 All right guys it's the hour has come and we're very excited to hear from Dr. Hageman this morning so we want to be able to start without any delay. Dr. Hageman really goes without introduction. He's one of the leaders in the field of ophthalmology. He's made paradigm shifting breakthroughs in the field of molecular degeneration. One of the great things about Dr. Hageman as well as he's very interested in resident education we've already had a couple residents who've worked with him and so just from our perspective we're very happy to have him here as well. So we're happy to hear this morning from Dr. Hageman. So thank you Derek. I hope the very excited part is true for all of you so I expect a lot of enthusiasm here. Now it's really great to be here. What I'd like to do is just share a couple things that we're doing on the research side of AMD and if we have time at the end I thought it might be appropriate to tell you a little bit about the Center for Translational Medicine. So before I start I mean I'd like to thank all of you out here who have helped us with our study, our patient recruitment with the research both faculty and staff. You guys have been great. We've recruited I think close to 1,500 people since I've been here so that's no small task. On top of that you know it's been my great fortune for many years to just have a wonderful set of colleagues to collaborate with so a lot of what I'll talk about today just remember comes from them as well. So for those of you that are in the field of macular degeneration I think it's the last five to six years in this field have been phenomenal. We've gone from an understanding of zero 20 years ago in fact when I first wanted to work on this disease the director of the National Eye Institute said Greg I'll never fund you to work on macular degeneration there's nothing we can do about it and that's really what took me kind of down the corporate path a little bit. So we've got some of our initial funding from Johnson and Johnson and those relationships have actually helped tremendously and really actually feed into the Center for Translational Medicine. But about five years ago I like to think of it as a convergence we had incredible amounts of clinical data, genetic data, biological data all of that kind of came together and really started pointing this towards the identification or clarification of pathways that associate with the disease. You know we started 20 years ago with a very simple concept and that was you know what are these drusen that form in the back of eyes and individuals with this disease what are they comprised of and if we could learn something about that would it teach us something about the biology of the disease. And that went on for probably 15 years and we made the startling discovery I think at the time that drusen were comprised of proteins associated with inflammation. And that was not a well touted concept you know 10, 15 years ago we took a lot of flak for that. And I'm not sure why but nobody really wanted macular degeneration to be to have these immune mediated pathways involved. But interestingly enough those observations that the complement system was very over represented in drusen and the idea was then that there's activation of complement at the RPE corroid interface and that is uncontrolled and it's uncontrolled because there are mutations in this complement factor H gene. So the first big discovery of a gene that associated with AMD was that of complement factor H. Our group quickly showed that there were some associations with some of the other complement genes in that locus and on other chromosomes and then of course the second major locus that associates with the disease is this chromosome 10. Contains two genes, arms two, HTRA1 I'll come back and talk a little bit about those. But I'm not going to spend a lot of time on the genetics just take home message here is that we really have two major loci. One on chromosome 1, one on chromosome 10 that account for probably 90% plus of all risk for developing the disease. So that's actually a real treat right? Unlike cancer and some of these other diseases where there's 400 genes we're down to two loci that really explain a great proportion of the disease. So much of our work for the last five years has really been focused on this concept that I like to call refinement. We really need to get down understand frank causality within these two loci. And I think it's only when we do that that we'll be able to develop effective diagnostics and therapeutics. So on the one hand we're fortunate to have two major loci. On the other hand we don't know enough about these loci to really I think develop these effective diagnostics and therapeutics. So what I thought I'd do today I started to tell you a little bit about the genetic refinement. I'm going to skip that part. I'd like to tell you about some new concepts that are fresh out of the lab and give you a feeling for where we're headed. But I'd like to talk about the concept that perhaps macular degeneration is not a single disease. We try to make it easy. We try to talk about the fact that the disease progresses from one stage to another. But I'll show you some data that suggests it's probably not a single disease. I really want to talk about this reticular pseudo drusen phenotype that we've spent a lot of time on the last year working. As I go through those I think we're very fortunate that we have a cadre of incredible resources. We have this human donor repository. We have patient resources. We have things like the Utah population database. And we really utilize those resources to get towards this question of refinement. And like I said at the end if we have time I'll tell you a little bit about the center. So I think in the field I think a lot of you would agree that we have a lot of biases with respect to this disease. So I want to challenge some of those biases as we go through. But we talk about AMD as a single disease. Is it really? We talk about the disease as a progressive disease, right? We have ARADs, grading scales. We have Rotterdam. We have the National Classification. And we actually assume in all of those classification systems that macular drusen are a prerequisite to the diagnosis of macular degeneration. We like to talk about it as a complex genetic disease. I think I'll show you data today that says perhaps it's not as complex as we think it is. We think we know what regions of these genes are causal, but I would challenge that as well. And I think we're forgetting with a lot of the new instrumentation, the imaging modalities we have, we're kind of forgetting the fact that we have a lot of sub-phenotypes within the disease, right? Good example is carotoneovascular disease. We have all kinds of phenotypes. The question is, are those genetically determined and are they really the same? So I throw this up not to give you a lecture on the stages of macular degeneration, but again to remind you that we've classified this disease based on the presence of macular drusen. In fact, you don't really diagnose a patient with the disease in the absence of macular drusen. And then we talk very often about this disease in 20% of patients progresses to one of the advanced stages, right? Carotoneovascular disease or geographic atrophy. And I'll remind you that even if you look at these advanced stages, so clearly in geographic atrophy, there are multiple very distinct phenotypes. And we need to understand those phenotypes, especially the genetics behind the phenotypes, are you really going to use these phenotypes, for example, in treatment trials, right? So the FDA has allowed reduction in lesion size, if you will, as a surrogate endpoint. But if really these different phenotypes are distinctly different genetically and biologically, then every trial out there will fail. And I think that's what we're actually faced with right now. And I think we've lost track of this. Not only are there multiple phenotypes in advanced disease, there are multiple phenotypes with respect to drusen. You know, we have these large fluid-filled drusen. We have what I like to call substance-filled drusen. And then we have things that look like drusen, which in this case, this is basal laminar deposit you can see in the electron micrograph. This material is never going to go away with any drug treatment. So we need to know how to image these various drusen subphenotypes, I think, because clinically they very much can look the same as large soft drusen. So again, focusing on clinical trials, we need to understand what we're looking at. And then, of course, we're learning that there are entities that we've all called drusen clinically that aren't drusen at all. And I'll come back and talk about this reticular drusen phenotype. So let me talk about this concept that perhaps AMD is multiple diseases. So when I first came here two years ago, I was bored for the first few weeks. And I actually dug into the Willow database and was actually very surprised. I actually was very interested in patients that looked like this that went and straight to geographic atrophy or CNV without ever having any macular drusen. And when I went into the Moran databases and looked at, I think we looked at about 9,000 patients that had a history of CNV, 18% of those patients never had the diagnosis of macular drusen. So they looked like this and they drove straight to neovascular disease or geographic atrophy. So what's that all about? And that got me thinking a lot about these two major loci. So let me try to tell you what I've done with this slide. We've just taken two cohorts, the Utah cohort, actually three. The Utah cohort, the Melbourne cohort, and a part of my Iowa cohort. And we've taken the grades for those, separated them out by grades 1B through 3 on the international scale. Geographic atrophy and choroidal neovascular disease. Then we've looked at the association of macular degeneration in that cohort at chromosome 1. And we get what we expect, chromosome 1 is highly associated with macular degeneration. If we do the same thing for chromosome 10, same result, very strongly associated with chromosome 10. Interestingly, what we've done here is we've taken all the patients in the cohort out that had risk at chromosome 10 and reanalyzed the association with chromosome 1. Again, we get strong P values, including strong P values for the advanced forms of the disease. If we do the opposite, if we take out all patients that carry risk at chromosome 1, reanalyze the cohort, we get very strong association with late-stage disease, but interestingly enough, absolutely zero association with drusen. So put another way, chromosome 1 and chromosome 10 dictate very different forms of macular degeneration. In fact, chromosome 10, as I said, is associated with only late-stage disease. We've taken that a step further, and it turns out that even on chromosome 1, that grades 1 and 2, so drusen grades 1 and 2, don't associate with either chromosome 1 or 10. So I think we've misled ourselves a bit with this drusen thing. So just remember, when you see that patient with a lot of small, hard drusen, that probably patient is not associated with the disease at all. So the message here is late-stage disease can segregate independently with either chromosome 1 or with chromosome 10. And the question here, and the question that we need to answer is, is that phenotype related? Is the chromosome 1 association with GA a specific phenotype as compared to 10? And I think it's going to be very important to sort that. The same is true with neovascular disease, is perhaps a wrap associated with one chromosome or the other. The interesting thing for you as clinicians is because the frequency of these two genes are so high in the population that a lot of your patients actually have two diseases. And that's going to be important that we sort that out in clinical trials. You may develop an anti-complement inhibitor drug and give that to a patient that has both diseases, do a great job on inhibiting complement but not touch chromosome 10 whatsoever, and the patient continues to develop disease. So we need to sort this, and we need to be thinking about this in clinical trials. The really remarkable thing is if you take what I call pure chromosome 10 disease, so these are patients that have only risk at 10, and if you take patients that only have risk at chromosome 1 and you go through lots and lots of funnest photos, you begin to see very specific phenotypes associating with those individual diseases. So chromosome 10 disease, this is a classic picture of what we think of as pure chromosome 10. In fact, I think this patient probably has a wrap lesion, which is something we think will turn out to be specifically chromosome 10. Lots of vascular issues, no macular drusen, tessellated fundus, it goes on and on. Chromosome 1, not a terrible disease, but of course characterized by the presence of macular drusen. And a much smaller percentage of these patients actually develop late-stage disease. So another thing that I'm very fond of, as I've had kind of this hobby of traveling around and the idea was let's go to ethnic groups that have different forms of macular degeneration or have a prevalence of one form or the other, or don't have any disease at all. And let's ask the question if the genetics of those patients will help us sort this Caucasian genetic issue. Because of course in the Caucasians for some reason the prevalence of these minor risk alleles for both chromosome 1 and 10 are very high. So it turns out that in our African cohort I think we've never seen a patient with carotoneovascular disease and we've looked really hard. African patients are characterized very much by macular drusen association with chromosome 1, zero association with chromosome 10. Asian populations completely the opposite story. Lots of neovascular disease, strong association with chromosome 10, very weak if any association with chromosome 1 and almost no macular drusen in those ethnicities. So just something to think about. We have a lot to do on this front. We would welcome any help. But just to take home message would be that chromosome 1 associates with both early stage, so drusen and late stages of AMD. Chromosome 10 associates only with late stage disease as an entity, right? Remember lots of your patients will have both diseases. These advanced forms segregate independently amongst these two chromosomes and I think our job now is to really ask the question about sub-phenotypes of these diseases. And then chromosome 1 and 10 directed AMD really give us specific phenotypes in their purest form. So I think it suggests that perhaps AMD is much more a monogenic disorder than we thought. The problem is a lot of patients have multiple diseases. So let me talk a little bit about this reticular pseudo-drusen. Back to this issue of patients that develop macular, advanced forms of macular without a lot of drusen. For those of you in the front row, you'll see that this patient has some white spots. I think we would have graded this patient probably a 1b, but we were wrong because these little white spots aren't drusen at all. And it turned out when I first came, we again were playing with this cohort of patients. And if you look at these patients with the infrared mode on the spectralis, you see this just amazing pathology that associates with this individual's fundus. So being a morphologist by nature, I was very intrigued by this phenotype. The question really was, is it important or not at this point in time? But this patient developed CNB in this eye two weeks after we took this picture. So it really got me thinking. At the time, we had visitors from Germany and Austria and Ireland here at the same time. So we really dug into the databases here. And realized that this very specific phenotype preceded a huge proportion of advanced stages of macular degeneration, both geographic atrophy and CNB. Enough to get my interest. Paul Yang and others really worked very hard to look at some of the ERGs. So we started realizing that there were retinal dysfunctions associated with these patches or this particular phenotype. And I guess, again, I was most struck by the fact that these lesions were very similar, very much spherical, very much the same size. And you know, that always gets my attention as a morphologist. So the issue really is, is that phenotype that we're seeing using the infrared modality the same as this so-called reticular pseudodrusin phenotype that's been described primarily in color photographs. So, you know, this is a phenotype that Giselle Sebran's group first described a number of years ago out at the arcades, typically characterized by this lace-like morphology. But rare. I mean, this phenotype on colors, I think, in our cohort only occurs about 1% of the time. So one of the issues is, is this the phenotype that we're seeing in infrared? And we have reasons to think that the two may not be the same, but we're trying to dig into that. And importantly, if you look at this particular phenotype with OCT, you get these very characteristic spikes that associate with this phenotype. It's been assumed that this represents, this material represents, debris in the subretinal space. And I had a hard, a big problem with that because, you know, we've got 5,000 pairs of eyes that we've followed for many, many years. And I've never seen eyes with patches of subretinal debris. So this OCT image really bothered me a lot. So we played around a little bit. I won't bore you with the details, but if we change the angle of the laser on the spectralis, these subretinal deposits actually line up with the angle of the beam, okay? So it's suggesting to me that they're not in the subretinal space, or at least one piece of data. They actually pivot. So you'll notice that there's also shadows that associate with each of those subretinal spikes. So there's a reflection and there's a shadow. And actually, there's a pivot right in the middle, which sits here right at the RPE corroid interface. So kind of a fun experiment. We also went into the repository and looked at, I don't know, about 2,000 or 3,000 eyes. And the bottom line from that analysis was, yes, there are subretinal deposits. When photoreceptors die, you get subretinal deposits. But no way were they arranged in the same topographical pattern as we were seeing in these infrared images. And I think the big contribution we made, which hadn't been realized, is if you take a scan through one of these individuals that has a lot of these particular lesions, it's only where the scan crosses through the middle of one of these donut-shaped structures that you actually get one of these spikes, okay? So that means, you know, what looks like a random distribution of material here in three-dimensionality really has to be very precise. So not only would you have to have subretinal deposits that were pretty large, they would have to be very regularly spaced, and that's just not happening. So that really brings us to the issue of we spent a lot of time measuring these. These lesions are about 250 to 350 microns in diameter. And so for those of you that don't know the story, any guesses on what the nature of these. So they're round. They're 300 microns in diameter. They're pretty much macular-specific. So what do we know in the macula that follows that kind of topology? So I think the answer was amazing. You know, we know from the literature that the Coriocapolaris in the macula exhibits a very unique morphology in the macula. And that morphology is manifest by these round lobules of capillaries. Each is fed, interestingly enough, by a central arterial that actually comes in and at a very strong right angle to each of those capillary lobules. And interestingly enough, if you go back to the old literature, the size of these lesions that we're seeing in the pseudodrusin phenotype matches up very nicely with this Coriocapolaris morphology. As the Coriocapolaris, as you get out to the arcades, that capillary structure actually returns to kind of a parallel arterial venous system. So in the macula, very specific lobules and incredible pathology, if we take this image and we do some high resolution scans that are available with Heidelberg, you can actually begin to appreciate that this morphology we're seeing on infrared is very much similar to that Coriocapillary plexus. Lots of old literature. It's a fascinating subject. This is a paper that was published in 1976, but shows you this is a flat mound of coroid from the macular region, but shows you how these lobules are really distributed in the macula specifically. So we spent a lot of time asking functional questions. We knew a little bit about the multifocal ERG results that retinal function was decreased over patches of the pseudodrusin. We did a lot of angiography, and the story was basically always the same. In late stages of the angiographs, you can actually see the recapitulation of these lesions that were seen on infrared, and they aligned perfectly. So two interpretations here. One would be that indeed there is subretinal debris, and it's blocking the fluorescent signal. The other is that these Coriocapillary lobules are not perfusing very well, and I think everything we have at this point suggests that those lobules are not perfusing. So when we see an infrared lobule, especially these donut-shaped lobules, likely not perfusing. And if you want to go back and read some fantastic literature, go back to Sohan Heire's literature, but he basically has described this in a lot of experimental models, so different ligations of different arteries, and you can show very nicely using those techniques that you can actually kill these lobules, these very specific lobules fairly easily. Now I'm a great fan of experiments of nature, so we've seen actually, I think about 25 or 30 patients now that have a phenotype that looks like this. So coming out of the phobia, they have a beautiful wedge of what looks like just perfectly normal retina surrounded by patches of pseudorhuzin. And if you do fluorescent angiography in patients like this, it's not a great picture, but what you'll see is the coroid under this region fills on time and as it should, whereas the coroid back here is not filling very well at all. And interestingly enough, these morphologies, these segmental patterns very much match the distribution of the posterior ciliary arteries in the back of the macula, and probably very nicely match these watershed zones that Sohan Heireg has so elegantly described. So the idea here is the vessels that are feeding this particular wedge of retina are perfusing just fine, whereas these ciliary arteries that are feeding the rest of this fundus are not. So suggesting to me that perhaps what we're looking for is an occlusion further back in the orbit. This is just an example. This is one of Robin Geimer's patients that we did recently, but this patient had a very nice wedge of normal retina, and you can see that the ERG function over that region of retina is just fine compared to the rest of this eye over regions of pseudorhuzin. And the orbit thing is fascinating. If you again go back to the old literature, you'll find that in about 20% of individuals, there's a very different architecture of the ophthalmic artery in the way that it crosses above the nerve head rather than below the nerve head. So we're interested very much in asking the question, is it possible that the topology of the vascular tree in the orbit is putting patients at risk for occluding the coriocapillaris? So a fun study. We've just begun to start that study using this 3T magnet, and so hopefully we'll have some answers on that quickly. The wonderful thing, and thanks to Chris Hanna and his staff, we've been very fortunate since I've been here. We've ramped up the collection of donor eyes from I think about one pair a month to close to one pair a day now. Fantastic program. But we focus very much on trying to recruit donors who were previously studied patients here at the Moran. So interestingly enough in the last, I think six months, we've had about 29 of our patients that have become donors. So we have all of their clinic data. Six of those patients actually had a history of macular pseudodrusin. So we're now able to go in and really look at direct clinical path correlations. So this was one of our patients previously first visited the U in 2007. Her last visit was on March of 11, and she died on April of 11. So you'll notice that I'll come back to this, but past medical history of hypertension and MI, which becomes important. And actually, let me point out, one thing that also characterizes this pseudodrusin phenotype in our patients is the presence of a lot of paving stone cobblestone, which remember was always attributed to a collusion of capillaries, paroidal capillaries out in the peripheral retina. So another indication that this is a vascular problem. So this was the patient on her last visit, lots of pseudodrusin. This line here is the plane of which the section that I'll show you next was taken. But she, in her left eye, was given, I think, three injections of Lucentus. Right eye, no injections, so it's a good eye for us to work on. This is the section through the macular region of that eye, and I think we're all very struck by the morphology in these sections. And the corroid, if you'll note, is all but obliterated here. A lot of the large vessels are not large. The intermediate layer of vessels is pretty much obliterated. And that's compared here to what should be a normal age match control, showing normal architecture of the corroid. So very struck by that, very struck by the fibrosis that's occurring in these corroids by electron microscopy. And at higher magnification, what you'll see, again, very thin, fibrotic corroid. But the coriocapolaris is pretty much gone in the region where there were pseudo-drusons. So this coriocapolaris is not going to perfuse at all. Very robust retinal degeneration here. You're down to very few photoreceptors left. And I think very characteristically, that little arterial that I told you comes in at right angles to these lobules exhibits all kinds of hyalinization. So this is a classic small vessel disease, very much like you'd see in the brain of individuals with small vessel disease atherosclerosis. Interestingly, in Asian patients with polypoidal choradopathy, you see the same type of phenotype, a lot of hyalinization that goes along with polypoidal formation. Interestingly enough, no subretinal debris in any of these six donors that we had prior history of. So I think the subretinal debris issue we need to put aside. We know a lot about progression of these pseudo-drusons. So this is a patient we saw three months apart. These lesions start out as grayish lesions and they progress to these more donut-shaped regions. So we're trying to understand what that means. But I think the donut shape is probably when the capillary plexus is pretty much gone and you're just looking at a void in the caroidal stroma. And back to OCT imaging, same fundus, but if you pass the OCT through one of these gray lesions, you get these characteristic undulations that look like they should be druson. Whereas if you pass through one of the donut-shaped structures, then you get the projection into the subretinal space. Here's a paper published by Zwiffle that really shows out in this region a field of these undulating druson. Now, I can tell you from looking at lots and lots of donors that we never see donors that have perfectly sized druson. They're all about the same size. They're all about the same height. That never happens. So I think we're actually looking at an issue with artifacts in this Heidelberg instrument. And certainly we've been working with Heidelberg to address that issue. They're well aware of it. But I think we're not doing the service to a lot of our patients when we diagnose this individual with a lot of druson. You know, a patient has a lot of pseudo-druson, which is just as bad in this particular case. This is an incredible patient that we followed over a 14-month period. But I want you to focus down in this region. You'll see that you have a couple of these individual lesions. They're always characterized by kind of a bright spot in the middle. But what's happening in the interpretations is as each of those coriocapillary lobules begins to not perfuse well, the RPE directly above that lobule is dying. And as more and more lobules become involved and occluded or not perfusing, you end up with what we call geographic atrophy. So the crux of this phenotype of geographic atrophy, which I like to call multi-lobular, is very much caused by these lesions that we're seeing on OCT. So probably occlusion, which makes a lot of sense. In fact, we're able to separate our patients from their geographic atrophy into phenotypes based on presence or absence of these pseudodrusin. So this multi-lobular phenotype, very different than these large unilobular phenotypes. In fact, we've taken this a step further and we can pretty much segregate these phenotypes based on genetics. So again, back to the issue of clinical trials, if you're enrolling every geographic atrophy patient that you can find in a complement inhibition trial, and this is the only entity that associates with complement, you're going to fail that trial every single time. And I can't emphasize that enough. Another association that we're very interested in is this idea that a lot of our pure chromosome-10 pseudodrusin-driven patients are rap lesions, and that makes a lot of sense to me. So ischemic coroids, ischemic retina would probably very much drive rap lesions. Again, I think that's very important because it says rap lesions may be far more common than we think they are, and they may be the non-responders to some of these anti-Vegettes or the opposite. But we need to know who this 40% of non-responder population is. So the more we can phenotype and genotype these patients, the better off we are. This reticular drusin phenotype, as I told you earlier, associates with about 70% of all advanced macular degeneration. So that's, if you see a patient with a lot of these pseudodrusin, I can almost guarantee you that that patient will develop disease. Interestingly enough, in our cohort here, we're 83% female, 17% male, with respect to individuals with pseudodrusin. Robin's cohort was actually 90% to 10%. So this issue of female predominance has really gotten our attention. And it was really notes like this that made us start thinking a lot about what's going on. So either males don't get the disease, they're not coming to the clinic, or they're dead. And we think what's happening is that males with pseudodrusin and the genetics or the genes that are behind that pseudodrusin are dying before they ever reach the age that they'll have macular degeneration. We've seen a lot of families like this. We had one last week, a man with seven brothers who have all died from MIs in their 40s and 50s. He's the only survivor. If we go back to the genetics, this is mostly chromosome 10. And it looks like if your homozygote risk for chromosome 10 and you're a male, you're dying on an average of about 12 years earlier than our female patients with that same genotype. But it gives us some clues. I think it'll get us into some pathways that are important. We've dug into the Utah population database. We're just starting to get some data with respect to what diseases co-segregate with pseudodrusin, what diseases co-segregate with pure 1 and pure 10 disease. But it does look like myocardial infarction and some other cardiovascular diseases are very strongly associated with chromosome 10 and pseudodrusin. In fact, I think we just looked at the numbers between Robyn's cohort and mine, which is about 5,000 patients. If you pull all the individuals that are homozygous risk at 10, we only have six that don't have any macular degeneration at all. It's really a very powerful diagnostic if you're homozygous risk at that particular locus. We've just started a very nice collaboration with Intermountain, with the cath lab there, 20,000 patients with very well-characterized disease and DNA samples. We can come at this question from the other direction. Again, I should have shown this slide earlier, but very strong association of that pseudodrusin phenotype with 10, but not specifically to 10. We're trying to figure that out, but we do have some pseudodrusin patients in our chromosome 1 cohort, and we have some that sit outside of both loci, suggesting that there may be a gene out there that is even larger and really dictates presence or absence of pseudodrusin phenotype. That makes a lot of sense. You know, you carry gene X, and you also carry chromosome 10 risk, and it exacerbates whatever that gene X is doing. So, we're very much wanting to move forward. I think this issue with coriocapularis lobules in the macule is going to explode. You can see these things at the crux of all kinds of macular problems. Patients with pseudosanthoma elasticum, that centrifugal degeneration that you see in those patients is 100% associated with loss of those macular coriocapularis lobules. And yet the gene for that disease is very different. We know what that gene is, and it's not chromosome 1 or 10. It's ABCC6. Stargardt's disease, we see the same thing. A lot of pseudodrusin lesions. So put another way, I think that macular circulation is at risk with all kinds of genetic diseases. Al and I have been looking at a lot of the kind of the white spot syndromes. It looks like those are all going to be, or a lot of those are going to be involved, these coriocapularis lobules. So, lots to learn on this front, lots to do. The messages that I'd like you to take home is pseudodrusin are significantly associated with both forms of late-stage disease. We still need to sub-phenotype and look at those associations. But 50% of our geographic atrophies between our combined cohorts were preceded by the presence of pseudodrusin, but that's actually about 100% of all these multi-lobular geographic atrophy patients. 72% of our pseudodrusin patients with CNVs, and that's a very conservative number. I think it's actually higher. Certainly asking this question, is it primarily rap-driven, caroidal neovascular disease? Strong association of pseudodrusin with the chromosome 10 locus, but not unique to the chromosome 10. Female predominant, thinking that we're really looking at a small vessel disease, which really gets us into that whole issue about co-segregation of other diseases. And we do have some nice data that really suggests that that will fall out the way we think it will fall out. So let me take five minutes and tell you just a little bit about the Center for Translational Medicine, for those of you that don't know a lot. You know, when I was recruited here, very much wanted to do something on the translational front. And the question really, you know, you kind of come and you say, okay, I'm here, what are we going to do? We spent a lot of time as a leadership group over the first year I was here trying to decide what this Center should look like. And the upshot of that is we're very much focusing the Center at this point in time towards the, I would say, identification and validation of therapeutic targets for macular degeneration. On top of that, very much interested in propelling forward the diagnostic world on this front. But the focus of the Center, not exclusively, but the real focus at this point in time, is really on macular degeneration and these co-segregating diseases. I think it would be nothing better than to find a drug that prevented a lot of heart attacks as well as macular degeneration. So we're pushing very hard towards that. We've spent a lot of time, I would say in the last year, really building the operation. You've all seen the space on the second floor. That's to house the clinical operation. We really like to increase the number of study patients that are coming through the Center. So we've built very quickly. We've added a lot of people to the Center. I think we've now have probably 20 or 25 individuals. A number of those people we've been able to pull out of previous drug discovery efforts. One of Mary Ed's pharmaceutical spinoffs recently shut down and we actually were able to bring in the entire team. So people with experience in drug discovery and development. Wonderful group of personnel I would encourage all of you to make your way to the sixth floor and meet some of these people. I think the important thing is a lot of you in the audience have become very interested so we have incredible participation by a number of the faculty. Ying Bin, Al Vitale, Paul Bernstein, et cetera, et cetera. So that's been a lot of fun for me. Thank you, Meg D'Angelois. We're pushing very hard on the intellectual property front with respect to some of the data I just showed you. In fact we have four patents that are due at midnight tonight so if my eyes are a little baggy that's why. We've decided to fund the initial efforts with our donors so we've had incredible responses from a lot of our donors here. The idea is to get off the ground fast and start pushing and then bring in additional monies as we need from industry. We have a lot of active conversations right now with outside sources, pharma companies, VC groups that really want to put their efforts and their funding into this. Of course we're building resources. I think that's the crux. So it's the people and the resources that are so important to this. And of course the partnerships and alliances. So I've talked a lot about the iBank, incredible. It's been a lot of fun working with Chris and his staff. We have lots of nice collaborations within the university and also because of my R24 outside the university. So I think we figure with my collaborative groups outside we have access to right now about 28,000 well characterized patient samples. So that really will help us with this refinement that I talked about. And that refinement will lead us, I think, to great targets for drug development. So we've got the UPDB, some of the larger affiliations. We've created an LLC that sits outside of the Moran, which the sole purpose of that really is to house intellectual property from both this university and others. So that was incorporated in January and we've already done the first license agreement with Utah. And then interestingly I have a great relationship with Sequinom, a diagnostic company. And we're very hopeful that we will soon announce the opening of a Center of Excellence for Sequinom that will kind of cover this entire western region and be a place that people can come in for diagnostics. So I won't bore you with the details, but this is how the group currently looks. We really have a very strong group in kind of target validation, a nice group in earlier stage research target ID, and then of course our two big research groups, the tissue and the clinical side. We have a very robust plan, I think. It's very well vetted. We're pushing hard. We're giving ourselves a three-year window starting probably from this last July. I think it'll probably in reality take us a year or so longer than that, but the group is really coming forward. We have targets. We're very thrilled. Ying Ben has some nice mouse models of HTRA1 over expression that will allow us to test some of these drugs. And again, the approach really has been to take this genetic information that's been given to us is a wonderful gift. Really feed that into this incredible set of unique resources we have and grind away so that we can really get to this place where we're identifying very realistic targets for drug intervention. So that's been the general approach. It's working very well, and we're moving very quickly. So let me summarize today's talk by, I think again, you know, we're looking at one of the best characterized genetic diseases that exist, and we're fortunate that we really are down to two major loci. In fact, some of the minor loci we've been able to show as we segregate out have almost zero influence on the disease as an entity. That being said, I think, you know, we have this incredible opportunity here at the Moran to take that information, refine our understanding of that information, and really gain a robust understanding of the pathways that are at the root of these different forms of macular degeneration. And again, I can't emphasize enough that that's really where the Center for Translational Medicine comes in, that we really need to refine our understanding before we can develop these drugs that target specific pathways. So with that, I'll stop and happy to take any questions. I mean, I think it's a great... So there are two real issues there. One is that a lot of these patients with macules full of pseudodrussin and no other indication of disease, we've called controls in our study cohorts. And so that's really messing with the genetics. The second, which is the more egregious piece of this, is that these patients are very quickly going to advance disease. In fact, last week we had three patients that... So there was nothing I'd rather do than image every one of your patients over the age of probably 45 or 50. It's doable. We've got the space to do it. And I would love to figure out a way that we could do that. I think it would be something that the Moran could contribute to this field that would be just starting to try to break that up. You know, when we play this homozygic game, there's a huge interest in anti... I think it's a fantastic question. Certainly at younger ages, I would give them that's key. We are seeing so many males, although one thing we absolutely have to do is start moving back in time and recruiting patients in their 40s and 50s because we don't have a feeling for can we actually detect potential history of cardiovascular problems. One thing we've talked about, Randy and I have talked to the killer side, yeah. I mean, I think we are seeing these folks go to bad disease very quickly. So I think I would certainly genotype those individuals at that point in time because if they're homozygous, 10 on top of the pseudogreason, it's interesting, you know. We've seen that in all the AM studies, the ARED studies. And yet at the other end of the spectrum in the clinics, you know, you're injecting these patients. Okay, it was a lot of fun. Thank you very much.