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Therapeutic Approaches for Dry Age-Related Macular Degeneration

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Goldis Malek, PhD

Duke University

Our featured speaker is Goldis Malek, PhD, of Duke University. Dr. Malek's lab is focused on investigating the mechanisms underlying age-related macular degeneration, and to hopefully identify therapeutic targets for this debilitating degenerative eye disease.

  • BrightFocus Foundation
    Therapeutic Approaches for Dry AMD
    March 27, 2019
    1:00–2:00 pm EDT

    Transcript of Teleconference with Dr. Goldis Malek, an ophthalmology professor at Duke University Medical School, where she specializes in research on macular degeneration.

    The information provided in this transcription is a public service of BrightFocus Foundation and is not intended to constitute medical advice. Please consult your physician for personalized medical, dietary, and/or exercise advice. Any medications or supplements should be taken only under medical supervision. BrightFocus Foundation does not endorse any medical products or therapies.

    Please note: This Chat has been edited for clarity and brevity. AMD refers to age-related macular degeneration.

    PREETI SUBRAMANIAN, PhD: Hello, I’m Preeti Subramanian, the Director of Scientific Programs for Vision Science at the BrightFocus Foundation. Welcome to today’s Chat on “Therapeutic Approaches for Dry Age-Related Macular Degeneration.” Our guest today is Dr. Goldis Malek. Dr. Malek is an ophthalmology professor at Duke University Medical School, where she specializes in research on macular degeneration. BrightFocus has been fortunate to work with Dr. Malek over the past few years, and we are excited today to learn the latest news about better treating AMD.

    Before we turn to Dr. Malek, a few housekeeping notes—if you are new to the BrightFocus Chats, welcome! Once a month, we have the opportunity to spend about 30 to 40 minutes with leading experts on vision disease and eye health. Without further ado, let’s turn to Dr. Goldis Malek of Duke University. Dr. Malek, welcome, and thank you for joining us today.

    GOLDIS MALEK, PhD: Thank you so much for having me.

    PREETI SUBRAMANIAN, PhD: Before we talk about some of the exciting research coming from your group at Duke University, I was wondering if you could give an overview of AMD to our listeners, especially for those who might be new to this disease. I want to start by asking about the differences between the dry and the wet forms of AMD.

    GOLDIS MALEK, PhD: Sure. Age-related macular degeneration, or AMD, is a progressive degenerative disorder of the retina, and it affects approximately 30 percent of people over the age of 65. So you can imagine it’s one of the most common causes of vision loss or blindness in the elderly in the western world. It’s particularly impactful in daily life because, typically, it occurs in people when they are ready to retire and indulge in all those fun activities that we generally postpone, like reading a book or doing arts and crafts.

    As you mentioned, there are different stages and clinical subtypes of AMD. The early dry form is characterized by the formation of drusen, and drusen is basically the German word for “node.” These are lipid and protein deposits that accumulate between a cell layer that essentially is the nerve cell layer to the retina, called the RPE.

    There’s another stage following that called intermediate dry, and this is where those deposits—the drusen—become larger, and at this stage, patients may or may not notice a change in their vision. And then in the late form of dry AMD (it’s also often times coined “advanced dry” or “geographic atrophy”), there is a loss of not only RPE cells, but also the outer vascular cells that support the RPE cells and the retina, as well as the photoreceptors in our retina—these are the cells that absorb light and send the signal to the brains that allows us to actually see the images that we do. And finally, there is wet, or neovascular, AMD. This is where there is an opportunity for new vessels to grow and leak into the retinal space and affect vision negatively.

    PREETI SUBRAMANIAN, PhD: Thank you for the overview. The advanced form of AMD that you were talking about is also called the geographic atrophy. Could you tell us how the name come about—geographic atrophy—for the advanced dry form of AMD?

    GOLDIS MALEK, PhD: Yes, sure. Geographic atrophy… essentially, it’s just like it sounds. It’s when you have one or two regions of RPE that begin to degenerate, and oftentimes these regions can coalesce, and they can form these patterns in the back of the eye. So when the physician looks into the back of the eye, they can see basically the island of loss of cells, which is characteristic of the disease.

    PREETI SUBRAMANIAN, PhD: Thank you. Now if I may follow up this with a basic question about what inspired you to become an AMD researcher?

    GOLDIS MALEK, PhD: In many respects, if I had to reflect on this, I would say I kind of grew up in this field of ocular biology. When I was an undergraduate student, I volunteered in a lab—mostly because I wanted to learn about what it’s like to be a scientist, and I also really liked the teaching style of my principle investigator (PI), who was the head of the lab. The research focus at the time was on understanding the visual system, and we used a really unique model system. It was the horseshoe crab; it’s one of the oldest creatures on earth that’s capable of seeing both UV and visual light, so it’s a very unique model system. This was a really fun experience for me, and it solidified my interest in science. But in the big picture, model systems are a fantastic way to learn about basic biology and test therapies. In the next phase of my career, so to speak, which was graduate school, I wanted an opportunity to study the disease at the level of human tissue. And that’s simply because if you understand the biology as it occurs in human disease, then you can start asking those questions of why and how does the disease develop? And it just arms you with the necessary questions to dig deeper.

    When I joined graduate school, I was lucky to find a lab that focused primarily on the pathology of ocular diseases, and specifically AMD, and my PI was wonderful and resourceful. She formed this relationship with the local eye bank, and as a result of that we had access to a large library of human donor tissue. This was where I was so excited to see the complexity of the tissue and to start understanding what really happens in AMD in humans. What does it look like? What are the variety of pathologies?  What are the different cells? How was this so complex? I think it was there where I really fell in love with the eye, essentially, and wanted to ask the questions and formulate hypotheses as to how does the disease develop, and what kind of therapies should we be looking into?

    PREETI SUBRAMANIAN, PhD: This is really fascinating to hear about the motivation and your interest, and we at BrightFocus appreciate your dedication to improve the understanding and finding better treatment to benefit those who are suffering from this condition. Since today our topic is on dry AMD, and there is currently no available treatment for it except for the antioxidant AREDS 2 formulation, which helps to prevent progression in the early- and mid-stages of the disease. It really seems like a complex condition, so can you tell us what’s currently known about some of the key contributors for this particular disease?

    GOLDIS MALEK, PhD: Sure. Like you say, it’s one of the most glaring challenges that researchers have faced in trying to identify effective therapies. It’s the fact that AMD is multifactorial, and what that really means is that there are numerous risk factors that have identified to date, which can contribute to not only initiation but also progression of the disease. Beyond that, the contribution of these individual risk factors can vary from individual to individual. These risk factors include everything from age, which is the most established risk factor—the longer you live, the greater your chances of developing the disease, unfortunately; systemic health; environmental risk factors—once again, one of the most established risk factors second to age is smoking—if you were a smoker, then you have a higher risk for developing the disease; and finally, genetics. Genetics is a really big one. At last count, I think there were over 50 different loci that are associated with AMD risk. These genes can fall into a variety of categories, including the genes that are part of our immune response, genes that are involved in lipid regulation. But I’ll just step back and say that, once again, this is an incredibly complex disease, and just because you may or may not be a carrier of a potential risk, it does not dictate that you will not develop the disease or how your disease might even progress. Those are the questions that we are still trying to figure out and the research community.

    PREETI SUBRAMANIAN, PhD: Thank you for that information. Dr. Malek, you’ve been the recipient of the BrightFocus macular degeneration research grants to study different aspects of this disease. In addition, with some of the data that you obtained from these studies, you were able to get a bigger grant from NIH to perform further studies. Can you tell us about these studies and what your findings were from them?

    GOLDIS MALEK, PhD: I was really fortunate. I was awarded two grants at two very different timepoints in my scientific career. And I think the grant that you’re talking about … the focus of that grant was essentially to study a transcription factor, which is called aryl hydrocarbon receptor. The reason we wanted to study this receptor was because it’s involved in clearing toxic material—you can imagine drusen material are toxic, so it’s involved in potentially clearing toxic material. It’s also involved in immunoregulation, so what we wanted to ask was … is it actually capable of regulating those same pathways in the AMD—these two pathways that are also important in AMD? And with the BrightFocus grant, we were able to look at whether or not—if you activate this particular pathway, could it improve the overall health of RPE cells, the nerve cells to the retina? Could it improve cellular metabolism? Could it improve energy production?

    We were also able to test drugs that we already know are available and can activate the receptor and see how they work in cells and also in model systems. So from there, we were able to take these data and launch it into a larger grant from the NIH.

    Right now, we are looking at other pathways that are lesser known to be regulated by this receptor but are incredibly important in AMD development, and those are specifically how does it regulate lipids—because once again, drusen are chock-full of lipids and proteins. So if we can somehow regulate how lipids get in there, maybe we can also regulate the formation of these deposits that shouldn’t be there.

    We’re also looking at these novel drugs that we have developed in collaboration with a small-molecule company that we know can activate the receptor, and now we are trying to see whether or not—if we test it in our model systems, will it result in no toxicity, higher length of time in the eye, and are they effective at actually clearing this abnormal material that is so characteristic of dry AMD?

    So, those are one of the grants, and another grant, which was also I thought very exciting—and it’s a more recent grant that we’re, hopefully, going to launch into another NIH-funded opportunity—it was to look for biomarkers in human serum and to try and understand a particular molecule that is involved in the recruitment of immune cells.

    Immune cells can be good guys, or they can be bad guys, and we’re still trying to figure out the extent to which these immune cells—the good and bad—contribute to the different clinical subtypes…so the early dry, the intermediate dry, the geographic atrophy, and wet AMD. With the BrightFocus grant, we were able to screen samples from human donors and to look at the expression of this particular molecule and see whether or not there is a change as a function of the severity of the disease. And beyond that, we were also able to look at what exactly does it do in RPE cells, and is it involved in recruiting immune cells? That’s the second stage that, hopefully, I will be able to talk about in greater detail in the future, and hopefully we’ll be able to turn it into a larger funded study sometime soon.

    PREETI SUBRAMANIAN, PhD: That sounds very exciting. You mentioned in the first study about finding pathways to identify targets to degrade the damage caused by AMD. I wanted to ask if you think those activators that you were talking about—small molecule—would they act in a situation where the damage has accumulated over a period of time that happens in age-related disease like AMD, or is it something that has to be administered in parallel to the damage that occurs at the beginning of the disease?

    GOLDIS MALEK, PhD: The preventive versus the treatment question—that’s always the hardest question. Right now, our early studies have been primarily tested in a preventive platform. In other words, before we know in a model system that there are characteristics of the disease that develop, we use this activator and see whether or not that is keeping the cells strong enough to handle the injury. The next phase, which is part of our NIH-funded grant, is to test treatments, and that’s specifically in a model system where the injury has already occurred: Can we add it in, and would it be able to clear the so-called garbage—the lipid and protein drusen—from an eye? So, that question is to be determined.

    PREETI SUBRAMANIAN, PhD: Thank you. That’s really exciting. Based on the second study that you mentioned, would that be kind of a biomarker that would be helpful to detect early AMD in a routine test, like a blood work, at some point if you’re able to characterize it?

    GOLDIS MALEK, PhD: The samples we used were serum and plasma samples from patients that had the different stages of AMD, and our hope is that it would translate into that. With BrightFocus, we were fortunate enough to be able to screen a minimum of 20 patients per clinical subtype, but in order for this to go to the next phase, we’re going to have to expand our number of patients so we can really see a nice trend. But the ideal would be that, as a biomarker, we could basically take somebody’s blood and look at the levels of this particular protein that’s involved in recruitment of immune cells and then determine whether or not they may progress—if this particular biomarker is there, or would it progress to a more severe form?

    PREETI SUBRAMANIAN, PhD: And would this be a biomarker that’s more relevant to the dry form of AMD, or would it also be for the wet form of AMD?

    GOLDIS MALEK, PhD: Right now, we are seeing that there is a nice switch in early to intermediate dry AMD, and we do believe that it actually plays a role in wet AMD, but whether or not it’s involved in the progression or the switchover to wet AMD remains to be seen. So, this is mostly an early phase; our data indicates that it’s is mostly an early phase.

    PREETI SUBRAMANIAN, PhD: At this point, I want to ask one of the questions that just came in. The question is does dry AMD worsen to wet AMD in the majority of the cases?

    GOLDIS MALEK, PhD: Does it convert from dry to wet in the majority of the cases?

    PREETI SUBRAMANIAN, PhD: Yes, dry to wet. Does dry AMD worsen to wet AMD in the majority of the cases?

    GOLDIS MALEK, PhD: There is evidence that when you develop dry AMD that I believe 20 percent may switch over to wet AMD in a period of 5–10 years. Once again, this is one of those really hard questions as to will it happen or will it not? The multifactorial and complex nature of the disease dictates that all these risk factors are going to behave in different ways in different people, and so though there is a risk, it doesn’t mean that it happens in everybody, as I understand it.

    PREETI SUBRAMANIAN, PhD: Thank you. Are there any other approaches that you are exploring in your laboratory to better understand or find treatment for AMD outside of the two studies that you mentioned?

    GOLDIS MALEK, PhD: Sure. Our goal in the lab has always been trying to figure out how we can make essentially old cells young again, because as I mentioned earlier, a major risk factor for the disease is age. So, somehow our ability or the cells’ ability to handle injury—or maybe high fats or the consequences of smoking—somehow our cells’ ability to handle that injury is compromised as we age, so I’d like to think of it as our cells becoming vulnerable.

    My lab generally has been focusing on this large family of transcription factors, one of which was the aryl hydrocarbon receptor that I mentioned earlier. And what we’ve done is we’ve looked at basically the expression of these transcription factors in the back of the eye. We’ve created this library saying, “Okay, where are they expressed, and at what level are they expressed?” And based on that, when we look at young and old cells, we can identify some candidate receptors to study in more detail.

    We’ve been looking at some other receptors, one of which is called liver X receptor, and the reason we’re looking at that particular one is because it’s a master regulator of the immune response and lipid metabolism. It’s been studied fairly extensively in other diseases that share pathways with AMD, like atherosclerosis and Alzheimer’s disease, and we’ve been looking at that in quite a bit of detail—specifically, whether or not we can target it, and would it help improve the health of cells and allow them to function better in an environment where they’re bombarded by potential injurious material? These receptors—a total of 48 of them—so far we’ve gone through four, so we have a long way to go, but that is the overall focus of my lab right now.

    PREETI SUBRAMANIAN, PhD: You mentioned about transcription factors; could you explain what transcription factors are?

    GOLDIS MALEK, PhD: Transcription factors are essentially factors that will lead to the formation of genes and proteins and molecules. These are regulators of very important pathways—for example, they could involve the formation of a lipid, they could regulate the formation of a particular protein, and some of them will regulate many proteins, some will regulate many lipids … And if we know, for example, that in drusen that they are filled with lipids and they are filled with proteins, if we take a step back and say, “What’s responsible for making those lipids? What’s responsible for making those proteins? Can we target that regulator—that thing that’s the master regulator and responsible for forming these? And maybe we can block it, or we can help remove it.” These are essentially these factors that are involved in regulating the formation of important molecules.

    PREETI SUBRAMANIAN, PhD: We have another question that’s come in on the AREDS formula, asking if people experience any side effects using the AREDS formula, if you would happen to know about that.

    GOLDIS MALEK, PhD: So, there are two formulations. There is the AREDS 1 formulation, and in the AREDS 1 formulation, there were individuals that had potential side effects, in particular because of the beta-carotene that it had. And this was specifically individuals who were previous smokers. The new formulation, as far as I know … I don’t know if there have been any risk factors. I think there’s been greater success, and it’s currently—because it’s supplemented with lutein, zeaxanthin. These are carotenoids. They’re basically plant-derived nutrients, and our body cannot make it, so it’s something that’s very important to us. It also has antioxidants, vitamins—like vitamin C and vitamin E—and zinc. I believe, so far, there have been good effects with the AREDS 2 formulation. And just to step back, there’s a lot that you see potentially if you step into your local drugstore; you may find a lot of these formulations. So really, the selection of which one an individual should take should be discussed in detail with the ophthalmologist that they have a relationship with.

    PREETI SUBRAMANIAN, PhD: Thank you. Dr. Malek, when you look down the road at the research that’s coming out from your group and other researchers in the field, do you think it is possible that this could lead to future treatments for AMD? What is your optimism for this type of research that’s currently happening?

    GOLDIS MALEK, PhD: When I look back 20 years ago, the amount of information that we have gained through research has just exploded, not only because we now have new tools to try and understand the progression of the disease, like new imaging technologies, but also because there’s been this explosion in the number of genes that have been identified that are associated with risk. And I think each of these basically gives us an additional window into how AMD develops. I do see that as we get more and more information, and as we have more and more ways of understanding how the disease develops and how it progresses, we will be able to identify pathways and target them successfully in the future. [As in] in 2005, when the immune link was really identified with complement factor H, I think that in the future, we will be able to, hopefully, target the disease and perhaps on a patient-specific basis. Because, once again, it is complex, so we have to learn more about what risk factors an individual carries and what progresses in order to target it effectively. I am very optimistic. I do think that there is light at the end of the tunnel.

    PREETI SUBRAMANIAN, PhD: Thank you. This is very encouraging to hear, and it gives us a lot of hope for the future. I want to ask another question that came in from our listeners. What are some of the current treatments available for dry AMD?

    GOLDIS MALEK, PhD: Well, for dry AMD, the most notable one is the AREDS 2 formulation. When you think about dry AMD, and when you think about the pathology, it’s obviously the accumulation of these deposits, so we do want to get rid of them. It’s also strengthening the cells that are vulnerable—that’s the RPE cells, the nurse cells to the retina; the photoreceptors, the cells that are involved in absorbing light and sending a signal to the brain; as well as the vasculature on the outside, which essentially also supports the RPE and the retina. And I don’t think that there is an effective treatment that is sanctioned for targeting all of those components, but certainly, the AREDS formulation has shown promise. And then changing your lifestyle and making it a healthier lifestyle certainly that has garnered a lot of attention. It may help slow down progression; that’s the usual suspects: avoiding smoking; exercising regularly; eating a really healthy diet, lots of omega 3-rich fat fish, leafy vegetables (your kale, your spinach, fruits like kiwi, things like that). I think that those are some of the steps we can take, at least now, to hopefully slow down the progression, but there is no treatment that I know of that is being purported as a therapy for AMD.

    PREETI SUBRAMANIAN, PhD: This is great advice, and it is amazing how much benefit one can get from not smoking, having a healthy diet, and remaining physically active, like you said. Another question that’s come in is about … the listener wants to know if it’s possible to reverse early AMD. If so, how could that achieved?

    GOLDIS MALEK, PhD: Yes, yes. Reversal, once again, would require getting rid of the things that are blocking the outside of the eye—the drusen, improving the health of the RPE cell. Many researchers are trying to do that. For example, as I had mentioned, if we could make an aged cell young again, that would, hopefully, help in the reversal, make the cell stronger, make it able to bounce back from injury. There is no treatment for that yet, but that is certainly the hope that one day we’ll be able to make ourselves strong enough to handle any kind of insult that gets thrown at them just on a regular, normal, day-to-day basis.

    PREETI SUBRAMANIAN, PhD: Thank you. That is really great. Before we wrap up, do you have any final advice to people who have AMD or who care for someone with AMD?

    GOLDIS MALEK, PhD: I am hopeful for the future. I think that having a great relationship with your ophthalmologist will help you have a nice healthy life, in spite of the challenge that’s been thrown at you. I do think that, once again, following the instructions of your ophthalmologist and doing everything in your power to slow down the progression is wonderful. To be vigilant, to look out for any changes that you see—the earlier you see or notice something and the earlier that you speak with your ophthalmologist, I think that is a strength to hopefully do a treatment. There are certainly treatments that are partially effective in wet AMD, so the moment you see something different—if you are a patient with dry AMD, you go into your ophthalmologist’s office. Hopefully, they can try and tackle any potential advancement to the wet form. I think that’s it.

    PREETI SUBRAMANIAN, PhD: Great. This has been very helpful, and it’s been a great opportunity to learn about the current research happening in AMD and the impact it might have on daily lives of people going through this condition. I want to thank you, Dr. Malek, again for your time and generosity. It was a pleasure talking to you today.

    GOLDIS MALEK, PhD: Thank you so much. I really enjoyed speaking with you, as well.


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