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Catalyst For a Cure 2007 Progress Report

For the Catalyst For a Cure (CFC) consortium, the year 2007 marked a significant transition in terms of developing a further understanding of the early mechanisms involved in glaucoma and in testing interventions that target these mechanisms.

Retinal Ganglion Cells: Not Dead Yet

Through the last few years, our view of glaucoma has been slowly transforming due to studies by the CFC as well other investigators. The CFC made the fundamental discovery a few years ago that the retinal ganglion cells are alive long after most people assumed them gone.

What we discovered was that retinal ganglion cells lose essential functions long before they die. For example, they lose the ability to carry transported material both to and back from the brain long before they disappear from the retina.

This means we may have a unique window of opportunity to boost their function before it is too late. Look for these results in a new Journal of Neuroscience paper to appear in early 2008.

Understanding Early Molecular Changes

In 2007, we expanded our studies to determine how and why retinal ganglion cells lose function. We have discovered that the retinal ganglion cells change early and slowly in a process that makes the cells atrophy, both in size and in the expression of key functional genes required to maintain their connection to the brain.

Even though the nerves look intact early in the disease, we now know they already show reduced function. We also have evidence that this process likely involves oxidative damage. We tested a dietary means to reduce this oxidative damage and found that antioxidants may have helpful effects in promoting cell survival in the retina.

Altogether, these early and progressive changes make ganglion cells susceptible to stressors that are normally well tolerated by healthy ganglion cells. To make the situation worse, once large groups of retinal ganglion cells have lost their connection to the brain, this appears to be an additional stress that promotes the rapid spread of the disease from focal regions to other sectors of the retina.

The good news is that we now know a great deal about the cells and molecules underlying these insidious changes and are developing strategies to prevent them. Our first results from this investigation are now published in the Journal of Neuroscience (January 9, 2008, 28(2):548-561).

Microglia Cells are Important in Glaucoma

The fate of ganglion cells is also controlled by other cells within the retina. The nervous system, including the retina, is thought to be the only place in the body that is not subject to surveillance by the immune system. To search for and deal with signs of trouble, the nervous system uses special cells named microglia. Recent evidence suggests that, while microglia are usually beneficial, in diseases of the nervous system they often end up doing more harm than good.

The molecular profile of glaucoma that the CFC published in 2006 had strongly hinted that microglia might be important players in glaucoma. This year the CFC obtained strong evidence that microglia are involved both early in the disease, perhaps contributing to the slow progressive atrophy of retinal ganglion cells, as well as late in the disease, perhaps mediating the spread of the disease from focal to widespread.

Needless to say, we viewed microglia as an important therapeutic target. To test this in 2007, we inhibited microglia activity using a specific drug that had been tested in other diseases of the brain. We found that not only was this drug effective in partially inhibiting microglia in the retina, but that by doing so we could promote a healthier connection between retinal ganglion cells and the brain.

The exciting results from this study, which will be published in 2008 in Investigative Ophthalmology and Visual Science, are encouraging us to find even better drugs and tools to block the damaging effects of microglia.

Blocking Pressure Receptor Protects Ganglion Cells

Another area of great promise that the CFC had focused on in the past was in identifying the molecules that allow retinal ganglion cells and other cells within the retina to sense pressure. Previously, the CFC had shown that blocking these specific receptor molecules could protect isolated retinal ganglion cells from high amounts of pressure.

Using a novel model of glaucoma created by the CFC that will accelerate the testing of future interventions, the CFC now has evidence that blocking these receptors can also be effective at blocking the deleterious effects of pressure in this animal model. While additional studies are needed in additional animal models before it could be tested in humans, we are sufficiently excited about this prospect that the CFC has filed a patent application to facilitate development of drugs that come out of these studies.

A Greater Understanding of Glaucoma

In this past year the CFC team has seen the completion of several important studies including our first interventional trials. These brought initial validation of several of the hypotheses that we proposed in 2006 and even earlier. In addition, we have generated new findings and new tools, many of which offer promise for therapeutic interventions. Perhaps the most important thing that occurred to the CFC team in 2007 was getting to a point where we have a clear working model for what goes wrong in glaucoma and why. The challenge now for us is to continue to test these ideas and initiate interventions in our final phase that will bring us closer to success in our fight against this devastating disease.

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The Catalyst For a Cure Principal Investigators are: David Calkins, PhD (Vanderbilt University), Philip Horner, PhD (University of Washington), Nicholas Marsh-Armstrong, PhD (Johns Hopkins University), and Monica Vetter, PhD (University of Utah).

Last reviewed on March 07, 2011

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