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Age-Related Macular Degeneration: Iron and the Immune System

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Dr. Joshua Dunaief

University of Pennsylvania’s Perelman School Medicine

The telephone discussion features Dr. Joshua Dunaief, of the University of Pennsylvania’s Perelman School Medicine, who specializes in the study of age-related macular degeneration.

 

  • BrightFocus Foundation
    AMD: Iron and the Immune System
    May 30, 2018
    Transcript of Teleconference with Josh Dunaief, MD, PhD from Scheie Eye Institute at the University of Pennsylvania.
    1:00–2:00 pm EDT

    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.

    MICHAEL BUCKLEY: Hello, I’m Michael Buckley with BrightFocus Foundation. Welcome to today’s BrightFocus Chat, “Iron and the Immune System: How They Impact AMD.” If this is your first time on a BrightFocus Chat, welcome, and I just want to give you a little overview of what we’ll do today.

    BrightFocus funds some of the top scientists in the world who are trying to find cures and more effective treatments for macular degeneration, glaucoma, and Alzheimer’s disease. And at BrightFocus, we try to share the findings and the latest information from these researchers with families impacted by these diseases. We do this through a number of resources on our website and free publications, and we also do it through the BrightFocus Chat.

    Today’s a great example of taking one of the top researchers in the world on vision disease and, through his generosity, taking some time to learn the latest from the world of research, particularly as it relates to iron and the immune system in age-related macular degeneration (AMD). Let’s start by introducing today’s speaker, Josh Dunaief. Josh is a Professor at the Scheie Eye Institute at the University of Pennsylvania. We have been very fortunate to partner with him on research through our macular degeneration research program. If Dr. Dunaief’s name sounds familiar, he’s been on several BrightFocus Chats over the last few years, and we’re very fortunate to have a number of articles written by Dr. Dunaief on the BrightFocus website—www.BrightFocus.org—so it’s a great opportunity to have you with us today.

    DR. DUNAIEF: Pleasure to be with you again, Michael.

    MICHAEL BUCKLEY: Dr. Dunaief, it’s always a pleasure to work with you. I know we’ve been able to partner with you and your colleagues at the Scheie Institute at the University of Pennsylvania on really some of the most exciting research on vision disease in the world, and we really appreciate the clarity with which you’re able to communicate this information to folks. So, I just want to welcome you to today’s BrightFocus Chat. What would you like to talk about today?

    DR. DUNAIEF: Well, thank you, Michael. It’s always a pleasure. I like to be with you and your listeners to talk about some of the latest findings in macular degeneration, and we have some pretty exciting new findings to talk about today.

    The first thing I’d like to talk about is a brief summary of some of the known modifiable risk factors for macular degeneration. These are things that many people have heard, but I want to emphasize that there are things that people with macular degeneration can do today to decrease their risk of losing vision. Those things include stopping smoking, if you’re a current smoker; eating whole foods, especially fruits and vegetables; and eating fish two or three times a week, especially salmon or sardines.

    These things have been shown in epidemiological studies to decrease the risk of vision loss. Another study shows that eating lots of red meat is a risk factor. So, I recommend eating red meat once a week or less to decrease the risk of vision loss from macular degeneration. Also, processed foods and lots of sugar are risk factors.

    In the summer, we should really think about light exposure as a risk factor, because several studies have shown that bright light exposure is a potential risk factor. So, when out there on the beach or by the pool, it’s important to wear sunglasses and a hat to avoid excess light exposure for the eyes.

    Those are things that people have probably heard before, but there are some more recent findings that we can talk about now. One of them is a clinical trial with an inhibitor of the immune system—an inhibitor of something called the complement cascade, and if you’d like, Michael, we could first take a step back and discuss what a clinical trial is and how they’re done.

    MICHAEL BUCKLEY: Yeah, that would be great. I think that would help our listeners and it would be interesting to see how scientists reach some of the findings.

    DR. DUNAIEF: Sure. A lot of the early studies in macular degeneration looked at genetics of the disease and also used mouse models or tissue culture models, where retinal cells are grown in plastic dishes, to identify molecules that could be targeted to help protect vision. Then, once we have good candidates for molecules that could be targeted, we start clinical trials with patients, and they’re divided into three types: Phase I, Phase II, and Phase III.

    Phase I is primarily designed to test safety. It’s a small trial. It will usually look at several different doses of the drug to ensure that it’s going to be safe. Then Phase II is a little bit larger trial that looks mainly at safety, but also starts to look at whether the drug is effective. And then Phase III is the largest trial, and it looks at both effectiveness and safety, and if the U.S. Food and Drug Administration (FDA) sees that the drug is safe and effective, then it may approve the drug for clinical use.

    So, if you go to your eye doctor and ask if you might qualify for a clinical trial, then you might be told that your condition is being studied in current clinical trials and that you might be eligible, or you might be told that there isn’t currently a clinical trial for your disease or your stage of the disease but to stay tuned and hopefully there would be one in the future.

    MICHAEL BUCKLEY: Yeah.

    DR. DUNAIEF: The one that’s got me excited right now is by a company called Apellis, and they’re studying a drug that inhibits complements. So, a complement is a part of the immune system—and for macular degeneration, it’s really not a compliment, it’s more of an insult—and what it does is it kills retinal cells when it’s inappropriately activated. So, this Apellis trial is a Phase II trial that shows that inhibiting a complement protein called the C3 could slow the progression of a form of macular degeneration called geographic atrophy. So that is now progressing to a Phase III trial, and we should find out within probably a year or two whether that Phase III trial was successful and whether inhibiting complement C3 can actually slow geographic atrophy expansion. If so, that would be the first drug approved to slow expansion in geographic atrophy, which would be wonderful.

    MICHAEL BUCKLEY: That’s amazing. And it sounds like a really helpful, promising development out of that clinical trial.

    DR. DUNAIEF: It sure is, Michael. Another clinical trial that just ended was a Phase III clinical trial, which tested gene therapy for patients who are born blind, and this Phase III trial showed effectiveness and the FDA decided to approve it. So, this is really remarkable; it’s the first FDA approval for a gene therapy that’s delivered into the human body, and it corrects a gene that’s defective in children who are born blind from a disease called Leber’s. The trial was conducted by investigators at the University of Pennsylvania—Jean Bennett and her husband Al Maguire, who’s a retinal surgeon—and they showed, along with collaborators around the world, that this gene therapy can be delivered into the retina safely. And children who were born blind can now navigate through a maze, or some of them can catch a ball; it’s really a ground-breaking development that is going to lead the way to gene therapy for other retinal diseases, because they have developed the methods needed to deliver genes into the retina safely.

    MICHAEL BUCKLEY: That is amazing. That is a true miracle, really, a testament to a lot of the work going on at the University of Pennsylvania. Before we turn to some of your own research, we have a few questions already from our listeners. A caller from Michigan is wondering, how many servings of red meat do you recommend in a typical week?

    DR. DUNAIEF: One or less. There’s evidence from a clinical trial in Australia that people who ate a lot of red meat had an increased risk for macular degeneration. There’s also evidence that red meat increases the risk of other diseases, like cardiovascular disease. So, one serving a week or less is my recommendation. If you’re a vegetarian and don’t have any meat at all, that’s probably even healthier, but I don’t think a serving a week is going to hurt very much, if at all.

    MICHAEL BUCKLEY: Sure.

    DR. DUNAIEF: One of the reasons that red meat may be harmful is that it contains a lot of iron, and you absorb a lot of the iron that you eat in red meat. A lot of foods that contain iron have it in a form that’s not easy to absorb, so it doesn’t get into the body. But when we eat red meat, 50 percent of the iron that’s in that red meat gets absorbed because of the form that it’s in. So, that can load our bodies with more iron than we need.

    MICHAEL BUCKLEY: And I know your research has been looking at the impact of iron in AMD. Would you mind sharing with us what you’ve been learning from studying the issue of iron?

    DR. DUNAIEF: Yes, absolutely. So, iron is kind of like Goldilocks. It needs to be just right: We need to have not too little and not too much. A lot of focus in medicine is on avoiding iron deficiency and making sure you have enough iron, because if you have too little iron then you can become anemic, meaning that you don’t have enough red blood cells, and that makes you tired. This is especially common among menstruating women because when you lose blood, you lose a lot of iron. However, there’s been very little focus on the potential risks of having too much iron, and a lot of people have too much iron because our bodies continue to absorb it as we age, but we have no way to get rid of it except when we bleed. So, there are some women who were told to take iron when they were menstruating, and then they just continued to take it when they were post-menopausal, and they can wind up with much more iron than they need.

    That’s a problem because iron can produce free radicals. It can cause something called oxidative damage. What is that? That’s when electrons get stolen from proteins or fats or DNA, and that causes structural changes—chemical changes—to the DNA, causing mutations or causing proteins to stick to each other inappropriately, and that can then lead to disease.

    So, we know that too much iron can lead to disease because when people get a piece of iron in the eye in an accident it very rapidly causes degeneration of the retina. We also know that people who have hereditary diseases that lead to excess iron in different organs have degeneration of those organs. So, there’s a condition called hereditary hemochromatosis where people absorb a lot more iron than they should, and that causes disease. It causes degeneration of the liver; degeneration of the pancreas, leading to diabetes; pain in the joints; and if the iron accumulates in the brain or the retina, then it can potentially cause damage there.

    We found that people with macular degeneration who then donate their eyes upon their death have more iron in the retina than age-matched controls. And because of what I said about iron causing oxidative damage, we thought that iron might be contributing to the macular degeneration. To test this, we used some mice that we genetically engineered to accumulate a lot of iron in their retina, and the iron buildup in the retina caused degeneration of the retina that looks in some ways like macular degeneration. We were able to recreate a degenerative disease in the mice, so they’re a model of retinal degeneration caused by iron. Now, I don’t think that iron alone causes macular degeneration, but I think that it cooperates with other factors like complement proteins and probably lipids and fats to cause damage to the retina over time that then manifests as macular degeneration.

    MICHAEL BUCKLEY: Wow. Let me just jump in for a second. This is all really interesting. I think your Goldilocks characterization of it is right on because a lot of us—growing up we’re told by our parents or told by our science and health teachers or the magazine articles we read that iron is good and the more you have, the better. This is really interesting research, and I appreciate you sharing this with us. How does someone know if they should be taking more iron or less iron? How does someone resolve the Goldilocks situation in their own life?

    DR. DUNAIEF: Yeah—really good question, one that isn’t frequently looked at by clinicians. So, people who are anemic—meaning that they have too few red blood cells—may be anemic because they’re iron deficient. However, there are other causes of iron anemia. Just because you’re anemic doesn’t mean you’re iron-deficient. There are blood tests that measure iron levels in the blood, and what should be tested is the blood-iron level; the transferrin saturation, which is a measure of how much iron is bound to the protein that carries iron in the blood, which is called transferrin; and the ferritin level. Ferritin is a protein that stores iron in the liver, and when iron stores are very high, ferritin levels in the blood increase. So ferritin, which is not very frequently measured and certainly not measured in standard routine blood tests—you have to ask for it—ferritin levels will tell you what your total body iron levels are. So, I think it’s a good idea to have the ferritin level test.

    People who have enough iron have a ferritin level somewhere in the 40–80 range. So in that range, you should have enough iron to make your red blood cells and to do the important other things that iron does in the body. But if ferritin levels are above 100, then it’s likely that you have a lot more iron than you actually need, and you could reduce the amount of red meat that you eat and eat more plants, vegetables, and fruits, and that iron level may come down a bit.

    Another way to reduce body iron levels is to donate blood, which not only could help you but, of course, is a good thing to do to help other people who need blood transfusions. Since there’s a lot of iron in red blood cells, every time you donate blood you get rid of a lot of iron.

    MICHAEL BUCKLEY: That’s really interesting. We’ve gotten several questions in about iron supplements, and Gladys from New York is wondering, is the amount of iron in a vitamin supplement that you’d get at a store—is that amount of iron too much? Or, what do you think of the vitamin supplements that are sold with iron?

    DR. DUNAIEF: Well, the amount of iron and the form of iron is going to vary depending on which supplement you’re taking. Many multivitamins will contain some iron, and if you’re taking a multivitamin every day that contains iron, then that may be leading to more iron than you need. So, there’s a supplement called Centrum Silver, which does not have any iron in it anymore. It’s for older people who are not menstruating or not losing blood routinely and don’t need iron supplements anymore as a group. I mean, there may be some elderly individuals who do need iron supplements because they’re truly iron deficient, but as a group, most elderly individuals will not need iron supplements.

    MICHAEL BUCKLEY: That’s interesting. I know that in the past we’ve talked about the AREDS—which is an acronym for the Age-Related Eye Disease Study—the AREDS supplements that researchers have shown to be promising for folks with AMD. Do AREDS supplements have any iron?

    DR. DUNAIEF: No, the AREDS supplements have a form of vitamin A called lutein, vitamin C, vitamin E, the mineral zinc, and a little bit of copper in them. It’s interesting that the Age-Related Eye Disease Studies showed that zinc is protective for people with early macular degeneration—it protects against progression of the disease—and zinc can actually compete with iron for uptake into the body or binding to proteins. So, one of the potential mechanisms of zinc’s protection is by protecting us from iron.

    MICHAEL BUCKLEY: That’s interesting. Another kind of vitamin question. We’ve got a caller from New Jersey who, probably like me, grew up thinking that spinach is good and you should eat a lot of it, and we always said that’s what made Popeye so strong. I’m just wondering, is spinach high in iron, or is that something that might not be good for vision health?

    DR. DUNAIEF: That’s a great question. So, iron is generally not very well absorbed from food, except from red meat. If we eat a lot of red meat, we absorb a lot of iron. Spinach has a fair amount of iron, but it’s not well-absorbed, so I don’t think that the iron in the spinach poses the risk. On the contrary, it’s been shown that people who eat more green leafy vegetables like spinach and kale and collard greens have a decreased risk of macular degeneration. So, the evidence is that spinach is helpful, not harmful, and I’m not worried about the spinach iron because not much of it is going to get absorbed.

    MICHAEL BUCKLEY: Well, that’s good to know. I’m kind of switching gears. We have a caller from Missouri wondering about acupuncture. She’s heard people talk about clinical trials or other forays related to acupuncture for AMD. Is that something that you’re familiar with?

    DR. DUNAIEF: Yes, I’ve heard of people doing it. It’s hard to evaluate. It hasn’t been tested in clinical trials; it’s hard to do these clinical trials. They’re very expensive, they require a lot of patients and a lot of time, so it wouldn’t be easy to launch a clinical trial for acupuncture for macular degeneration. Without clinical evidence, only with anecdotal evidence, somebody might say, “I had acupuncture and I think I see better now.” That’s just one person or a few people saying this. It’s not really evidence that it works, so I can’t really say whether it works or not.

    MICHAEL BUCKLEY: No, I appreciate that. We have another question that just came in—a caller from Washington State. They’re interested when you were talking about blood and AMD. Does it vary by particular blood type that a person has? Is there any connection between blood type and AMD?

    DR. DUNAIEF: No, there’s no evidence that there’s any connection between blood type and AMD. The blood type doesn’t impact how much iron is in the blood. There’s Type A, Type B, Type O. Those types just depend on what kind of a “flavor” of proteins, if you will, you have in your blood and that relates to potential immune reactions when you have a blood transfusion.

    MICHAEL BUCKLEY: Interesting. Another question relating to supplements. The supplement aisle at your local pharmacy or supermarket can be pretty overwhelming. Do you have any kind of guide for how to navigate, literally, a floor-to-ceiling array of choices?

    DR. DUNAIEF: It’s a huge industry, and for the most part unregulated. The only supplement that’s been proven effective for macular degeneration is something called PreserVision®, which follows the AREDS 2 formula. AREDS 2 was a study that was run by the National Institutes of Health looking at thousands of patients over the course of 10 years, and it showed that a specific formula decreases the risk of macular degeneration progression in people who already have some macular degeneration. That is, the ophthalmologist has seen little white spots in the retina called drusen and have told the patient that they would benefit from these AREDS 2 formula antioxidants. Any other antioxidant claiming to protect eye health has not been supported by clinical trials—not supported adequately. So, I would really not recommend at this time taking anything supplement-wise other than the AREDS 2 vitamins unless you’re directed by your ophthalmologist to take them. I would recommend eating lots of fruits and vegetables, lots of green leafy vegetables, and not a lot of red meat.

    MICHAEL BUCKLEY: I appreciate that. We have a couple more questions that we have time to get in. We have a caller from Michigan wondering about intermittent fasting. Does that have any effect on AMD and eye health, either good or bad, if one were to do strategic intermittent fasting?

    DR. DUNAIEF: That’s an interesting question. There is some evidence that high glucose in your blood can increase the risk for macular degeneration, and some evidence that ketones that are produced by fasting may be protective for neurons. So in theory, it might be helpful, but again, it’s something that hasn’t been tested in a prospective clinical trial, so we can’t be sure.

    Speaking of clinical trials, there’s one that we’re currently running based on our iron hypothesis. We are testing a certain nutraceutical that is available in drug stores over the counter—it’s called lipoic acid—and we’re testing it for its ability to slow the progression of geographic atrophy when taken orally. The reason we’re testing this is it was very protective in our mouse model of macular degeneration. Lipoic acid binds to iron, and it’s also an antioxidant, so it protects against free radical damage that could otherwise cause mutations in DNA or cause proteins to stick together.

    I do not recommend that anybody go out and start taking this yet, because we don’t know that it’s protective. You know, it’s our theory. It’s backed up by data that we generated in the lab, but we don’t know that it’s protective. We don’t even know for sure that it’s safe. There’s a lot of history with the substance suggesting that it’s safe, but until we have the results of the clinical trial, I don’t suggest that anyone go out and get it. But do stay tuned for the results of the trial, which is ongoing.

    MICHAEL BUCKLEY: Dr. Dunaief, just a concluding question. I know you’re on the forefront of a lot of exciting research projects. I know you’ve also seen a lot of patients in your clinic at the University of Pennsylvania. Just sort of the big picture…how do you feel about the future of vision disease, particularly AMD, whether in terms of more effective treatments or cures? What do you think the future holds for vision disease, particularly AMD?

    DR. DUNAIEF: Well, Michael, I’m very optimistic that we’re going to have better and better treatments over time. When I started seeing patients with macular degeneration 18 years ago, there was very little that we could do other than tell patients how quickly they were likely to lose vision and provide them with low-vision aids like magnifiers and reading glasses, which of course were helpful. But now for people with wet macular degeneration we have a drug that can slow the progression and sometimes even stop it. That’s only within the past 10 years. That’s Lucentis®, Avastin®, or Eylea®—drugs that block a protein called vascular endothelial growth factor (VEGF).*

    There’s been really a tremendous acceleration of biomedical research that’s benefitting all different fields, including and maybe even especially the eye, because we can see what’s going on in the eye very clearly—just looking into the eye with an ophthalmoscope or taking high-tech photos of the retina. We can know exactly what’s going on and test different potential therapies.

    So, we’ve developed these drugs for wet macular degeneration, but I think that’s really just the tip of the iceberg. We now know more about how to deliver drugs to the eye, we know more about how to do clinical trials for eye disease, we know how to image the eye; the techniques to image the retina are improving. Every year we get better and better resolution images of the retina to the point where we can now see single retinal cells in a living patient with a very fast, painless type of photograph. We can count the number of cells that are surviving over time, so I think the pace of discovery is going to increase; we’re going to see more drugs for people with dry macular degeneration.

    It’s going to take some patience, you know, research does take a long time. We have to make sure that what we’re doing is safe and effective. It took Jean Bennett and Al Maguire really 30 years of hard work to develop effective retinal gene therapy for the children who are blind. So, it takes a lot of patience and a lot of hard work, but we are accelerating that and we’re really developing some effective drugs now.

    MICHAEL BUCKLEY: Thank you. That is amazing. You’ve really given us a lot of useful information and a lot of hope for the future. Dr. Dunaief, I just want to conclude by saying thank you, not only for how helpful you were on today’s Chat, but thank you to you and your colleagues at the University of Pennsylvania and to all of the volunteers in clinical trials that you helped run. I think it’s really giving us a lot of hope for the future and I want to thank you for all you’ve done for people.

    DR. DUNAIEF: My pleasure, and thank you, Michael, and to BrightFocus, for getting this information out to patients and, of course, supporting research. And I want to thank all of the patients out there who are being patient and hanging in there and doing their best and trying to preserve their vision and waiting for better treatments, which are coming.

    MICHAEL BUCKLEY: Well, that’s great. We will keep up with your research through our website, BrightFocus.org, where we have articles about some of the latest research findings. We’re fortunate to have articles written by you several times a year and I hope we can have you back on a BrightFocus Chat.

    DR. DUNAIEF: Absolutely.

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