Video: Catalyst for a Cure Research Progress 2013

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Video Transcript: Catalyst for a Cure Research Progress 2013

Thomas M. Brunner (President and CEO, Glaucoma Research Foundation): Catalyst for a Cure is a unique approach to research developed by Glaucoma Research Foundation to accelerate the pace of discovery toward a cure for glaucoma. It involves bringing together scientists from different backgrounds to work collaboratively to understand glaucoma and find ways to improve treatment and ultimately cure this blinding disease.

Catalyst for a Cure: Neuroprotection

Philip J. Horner, PhD (University of Washington): When we first entered the field of glaucoma we were all neophytes, we weren't experts in the field and we garnered from the literature that the primary understanding of glaucoma was that this was, if you will, a mechanical disease in some way. There would be pressure elevated in the eye and when that pressure elevated ganglion cells would die.

But what we've found over the first few years when we began is that ganglion cell death isn't a rapid event, at least not in the case of glaucoma. What it is, is it's a slow, protracted event, and then what we decided and we set about to do, which I think has changed the thinking broadly in glaucoma, is to look at all the other elements that really hadn't been looked at very well during the cell death process.

So what we did is we asked, what happens very early, what happens upstream of cell death? If cell death is a slow process, maybe there are some hallmarks, some harbingers, of what happens before cell death that would give you a good clinical target for slowing or preventing the disease.

And we had some big surprises in the early days. All of these have been published; we noted that ganglion cells, before they die, begin to deprogram themselves, in other words, the genes that normally make them ganglion cells, those genes get to be turned off. So ganglion cells, before they die, make a decision to basically not be ganglion cells, not to be functioning cells anymore.

The second big surprise was that the support cells, so called glial cells, these are the cells that surround ganglion cells from their--where their cell body is in the eye all the way back to the brain. What we've discovered is that those cells become active very early in the disease, they become active even before we can detect that the neuron is sick, even before the ganglion cell shows signs of degenerating, we find the glial cells are becoming very, very active and that was a surprise and we published those findings.

And the third major thing that I think we've discovered is that the immune cell of the eye, which is called the microglia; it serves a special function in the maintenance of the health of the retina. And what we've found is that those cells also become very active early in the disease.

Monica L. Vetter, PhD (University of Utah): When the Catalyst for a Cure began, there was a substantial focus in glaucoma on managing pressure, which is still an important clinical problem, and also on understanding retinal ganglion cell death. I think what's really transformed the field in the last ten years and in part due to the efforts of the Catalyst for a Cure consortium, is really focusing on the earlier mechanisms and also thinking about glaucoma as a neurodegenerative disease and understanding that there are a lot of parallels between how neurons are degenerating in glaucoma and how they are degenerating in other prevalent diseases such as Alzheimer's or ALS and that has opened up a whole new world of thinking about the pathways and mechanisms that are controlling the decline of neurons and I think provides new opportunities in controlling the progression of these diseases at much earlier stages.

I think that this investment has accelerated to the pace of research in the field of glaucoma; the number of publications that are really focusing on these mechanistic insights have just exploded in the last ten years, so this investment by Glaucoma Research Foundation was really a catalyst that allowed us to dig in deeper to understanding what's actually happening in the disease as the disease is progressing. And then really thinking in much broader ways about what's happening and strategies that we might take to try to intervene or slow or halt the course of disease progression.

What is the unique contribution of the Vetter Laboratory to the Catalyst for a Cure?

Our laboratory initiated several collaborative studies that have been published and some of the initial work was really focused on trying to conduct a comprehensive molecular analysis of what are the early changes at the molecular level, the level of gene expression as the disease is first initiating and undergoing those early changes that are so critical in the course of disease. We obtained a molecular signature that really pointed us in a very specific direction which is looking at the interaction between the degenerating neurons and local, innate immune cells that are responding to early injury and stress in the neurons.

We think these cells are critical early responders to disease onset, they're part of the progression phase of the disease and we think that this is providing a key insight into some of those initiating events in glaucoma. And I think, before the Catalyst for a Cure did that work, there was never that really detailed understanding of what was actually happening and I think we've made a major contribution in sort of adding those players as important components in the course of disease.

How much closer are we now to finding a cure for glaucoma?

Monica L. Vetter, PhD: I actually have a lot of confidence that through the work of the Catalyst for a Cure and how that has actually impacted the field in general, there's a lot of excellent work going on all over the world now, that really critical pathways and players are now being identified and that there are true strategies in the pipeline that are very specifically targeted at components that we now know are involved in the course of disease.

When we started we didn't even know who those players were so I think a lot of the work of the CFC consortium has really mapped out who the players are, what are the molecular pathways that are involved in the course of disease, and we actually have invested significant effort into developing strategies and therapeutics that are going to take some time to develop and test but we think that we are well on the way to having in hand approaches that will have a significant impact.

Nicholas Marsh-Armstrong, PhD (Johns Hopkins School of Medicine): Glaucoma is that rare disease among neurodegenerative diseases, where, if we're only able to identify people with the disease before we currently can do, we have the potential of having a significant impact on human health. I think that the Catalyst for a Cure, as a collective, has really contributed to bringing glaucoma research to a different level from where it was before. We've brought the hard science to glaucoma and I think that is for the benefit of glaucoma patients today and in the future.

What is different now in the field of glaucoma research compared with 11 years ago?

So much is different, I think, where we were as scientists but how the field was as a community was at a state of naiveté, that is, we did not understand hardly anything about this disease. Now we find ourselves understanding so much about this disease and there's still a lot more to learn, but it's night and day. How we view this disease is completely different now than it was ten years ago.

What is the current research focus of the Marsh-Armstrong Laboratory?

We are extremely excited about the work that we're doing now. I should say that I'm more excited now about what I'm doing in science then I've ever been. We have redirected most of the laboratory to addressing something that came specifically from our studies of glaucoma that we think has much broader impact. We're focused on glaucoma and it has to do with a set of very surprising findings in a region that we know is critical for axon loss in glaucoma, which is the optic nerve head. So we have discovered a set of biology there that was not previously known to be, that we have every reason to believe to be critical for this disease and perhaps other diseases as well.

What is the future of glaucoma research?

I think that the future looks quite promising, certainly a lot more promising then it was ten years ago and I can't promise when we will have a very significant treatment to halt the disease in particularly those that are not helped by pressure lowering medications but I think it's probably going to be soon. I think that some of the neuroprotective strategies may make it to the clinic pretty soon; time will tell whether that's the case.

I think there are some very basic findings that I think may herald whole new approaches to therapy that may come online within ten years, so I'm extremely excited about those. I think, I'd be very surprise if we're not able to diagnose this disease earlier than we can now and, as I said, that will help preserve vision in millions of people, so I think that the future looks quite promising.

David J. Calkins, PhD (Vanderbilt Eye Institute): We're very excited right now because, having traced the earliest pathogenic events in glaucoma over the last several years we've actually identified several molecular cascades that we think translate stress in the eye, in glaucoma, to the earlier neuronal response in the disease. So a recent focus in my laboratory has been on identifying drugs that quench that stress response and abate degeneration and progression and we're very excited that in our preclinical models we've tested some of these new drugs and had very promising results.

Why is it important to find specific biomarkers for glaucoma?

Identifying the earliest events in neurodegeneration in glaucoma is important because if you can stop those early events then hopefully you can stop progression or slow progression and give the central nervous system time to recover from the initial insult. That information is useful in the laboratory; it's not so useful in the clinical domain where we really want our noninvasive measures that serve as surrogates for the earliest pathogenic events. So the Catalyst for a Cure a few years ago began looking at noninvasive ways to measure early progression of the disease and to identify those events using tools that really didn't exist before that.

The term "biomarker" is used to describe these surrogates that we're attempting to find that tell us that these pathogenic events are going on in the background, but to do so in a noninvasive way. So for example, we are looking at ways to image the retina in the living eye and identify cells that become reactive very early on in the disease. That tells us when we go back into the laboratory that if we can correlate that event with pathogenesis then we've identified a marker or a biomarker to tell us when the disease is progressing.

Another example, this is something that's going on in my laboratory, is that we're starting to look at protein and fat deposits in the retina and the optic nerve that we hopefully can measure in blood serum that tell us that the disease is progressing early on. The idea, of course, is to come up with a diagnostic tool that is more sensitive than the diagnostic tools that are used in the clinic.

Why is neuroprotection important in glaucoma research?

Neuroprotection ties into prevention when it is applied early on. Neuroprotection can also be applied later in progression to abate further degeneration and hopefully, hopefully, restore function by stimulating a self-repair response in the retina and the optic nerve.

What motivates you as a scientist?

What motivates me as a scientist is knowing that because of the Catalyst for a Cure my research is going to have an impact on patients. Many times it's difficult to see the light at the end of the tunnel when you're doing a particular set of experiments or initiating a line of investigation, especially a risky one. Because of Catalyst for a Cure has always had as its underlying theme helping patients, I have every confidence that the exciting results that we've generated will sooner or later make their way into the clinic, with proper development, so that we can improve the lives of patients.

Catalyst for a Cure: Biomarkers

Andrew Huberman, PhD (University of California, San Diego): The original CFC team really made some critical contributions to our understanding of how and where ganglion cells die during glaucoma. I think before they did that it was largely a mystery when and where ganglion cells dying during the progression of this disease.

Thomas M. Brunner: The Glaucoma Research Foundation is bringing together a second team of scientists to look for markers that can tell when the cells first get ill and how the disease progresses.

Jeffery L. Goldberg, MD, PhD (Bascom Palmer Eye Institute, University of Miami): Biomarkers can actually be very broadly defined. We have biomarkers for a lot of diseases. We can look at the biomarker of atherosclerosis and look at how the arteries feeding the heart have gotten closed off and use that to predict whether you're going to have a heart attack. It doesn't tell you 100% but it helps us identify patients at risk. We have some biomarkers for glaucoma that tell us whether patients have the disease, like visual field tests or imaging, just letting your doctor look at the optic nerve in the back of the eye is a biomarker for whether you have glaucoma and, at least at a gross level, whether it's getting worse.

The opportunity now is that we've entered into an era of molecular understanding of improved physics and optics, we have an opportunity to think about newer, better ways to detect the disease, to figure out which patients are getting worse or are at risk of getting worse, to catch patients before they've lost vision and give them treatments. Another big opportunity for developing more sensitive, more specific biomarkers, is the opportunity to then use those as measures when we want to develop new treatments for the disease. Without really good markers for the disease's occurrence, for glaucoma progression, it's hard to develop new drugs and test them on people and determine whether or not those drugs are really good for the disease in a reasonable time period so developing biomarkers is going to be good both for glaucoma disease protection as well as for disease treatment.

Vivek Srinivasan, PhD (University of California, Davis): I think that one of the problems in glaucoma and glaucoma diagnosis and management is that there's no real sensitive and specific way to track disease. There are subjective methods, there are some structural methods, but it's thought that there is a loss of metabolism and function before these occur, so one of the real challenges in the field is to develop early biomarkers for disease detection and progression. Another issue is if you have a patient who you know has the disease, when do you treat? By developing biomarkers which are not only sensitive for disease detection but also specific biomarkers you can solve the problem of both detecting disease early but also determining the course of treatment in a very specific fashion.

What is your area of expertise?

My overall interest is in optical imaging, I did my PhD work in the laboratory of James Fujimoto where Optical Coherent Tomography was developed and I focused specifically on retinal imaging and I was fortunate enough to be involved in some of the major advances in imaging speed in Optical Coherent Tomography or OCT as it's more commonly known. More recently I've been at the Martinos Imaging Center focused on imaging the brain and in particular hemodynamics in the brain under functional activation in neurovascular coupling but also changes in disease. So I'm looking forward to combining my expertise in OCT technology with my recent experience in brain imaging and thinking about neurodegenerative diseases to help solve the problem of biomarkers in glaucoma.

Alfredo Dubra, PhD (The Eye Institute, Medical College of Wisconsin): One of the things that we've been working on really hard lately is the idea of achieving very high resolution in imaging. So what we now want to pursue, now that we have that resolution, is to see how we can take advantage of that to study the function of the cell at that scale so that we can use that as a biomarker because many of the clinical measurements these days focus on structure and that is usually a very late indicator of the disease. So we hope that we can move the detection earlier to detect cells that are sick rather than cells that are dead and gone.

The technology that I bring into the group is called "adaptive optics" and it's a technology that was originally developed to look at the stars, and surprisingly the same technology can be applied to the eye to make sharp images of the retina. In fact, this technology enabled, ten years ago, to see the individual cells in the back of the eye for the first time.

In the last 10 years we've been working really hard at seeing the photoreceptors and studying other retina conditions but we're now going to focus really hard on trying to visualize the ganglion cells and the vasculature that serves the ganglion cells so that we can actually test some of the most contested hypotheses about glaucoma. For example, what is the role of the vascular insult to the nerve fiber layer?

What's your scientific area of expertise?

Alfredo Dubra, PhD: My area of expertise is also optical imaging. I've been working for the last 5 years in trying to bring image resolution to "in vivo" imaging comparable to microscopy because right now we believe there is a disconnect between the clinical imaging that looks at very microscopic features of the eye that are informative of the disease but usually at very late stages and the exquisite work that molecular biologists are doing. We hope that by allowing us to do "in vivo" microscopy imaging of the retina we're going to breach that disconnect between the two.

Andrew Huberman, PhD: We know a lot about the biology of healthy ganglion cells, both in terms of what those connections look like and how those cells signal information about the visual world to the brain, in effect, how they tell the brain what's out there in the visual world. We know far less as a field about what happens when the ganglion cell gets sick or injured and dies. What I hope to bring to Catalyst for a Cure is an understanding of both healthy ganglion cell biology and some insights into potential targets for rescuing and replenishing ganglion cells when they're injured in glaucoma.

Jeffery L. Goldberg, MD, PhD: I'm very excited about the opportunity to work with this group. I think the opportunity to blend people from different backgrounds, different disciplines, we have people who are biologists from the molecular level, through the systems level, blending with people who are really working much more in engineering, imaging, physical sciences and it's through those sorts of collaborations that I think we can really come up with new ideas and hopefully bring them forward to really make some progress on this difficult disease.

So for the last 15 years I've been studying retinal ganglion cell biology trying to understand why they fail to survive after injury or in degenerative diseases like glaucoma and also when their connections to the brain are interrupted why do they fail to regenerate to regrow, why do they fail to repair themselves, it's this fundamental problem that leads to permanent vision loss in glaucoma. Taking steps towards understanding that and reverting cells to being better at repairing themselves may be an avenue to improving on the vision loss in glaucoma.

In addition to spending most of my week doing research trying to tackle these important questions, I'm also a trained ophthalmologist and glaucoma specialist and every week I see patients with glaucoma. And although its true many patients with glaucoma, at least in this country, we can catch it early and really slow down the course of their disease.

For many patients we're catching it to late or their disease is too aggressive and people really losing functional vision from glaucoma, whether it's their peripheral vision or even eventually their central vision, it's very motivating to be able to take note of the fact that we've got patients in these tough situations losing vision to glaucoma and then to be able to go back to the lab and to hook up with great collaborators and really try to attack the problem scientifically. You know the dream is to be able to help not just the patient in front of you but patients everywhere by taking a step forward with the science of disease detection, disease treatment.

Andrew Huberman, PhD: I think there are things that are possible today and that are coming in the next few years that simply were unimaginable five or ten years ago. That there's just a huge influx of biomedical techniques and research techniques that have hit the field and it's no longer the case that only specific labs have access to these things. Here at this table we have a very nice collection of very specialized skill set around a particular problem and we all have available to us very important and powerful techniques to approach this problem from a number of angles. I think many of those imaging and biotechnical tools simply were not available a few years ago and now they're all available to us essentially and that the important step is to combine them in the right ways.

End Transcript

Read more about the Catalyst for a Cure research consortium.

Last reviewed on October 29, 2013

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