David Krizaj, Ph.D., Moran Eye Center investigator and professor of ophthalmology at the University of Utah, has discovered mechanisms that protect cells within the eyes from fluctuations in pressure, and has found that a drug that targets the so-called mechanosensor also blocks signs of glaucoma, a disease linked to high eye pressure and a leading cause of blindness. Krizaj explains how the work is leading to a new understanding of how the eye works, and how this knowledge could lead to a new therapy for the disease. Learn more about the research in Scientific Reports.">

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Aug 31, 2016 — When we rise out of bed in the morning, the pressure within our eyes changes massively - by 100-fold - and yet no damage is done. David Krizaj, Ph.D., Moran Eye Center investigator and professor of ophthalmology at the University of Utah, has discovered mechanisms that protect cells within the eyes from fluctuations in pressure, and has found that a drug that targets the so-called mechanosensor also blocks signs of glaucoma, a disease linked to high eye pressure and a leading cause of blindness. Krizaj explains how the work is leading to a new understanding of how the eye works, and how this knowledge could lead to a new therapy for the disease. Learn more about the research in Scientific Reports.

Interview

Interviewer: A new understanding of glaucoma could lead to new treatments, up next on The Scope.

Announcer: Examining the latest research and telling you about the latest breakthroughs, the Science and Research Show is on The Scope.

Interviewer: I am talking with Dr. David Krizaj, an investigator at the Moran Eye Center and Professor of Ophthalmology at the University of Utah. Dr. Krizaj, you've found a way to possibly block glaucoma. That sounds pretty significant.

Dr. Krizaj: Glaucoma is the primary cause of irreversible blindness in the world. So it affects more than three million of Americans. At least 50% of the people who have the disease have no idea that they do have it. And by the time they start experiencing loss of vision it's already too late.

Interviewer: And so what happens? What causes glaucoma?

Dr. Krizaj: The causes are still, to a large extent, unknown but there are major risk factors such as ethnicity, age, and especially increased intraocular pressure which is actually the only factor that we can treat at this point. The main problem here is that we don't actually know how pressure is elevated. So the major impetus has been to look at the molecular mechanisms behind this disease.

Interviewer: So does that mean that the pressure in your eye changes often or normally?

Dr. Krizaj: It changes almost hundredfold when we get out of bed. But that's just for . . . or when we do yoga, for example. But that's just for short periods of time. The problem is if the change is chronic and over a long period of time. Basically, what pressure in the eye is, is a difference between the production and drainage of ocular fluids.

Interviewer: What are some of the properties that you've discovered that people didn't really know about before?

Dr. Krizaj: One major challenge has been to identify the mechanosensors that allow the cells to regulate pressure under normal circumstances. The second major challenge has been to identify the mechanisms through which increasing pressure kills the cells that sends signals to the brain because it's the death of these cells that causes blindness.

Interviewer: And that's what you've done, is that right?

Dr. Krizaj: Exactly. We believe that we have identified the mechanosensor both . . . and which turns out amazingly to be the same in the front of the eye regulating pressure and in the back of the eye in cells that communicate with the brain.

Interviewer: And so why is that important? Why is that significant that it's in both of those places?

Dr. Krizaj: So if we could target this pressure sensor mechanism we would have the first time ever therapeutical approach to regulate pressure while we are neuroprotecting cells. This has been a Holy Grail of glaucoma research, I would say, over the past 30 to 40 years. And we have in fact, collaborated with medicinal chemists here at the University of Utah who have designed antagonists that are specifically optimized for eye drop delivery or ocular delivery and were able to block the disease in mice so far.

Interviewer: Yeah. And that's really amazing. When you add this drug or these eye drops to the mice, what are some of the changes you see?

Dr. Krizaj: So we have a mouse model where we can elevate intraocular pressure by artificially suppressing drainage. So pressure goes up and we found that when we add these antagonists developed by our collaborator, Glenn Prestwich and Ryan Looper at the University of Utah, pressure drops back down like a rock within minutes. And if we do this, and my graduate students have done heroic experiments where they applied these drops three times a day or two times a day for four months. We find that if we do this consistently we can completely prevent the generation of these neurons which is synonymous with glaucoma.

Interviewer: So how does that work?

Dr. Krizaj: Every cell has its own internal bone structure. And it's just like in humans. If these bones are too stiff and non-pliable, the cells become brittle and very sensitive to damage. And we believe this internal cytoskeleton, as we call it, is really a problem in increased drainage. So we found that when we block the mechanosensor there is an increasing calcium ions in these cells which dissolve this cytoskeleton and as you say makes cells more pliable.

Interviewer: Interesting. I was thinking about this. A few weeks ago, I was pumping up a basketball. And I put too much pressure in the ball and it basically burst. But if that were made of a more pliable material, maybe a more rubbery material, then it should be able to withstand more of the pressure and not see as much damage. Is it similar in that way?

Dr. Krizaj: As in everything in life, flexibility is really the rule of the game. We should always strive to be flexible.

Interviewer: That's right.

Dr. Krizaj: And I think ourselves have figured that one out as well.

Interviewer: In terms of this treatment, what are some of the next steps?

Dr. Krizaj: We want to do the final optimization of these drugs that we're developing and then immediately go into Phase 1 clinical trials. So we formed a company which holds the intellectual property for these compounds. And we really think that there is very strong potential of actually helping people who were resistant to the current drugs.

I don't think this project would have taken off the ground if my Chair, Dr. Olson, has not discerned the potential from the very start and then basically supported it from the get go at every single step of the way. So I and my colleagues in the department are very lucky to basically be able to work in such a collaborative and nurturing environment.

Announcer: Interesting, informative, and all in the name of better health. This is The Scope Health Sciences Radio.


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