 Thank you, Dr. Olson. So it's my great pleasure to introduce our next speaker. Dr. Greg Hageman is actually the head of our translational research group here at Moran Eye Center. And he's going to talk about some of the work that they're doing in terms of macular degeneration. And again, this being Translational Research Day, I'm really excited to have some of our researchers come in and educate us as clinicians as to what's going on and what the potential applications are going to be in clinical practice. So Dr. Hageman? OK, wonderful to be here. And a real pleasure to tell you a little bit about what we're doing at the newly named Sharon Ecclestiel Center for Translational Medicine. So Sharon has been a great supporter of all the work we've done since I've been here over seven years. And a couple of weeks ago, we actually celebrated the dedication of the center in her name. So the center really derived from a lot of conversations I had with Randy Olson back when I was at the University of Iowa. And for those of you that know Randy, he's pretty persistent. He talked a lot about getting me to come here. I thought, no, I'm headed to industry to do translational work in industry. But the more I talked with this man, the more I realized that we had a real opportunity to do something unique here in Utah. And that was the beginning of the Center for Translational Medicine. The sole focus of the Center for Translational Medicine, at least in the early years, was really focused on age-related macular degeneration. And really, to dig deep into the disease, to understand pathways that are active in the disease in the back of the eye and systemically, to identify targets from those pathways. So drugable targets, let's really get to that point. And ultimately, to develop therapies for the disease. And the Center, I think, was based on a unique concept. And that was, can we really partner with the pharmaceutical industry in a truly interactive fashion? I was used to making discoveries, filing patents, and licensing those patents off the industry. And that's the last you ever saw. The concept here was to find a pharmaceutical group that we could truly work with. And we could truly do the part that we do well. We can do the science very well. Industry can do drug development and target validation and those types of things very well. But what if we could truly pull these groups together in a very synergistic form? And the goal really being to shorten this timeline of drug development from discovery of targets to actually treatment of patients. So we actually did that. We had an incredible partnership for four and a half years with Allergan. It was more than I ever dreamed it would be. We truly shortened that time very substantially. Unfortunately, they were purchased last year. We're out looking for a new partner. And I had hoped you would be able to introduce a new partner today, but I think we're close. So if I look back six years, game changers in all of this, of course the pharmaceutical partnership was important. But people are the key. And I have been incredibly fortunate here at the Moran to work with this incredibly talented group of individuals, both in the CTM and in the community, et cetera. Key partnerships have been absolutely important. Some of the key partnerships are listed here. But certainly the lion's eye bank, the access to human donor tissues has been an incredible partnership. But lots of partnerships with Intermountain Health Care, et cetera, et cetera. I think intellectual property has been very important to this overall progress that we've made. And that goes a little against the grain of typical academics. So it's actually been difficult for me to not publish when we've made important discoveries. But it's an important part of doing true translational medicine, I think. So we've generated probably more patents than we could have generated publications. And I think most crucial to the studies we've done in macular degeneration has been access to resources and important tools. And the resources that have been most important in our efforts, certainly this access to human donor tissues. I've been pursuing this line of research for probably 30 years now, pushing 30 years. And really started back when we realized that there's not a good animal model for macular degeneration. There's never likely will be a good model for this disease. And if you're gonna look at human disease, let's get to the real source. So we currently have a repository now of somewhere over 7,500 pairs of eyes produced in identical fashion. And you can see that one of the real messages here is it takes large numbers to do good science. So it sounds like a lot of eyes, but when I show you kind of the process we've gone through, it really is not. Patient cohorts on the other hand have been incredibly valuable as we move forward. And we have access to about 70,000 DNA samples currently in the Center for Translation and Medicine. So those of you that are familiar with macular degeneration, I think you'll agree with this comment that there are really, there's a huge diversity of phenotypes, both for early stage disease, drusen, there's all kinds of drusen. And if you get to the histological level, you'll realize that there's even more phenotypes of drusen. And certainly you're familiar with lots of different forms of late stage disease, particularly in the vascular disease. And I think we're starting to lose the plot here clinically in identifying some of these subtypes of neovascular disease, polypoidal, rap lesions, coroidal, et cetera. But we thought one of the most important things we could contribute is asking the question, are there true genotype, phenotype associations in this disease? Okay, and so to get us to that point became really important to understand the background genetics of the disease. In my particular group, we've been looking at genetics of macular degeneration for somewhere over 20 years now. But I want to leave you with an important message, and that is there are two major loci that are associated risk for developing this disease in Caucasians, okay? One on chromosome one, and that locus contains complement factor H, and the factor H-related genes. And a second major locus on chromosome 10 that contains a pair of genes, arms two and H-T-R-E one. Make the point again that over 95% of all risk is associated with these two loci. Okay, so it's really this gigantic gift. But I think on the scientific side, we've kind of whitewashed that a bit by wanting to go out and find more and more genes. Yes, there are a lot of minor gene associations, but if you're really going to dig into the disease and understand pathways, you need to work on the two big ones. Put another way, clinically, if you look at my combined patient cohorts, only 5% of our AMD cases, grades one B through four C, using the Rotterdam scale, only 5% of those cases don't carry any risk alleles at chromosome one, chromosome 10, or C3. And I recently went through these 161 cases and there's a lot of misdiagnosed AMD in those cases, Stargardt's disease, Pseudosanthoma, Elasticum, et cetera, et cetera. And probably the remaining bit is associated with some of these minor gene associations. So the strategy we've used from day one is we knew we needed a really robust understanding of the genetics before we could do anything. Again, we're lucky, two major genes. Resources became critical, and this is the piece that the pharmaceutical industry just doesn't have access to. They don't have access to these human tissues. In fact, none of my colleagues in Europe have access to these kinds of tissues in patient resources, and this has been really important. We can do lots and lots of good science, but without the knowledge of genetics and the resources, I don't think we'll ever get to this place where we're really finding true, drug-able targets for the disease. So just a little bit about the genetics. Chromosome 10, as I said, contains these two genes, arms two, HTRA one. It's been a real enigma as to which of those genes or perhaps both of these genes play a role in actually causing risk for the disease. This very interesting genetic block, strong linkage disequilibrium, but it becomes quite simple after you make it really complex. And there's a single variant, this A69S variant, tags all risk for this disease, at least in Caucasians again. And so that makes things a bit simpler. The chromosome one locus is a little bit rougher. 360 kilobases contains complement factor H in a truncated isoform of factor H called truncated. And five of these so-called factor H related genes and numbered, of course, one through five. If you look at haplotypes across this locus, a couple of really important points to leave you with, there are two major risk haplotypes, so not a single risk haplotype. More importantly, two major protective haplotypes. And those protective haplotypes are the most significantly associated haplotypes with AMD, but skewed towards the protection. And that's a way very prominently in our thinking about developing therapeutics for this disease. In addition, that things weren't tough enough, there's a neutral. So, and I'll leave you with one clinical thought. I think, you know, if you're doing genotyping, you say, oh, my patient's carrying one risk allele of factor H, so he or she is at increased risk for developing the disease. It actually turns out that that's not true if this major risk allele is present with the second allele that's protection. So protection at this locus rules the day every time. So we spent a lot of time in Iowa looking for biological relationships between chromosome one and 10 biology and we were never able to identify a direct biological interaction between those two pathways. And that has held true. We should have thought about this a long time ago as I've gone around looking at patients in Africa and Asia and Easter Island. One striking observation is that Africans are mostly characterized by drusen. In fact, we've seen maybe one carotidoneovascular lesion that's due to AMD in our African cohort from Ghana. Asia on the other hand, the disease is primarily neovascular and very little in the way of drusen about preceding disease development. And it turns out that the African genetics all skewed towards chromosome one and the Asian genetics all skewed towards chromosome 10. More recently we've seen a lot of skewing towards chromosome 10 in the Native American population in others, so it turns out Caucasians are a mixture of the two and it makes for an interesting set of studies. But we thought at that time, wow, this is probably two very different diseases and so we need to really dig in and look at what is chromosome one doing all by itself in the absence of 10 and in the reverse. And so we've done a lot of that and I don't have time to show you today but we've addressed this at the ocular level genetic mechanistic gene expression that goes on and on and systemically through blood biomarkers, through blood cell composition, co-segregating disease. And the message that I really want to leave you with today is that we strongly believe that macular degeneration is at least two major diseases and it means that those diseases that a lot of patients will carry both diseases. And here's one example, one of the early examples with genetics. If we reach into these cohorts that we have from Iowa, Melbourne and Utah and we look at the association of what I call pure chromosome one which are homozygous risk at one with no background risk at chromosome 10 and pure chromosome 10, risk at 10, no risk at one. And you look at the association with AMD. You see the strong association of both genes. They're both driving geographic atrophy and carotoneobascular disease. But the striking observation is chromosome 10 does not associate with early stage disease and that means basically drusen. That doesn't associate with drusen formation. And if you dig in clinically and start pulling out these groups, these pure chromosome ones and 10s, you'll find that the chromosome one group is driven by the formation of drusen. Drusen are much less prominent in the chromosome 10s and you can see a lot of other clinical features that are different between the two. There's this obvious optic nerve issue that skews with chromosome 10. We've been chasing that a long time. And there's a whole plethora of differences between chromosome one patients and chromosome 10 patients. I'm gonna go through those very quickly since most of the audience is clinical. But if you just look, of course, this drusen observation comes screaming out chromosome one patients are strongly associated with the development of large macular A-reds, grade three drusen in the macular pigment epithelial detachments, 55% of our chromosome one patients over the age of 60 show this phenotype in contrast to about 8% of our chromosome 10 patients. Histologically, you can see here's a donor that had large soft macular drusen. You can see the phenotype very nicely. Again, chromosome one very much characterized by these sub-RPE deposits, pigment epithelial detachments. And interestingly in the donor eyes, very often the separation between the RPE and the Brooks rim rate, which I think is important from the biological mechanism. Chromosome 10 patients very little in the way of drusen. You can see here's a little drusen. They tend to have these cuticular drusen that don't move or change shape with aging. And the retinas, I think you'll all appreciate if you look at these on Mosley, but the retinas seem thinner than the chromosome one patients. Chromosome 10 patients histologically, if they do separate, they separate between the retina and the RPE. So very different separation. Phil Luthert, a very good pathologist from Morefields was here the last few weeks, he said, these look dodgy. And remember, they're all fixed in the same period of time. So we're working hard to quantify what the differences are. But one interesting clinical observation is the chromosome 10 retinas are thinner across the board, beginning from an age about 40 or 50 years of age. The retinal and carotid vasculature is far less dense in the chromosome 10s than it is in the ones. You can see that here. On average, about 30 to 40% lower vascular density. We thought we could really dig into this heavily with OCT and geography, and it's just not quite there yet. So we'll have to continue to do it the hard way. Fluid distribution in neovascular phenotype are very different than the chromosome ones in 10s. The chromosome one patients strongly characterized by the emulation of sub-retinal sub-RPE fluid in comparison to the chromosome 10 patients characterized primarily by intraretinal fluid. Phenotype, you can see this was grading that was done. I think Al's sitting in the back. Al helped us a lot with this early on. Chromosome 10 patients varies much skewed towards a classification of classic CNV as compared to chromosome ones which are graded primarily as classics, probably speaking to the type of neovascularization. And we think the 10 is largely associated with rat lesions and have certainly shown that to be true in a Japanese cohort. The response to anti-vegeta agents varies dramatically between the chromosome one and 10 patients. Basically, your patients that take injection after injection and kind of maintain vision are your chromosome one patients. I don't have a lot of time to talk about the biology but the biological manifestations of these two disease also differ dramatically. We've seen incredible associations of histological features with one and 10. Basal laminar deposits for example, strongly driven by chromosome 10 as compared to chromosome one. Serum biomarkers, blood composition are dramatically different in the two groups. And I'm gonna show you one example, gene expression which is really getting down to the nitty gritty of what pathways are chromosomes one and 10 driving. And we've been very fortunate this relationship with Allergan, the one thing that it did do is it gave us the opportunity to run this huge gene expression study. And basically without going into details, sorry about that, we used seven pure genotype groups with about 50 donors and 50 patients per group, 1400 total samples. And this platform, this particular platform we used was called the DIACS on HIP platform, six million probes for 23,000 genes and we generated about eight billion data points. But more than any other experiment, this has really started to teach us about pathways that are driven specifically by one and 10. There's no good way to show that, of course, so this is actually, this is real data. And you can see that there are dramatic differences in gene expression profiles between ones and 10s. And we looked at macula, extra macula, RPE corvoid and retina, so four pieces of tissue for each donor. What we have learned, we've learned a ton about ocular sites of gene expression. And that becomes particularly important on chromosome one. Where is complement factor H actually being made? And we've had some surprises on that front. We've learned a ton about biological mechanisms and then we've been able to use the data to go back into the same eyes and show that yes, indeed, those mechanisms truly are active. And we've learned a lot about potential targets for drug development. So I'll give you one example. The complement system is, of course, comprised of about 85, 90 different proteins. And for the first time, we have a very robust understanding of what's happening in the back of the eye with the complement system. And that becomes very important when you start thinking about is factor D antibody treatment really the right way to go? Do we have any data whatsoever that factor D is up-regulated or down-regulated in the back of the eye that we need to inhibit it? And that story goes on. We've had a lot of surprises here. And we've been able to take that gene expression data and combine it with RNA sequence data and functional data and protein distribution data, et cetera, et cetera, and really show that the pathways that we think are good candidates for drug development truly are that. And I'll leave you with the message that really these are just examples of haplotypes across that chromosome one locus and their association with the presence or absence of macular degeneration. No AMD being the brown bar, AMD being the blue bar. And you can certainly see in the case of chromosome one, our therapies need to mimic this highly protective haplotype in the form of the disease. I think we would have probably had drug in patients sometime in 2017 if we would have been able to maintain the allergen relationship. But we are ready to treat chromosome one and we're ready to do it in the right patients. Chromosome 10, I would have stood up six months ago and said, it's a difficult locus. We're not making much progress, but the team has really made some important discoveries. And I think this very complicated locus that I described early, we are now at a place where we think we have really found the region of frank causality within that locus. And that knowledge is really quickly pointing this to the mechanisms that are active in chromosome 10 disease. And hopefully next year I'll really be able to tell you the end of the story. So I'll leave you with a few messages. Hopefully the message that all of you will take home is that AMD is very, very likely two distinct biological diseases. Do these minor genes play a role? Probably, modulating to some degree, but we've looked at that a lot using the same strategies and we don't see a lot of these actually being causal for macular degeneration. We've learned a lot about the underpinning biology of both chromosome one and 10 directed disease. We've identified critical pathways, mechanisms and targets. We're really at the place where I think on chromosome one we're ready for developing treatments, chromosome 10 a little farther behind. And I think I hate seeing this situation out there where I think potentially good drugs are failing trials because of lack of this knowledge. And so certainly one thing we will do here at the Moran is group our patients appropriately for trials. I envision the first trial with the chromosome one directed drug to be directed towards chromosome one patients, not with chromosome 10 in the background, right? Two very different pathways. And I think it's obvious why some complement inhibitors have failed in trials because they have a huge amount of chromosome 10 in the background. So let's not lose potentially effective drugs for the wrong reasons. So with that, I'll stop happy to take any questions. Great. So fantastic. I've loved following this along, but here's a chance for me to talk to all the clinicians here in the room. This is an example where we very much would be involved. He's got a group ready, prepared to look at patients, but who's seeing the patients? We are. And the groups that they need to look at, they wanna look at people with macular degeneration. The more we can get, the more robust. And it's hard to look at them to differentiate, but that can be done. Also interested in people who are younger with a family history of macular degeneration. And frankly, probably one of the shortages are people who are older, who really don't have any changes in the retina at all. Those people over 70 or 80, you know, you see them, they don't have any grooves or anything, but what I've got is super normal. And if you're not sure, that's fine, but if I found all you need to do is you just say, listen, we're really working hard on macular degeneration. And often these people either have a family history or they're older, they know people and said, could you give us a few minutes? You let your clinic coordinator, they'll talk to Jill and her team, everything else is taken care of, it doesn't take very long. I've never had a complaint about it, but all of us seeing patients here can help dramatically expanding those cohorts to help us to where we can further understand this disease. And remember, the future treatment's gonna be pure ones, pure 10s, and there's no place in the country that has large groups of these, and we have large groups and we need larger. So just a shout out in regards to that, all of us can be involved in this, and I think it's gonna be really important. We announced this major partner, it's to hit the ground running. We wanna move this into new core treatments getting at the basis of the disease. Thanks, Brandy, I appreciate that. I also wanna, you know, it was a little bit remiss not thanking those of you that are out in private practice. I know a lot of you have spent a lot of your time helping us with records from our eye donors and also sending patients, so thanks for that. Thank you, Dr. Chairman.