped a week after starting the drug because they thought that there was hair loss related to that, I don't think that was the case. In any case we had 23 subjects who completed follow up with a minimum of 12 months and 10 out of the 23 showed regression of the Jerusalem deposits, eight nearly complete. We had no atrophy and no progression in the ambassador AMD and those who responded anatomically all showed very minor visual acuity gain and the average time to response was about a year. So we looked at those who responded meaning that their Jerusalem deposits got better and those who didn't to sort of see if we could tell any difference between them. And in particular looked at how effective we were at lower cholesterol and you can see actually that the non-responders had a greater decrease than those who responded and really otherwise there was not much in the way of difference between the two. So previously as I said, we can get the Jerusalem deposits will go away but usually you end up with atrophy and vision loss and in this pilot study we were intrigued because we got regression of the Jerusalem deposits with vision gain or at least stable vision and without atrophy and we had no cases progressing to the ambassador AMD although you would have expected a few of those to occur. So you might wonder, well, yeah, how is this working? What do we think it's actually doing? It doesn't seem to be based on lowering serum cholesterol as I've just showed you. Maybe that we're altering the RPE like a protein metabolism. We may be creating enough of a local gradient that you can have e-flex of the lipids from the outer retina. You may actually be just affecting lipid e-flex from the macrophages which we know in the outer retina as part of this process. And then of course on top the statins have all these other good effects including anti-inflammatory and neuroprotective and anti-angiogenic, they are kind of a wonder drug but that's not related to what we're seeing in terms of the Jerusalem deposits. So based on that we're planning a larger phase three controlled multi-center study. We would like to include some genetic analysis and look also more carefully at the lipid subspecies. We did not include dark adaptation in this early trial that we would now, I mean the photographer was sort of his own dark adaptation tester because that's part of his job and that was actually what he noticed changing first. And then of course imaging and other functional studies. So moving on to the next pathway, inflammation and immunity as another sort of opportunity. And inflammation in terms of a sort of low grade smoldering inflammation seems to be involved virtually in all the stages of AMD. And in the early stages it may actually be that there's an impaired inflammatory response and that the inflammatory, which is important perhaps in removing these fluids by being sort of underactive allows them to communicate. And then once the lipoproteins are present you seem to get a chronic inflammatory response to them. And this inflammatory response is targeted to the RPE, the Coriocapolaris antiprox. So there are different targets within all of these inflammatory pathways that include complement regulation in which there's been a lot of study. The inflammasome also is sort of a relatively new one that people are looking at. There's also actual inflammatory cells that seem to be involved and can either be circulating or resident within the retina. And all of these may be possible targets to go after. Of course the genes, gene associations in AMD were strongest of course with complement and there are others involved in these inflammatory and immune pathways. So there are clinical trials ongoing. So far none of the complement inhibitors have worked. There is one still ongoing that we need to learn about which is the CFD trial from Genentech. Part of the trick with these complement trials is that people are really trying to prevent progression to geographic atrophy and that's really sort of the latest stage of intermediate AMD as it were that you're now sort of on this trend, on this, you know, the train is rolling down the tracks you're trying to prevent cell death. It's not that you're trying to influence something very early in the disease. There are this interest in the inflammasome. There's actually sort of two camps, Sarah Doyle and her group in Ireland think that the inflammasome is underactive and are developing agents to increase its activity. Jam body and others have the anti-inflammasome camp that are developing inhibitors that all of these actually will end up in clinical trial and we will probably get the answer in the clinic. So the angiogenesis we sort of talked about, I think we've done reasonably well with that. I think the cellular stress and toxicity, we could do more with neuroprotection. So lots of good success with this. People had tried to improve quite recently on anti-angiogenics by incorporating an anti-PTGF with anti-vegeta, which just failed. I mean, I was sort of chatting about that. We really, we're not big fans of that approach, but that one has failed and people are still thinking about other combinations. But I think clearly trying to figure out how to prevent RPE and photoreceptor cell death is a good target. In terms of thinking about the treatments to go after early and intermediate AMD, I really do think that these pathways of agents in essence, lipotransport and metabolism and inflammation are really the sort of the three large categories that hold the most promise. One of the problems with, and sort of the last piece that I'll go through this afternoon is thinking about developing treatments for early and intermediate AMD. We have several different ways. One is that visual acuity is not a good outcome measure because vision does not change enough in these early stages. So we need to figure out other outcomes measures. And then as I've sort of alluded to, I think particularly the intermediate AMD classification is a very heterogeneous group and may actually be more than one category of disease. So I think the clinicians really need to get going and working to improve our phenotyping and classification within this group. And using strategies that we have including different forms of OCT, autofluorescence, dark adaptation. And we're actually investigating others, our totalomics, that one could then combine with genotyping. So we have a collaboration arising on what's the Harvard Portugal program. And we're sort of looking at both these aspects, trying to improve the end of type and also developing biomarkers. And the groups on the Portugal side is the Coimbra University of Medicine, AB Lee, and then also the Aburo University. And on sort of on the other side of the Atlantic we have our Harvard Department of Ophthalmology. Also working with the Harvard School of Public Health and the Broad Institute. So we're looking at AMD, Structure Function Correlation, and then actually doing a totalomics on plasma and urine to try and develop a biomarker. So in terms of the structure function we're trying to look at other measures of rental functions. So dark adaptation using the Adaptex DX, distortion, reading speed, microparametry. And then trying to correlate that with imaging, mostly with various forms of OCT. So we've just sort of started to collect and impel or some of this. It's just for one of our projects looking at, again, OCT finds prepared to actual changes on the dark adaptation and the patient. Biomarkers I think are of interest in a number of diseases, including AMD. The goal is to identify a biomarker other than looking at the fundus that identifies subjects with AMD and concurrent with disease progression. So people have tried previously to look at serum biomarkers and it's been somebody consistent in some of the approaches of included looking at C-reactive protein, homocysteine, and lipids. And people have been looking at proteomics and started to look at my totalomics. So proteomics of course is downstream of translation and transcription. It does reflect sort of both the micro and macro environmental conditions. And the totalomics is another step further. It's looking at the metabolites all less than a kilodalt. And so of course it's downstream of translation, transcription, but also metabolism. And it picks up characteristics related to the environment, to the diet, until they got microflora as well. So this just sort of shows you sort of how downstream you are. So you're hoping that you're caching information that's related to the genome, transcriptome and proteome as well as these other aspects. And then the idea is that by correlating that with a phenotype you may develop your biomarker. So we, as I said, just really getting started on this. People have used metomolomics to try and profile other diseases, including cancer. And our goal is to develop this biomarker for AMD. There's different mechanisms or different ways to test for metabolite NMR. It's something that's sort of good as a screening tool. Mass spectrometry is sort of more labor-intensive and something when you're sort of starting to hone down on a particular pathways. And what we've been looking at is doing this metomolomics of both AMD subjects and controls. And some of our early findings just suggest that there, perhaps not surprisingly, there seems to be an altered fatty acid metabolism in all the stages of AMD. It's a mechanism to increase cell membrane metabolism and then lower levels of antioxidants. And so I think it's these kinds of approaches, again, particularly in the early intermediate stages, to get better at our structure function correlation and then perhaps use metomolomics and genomics to develop a biomarker. Ultimately, we want to come up with better treatments and I think sort of thinking about targeting within these specific pathways is how we will get there. As I've alluded, I think for the early intermediate, it's really the agents in essence, the lipids and inflammation. And just want to acknowledge my collaborators in particular, Demetrius Babus, who was sort of mentioned quite a bit, but our sort of AMD group, the biomarker study really led by Diva the same. Neuro-protection, again, Babus, really driving a lot of that. And our collaborators for the Hytos-Potorvastatin and our funders. Thank you very much. Joan, fabulous. And the work on this is truly been landmark. As you know, there's the two big genetic markers associated with this disease and the Conflict Factor H has an affiliated base associated with Conflict System, not the one big. But there's this other one out there, this HRI1-Arms II. You can clearly get severe macular generation without any of the Conflict Factors but dysregulated just with his arms too. What is your thought about how it responds to the things you're talking about and could it be something that would be quite dramatically different? In other words, we're lumping two totally different diseases inside of one basket. Well, I think that that's quite likely that we are sort of lumping, if not two, maybe multiple diseases in the basket and maybe, there may be different ways to get to sort of things that look similar to us as clinicians. And that's certainly, once you get to a certain point, falling off into either a geographic atria or the ambassador AMD, you can sort of get there from different categories. So I think, again, sort of trying to understand the phenotyping, I think is gonna be key and I think that's been an issue even with sort of a wonderful genetic work that's been done. I mean, again, the clinicians sort of were using the tools that we had available and the tools keep getting better. So I was like starting to understand how we can learn more about the disease with better tools and really come up with better categories. It's sort of not sexy and I was sort of splitting and categorizing diseases. It's not something that we think is really sexy science at this point but I think it's gonna be key for really moving forward. Just one interesting tidbit on that is that we're trying to look at some pure chromosome 10. So homozygous 10, no risk of HRI one, no risk anywhere else. Is that we're seeing a fair number of these people who are going right to geographic atrophy or right to the ambassador without using a hard brain change at all. So they would be called normals and suddenly they have bad disease. So that's something that's got a scratch in our heads. Yeah, this is intriguing. You get sort of similar questions but different when you talk in Asia because in Asia people say, well, people just erupt with polypoidal so they're just erupting with the vascular and they certainly don't have drusen. I guess the question is, if you did an SDO CT on those folks, I mean, do you think they have some thickness or abnormality of drusen? I suspect that there's something there. I mean, the drusen are just the expressances so you see it's really not even the underlying abnormality that's there. But again, I think there's room to think that there's sort of different categories in here that we've longed. And a similar problem that you remember I was talking about today, with the glaucoma or just sort of open-angle glaucoma, it's probably more than one disease. So Joan, can you talk a little bit about the challenges you may have going forward on a statute trial where it's a relatively inexpensive drug? Can you really get the drug companies interested in this and get it funded? Right, so we're... So, yeah, a little bit of a statin is off-patent. So it's about $11 a day, or $11 a month, sorry, excuse me, in the US, still expensive. The Indian, when I presented this in India, they were not happy with it. So, yeah, we're not getting, the people who are not excited about it from a drug company standpoint unless someone were to figure out that their statin was better. So we have talked to those that might have better statins. But we don't think we're not gonna go rely on the drug companies. We're actually sort of raising funds around and going to NEI, hopefully for health. And it won't be a hugely expensive study. So I think we can probably get that done. You know, and it would be, even if you could have a treatment that was just sort of for the fat, juicy groups of people, that would be pretty exciting. And again, to maybe just push them back, a decade or two would buy them a lot of time. Now, it may be we're wrong and that these guys are gonna end up in geographic, actually we would just have had two smaller groups to see it, you know, and that's what it is. And you do have to watch. I mean, we've had people call up and wanna be on the statins, and you know, try not to get that going until we really know the answer having been through like intercurrent and other things. But if people do it, you do wanna have an internist involved and monitor the function test because you can get somebody into trouble, right? In the back, maybe first of all. Are there environmental or geographic or vocational variations that keep you on the cruise? So there are certainly different phenotypes in different realms, regions of the world. So that's what we're alluding to in terms of, Asia shows up with polypoidal and some of the genetics have been different when people have looked at different populations. You know, there are certainly lifestyle risk factors that increase your risk and smoking's been the most consistent. And smoking, and Meg's done this work with smoking with certain genetic risk factors really, really increases your risk. Just related to the statins, do you think that once you kind of clear the druzen that you'd have to maintain that high dose or do you think you'd taper off from down? So I mean, we, you know, early to even know that we have generally pulled people off, we think that it probably takes decades for that to accumulate and we're seemingly able to wash it out pretty quickly that you would not have to certainly stay on high dose. Sometimes hard to get the patients to come off, which you can kind of imagine if you wanna stay, but you can get them at least down to something that's not wrong reasonable, guys. Related to that, the plasma for instance was done for RAAA as a study, right? And didn't work in AMD, but people would show anecdotal cases where somebody had plasma for his sister in the Philippines and they did seem to respond and they did have those great bruises. And I wonder if you have any insight into has anyone ever divided out those and could it be that they just walked everyone together and if they had just a category of the juicy bruise and they couldn't have been helped? And then the flip side is, what happens when you step plasma for instance? This doesn't come back, especially. Yes, so again, if you look, you know, the responders, non-responders of our group, once we did better, didn't have as big a drop in their cluster also. You know, the serum levels may not, you know, it may be much more local phenomenon, but I don't know other people have looked in the categories from plasma for reasons that might be interesting. Not sure that I want to get that going again and sort of dive in time again. Yeah, I agree. Thanks very much. Thank you. Thank you.