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Clinical Update: Glaucoma
Neuroprotection Research, Part One
Glaucoma research has evolved from a focus on the front of the eye—the so-called plumbing problems—to a focus on similarities with other neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. No longer defined simply by increased intraocular pressure, glaucoma is now also considered a problem of progressive neurodegeneration.
This new view resulted in part from the realization that the disease cannot always be arrested by IOP-lowering treatment. For about one-third of idiopathic open-angle glaucoma patients, in fact, vision slowly worsens despite the best treatment efforts of ophthalmologists.1 There is a silver lining here, however. Slow progression opens up the therapeutic window very wide—for years or even decades, according to George A. Cioffi, MD, professor of ophthalmology at Oregon Health & Science University and chairman of the Devers Eye Institute in Portland.
In this two-part series, EyeNet takes a look at how notions explored by a new generation of researchers have illuminated the potential of neuroprotection in glaucoma management.
Neuro Disease, Neuro Research
“The concept of neuroprotection for glaucoma has been around for more than a decade,” said Robert N. Weinreb, MD, director of the Hamilton Glaucoma Center and professor of ophthalmology at the University of California, San Diego. Neuroprotection is being developed as a therapeutic regimen for slowing, preventing or reversing the death of neurons following an initial insult, said Dr. Weinreb. For most patients, it is likely that it will complement IOP-lowering therapy, not replace it, he said. In some cases, however, neuroprotective agents may also become an alternative for those who can’t tolerate IOP-lowering therapy or for whom they have been ineffective.
Neuro research. David J. Calkins, PhD, associate professor of ophthalmology and visual science at Vanderbilt University in Nashville, said that making comparisons to other neurodegenerative diseases will allow researchers to better understand the optic nerve’s response to glaucoma. “Reasoning through analogy, researchers have been able to identify different components of the disease,” said Dr. Calkins.
One injured neuron looks a lot like another. Although glaucoma is not associated with cognitive or motor deficits, it is, at the cellular level, structurally comparable to other neurodegenerative processes. “Nothing is fundamentally different in glaucoma than with other neurodegenerative diseases,” said Monica L. Vetter, PhD, professor of neurobiology and anatomy at the University of Utah in Salt Lake City. “The initial triggering events are distinct, and there is clearly a different initial pathology,” she said. “But at a certain point, neurons are responding to stress, and other cell populations are recruited, and, in the cross talk between them, I think there are a lot of shared mechanisms during progression.”
Work by Drs. Calkins, Vetter and colleagues has thus far supported the notion of shared disease mechanisms among neurological disorders. For example, while identifying changes in genetic expression related to increases in IOP, researchers found that one of the most robust changes occurs in a family of genes associated with inflammation and involved in pathologies of the brain like Alzheimer’s.2
The eye as a window on the brain. Not only is Dr. Vetter hopeful that glaucoma researchers can learn a lot from diseases such as Alzheimer’s and Par-kinson’s, but she considers glaucoma an attractive reciprocal model for figuring out what’s happening temporally and spatially with neural degeneration in other diseases. “In the brain, you have a very complex architecture—neurons, axons and synapses—that is not always easily accessible,” said Dr. Vetter. “But in the eye, everything is compartmentalized in a way that’s not possible in the brain. You have a very distinct neuronal population with highly laminated tissue; the synapses are organized in discrete layers; and you have this beautiful axon bundle that exits the eye and traverses the rest of the brain.”
Strategies for Neuroprotection
One disease or several? Dr. Calkins and many other researchers consider glaucoma a multifaceted disease, or a collection of diseases. “Glaucoma can start out in one spatial region and then spread spatially and temporally,” added Dr. Vetter.
Dr. Cioffi, in contrast, describes himself “more as a lumper than a splitter. I know there are those who try to split glaucoma and glaucoma’s optic neuropathy into a half-dozen different diseases. But my bias is that there is a very characteristic optic neuropathy we know as glaucoma and that has retinal ganglion cell death.”
Glaucoma experts appear to agree, though, that glaucoma processes call forth both destructive and protective components. “There are protective cascades that are inducted in response to glaucomatous injury,” said Dr. Calkins. “The nervous system responds to the disease as though it is trying to rescue the cells from death, and so the disease takes time to finish its course.”
Block damage or boost repair. Whether glaucoma is one disease or several, there are at least two broad neuroprotective drug-development strategies. One is to try to neutralize the effects of nerve-derived toxic factors; the other would work to boost the body’s own repair mechanisms.3 Dr. Cioffi described some of the neurodynamics behind the two strategies.
Genes that help, genes that hurt. Functions of Bax gene expression are detrimental and promote cell death, while functions of the Bcl gene and nerve growth factors promote survival or enhance repair. “These offer us two approaches to neuroprotection,” said Dr. Cioffi. “We can either block cell-death promoters or enhance cell-survival signals. If we decided to enhance survival signals, do we try to turn on the cells’ innate protection systems—prompt a cell to make more nerve growth factor—or do we try to provide the end product? We could provide the retinal ganglion cells with a growth factor or other macromolecule via an intravitreal injection or sustained release system and thereby enhance survival.”
Robert W. Nickells, PhD, professor of ophthalmology and visual science at the University of Wisconsin in Madison, is focusing on the Bax gene. “We think it is a really important step in preventing apoptosis because it blocks the involvement of mitochondria,” he said. “As long as you can keep the mitochondria from becoming involved, you’ve stopped cell death before the point of no return.”
In any case, success requires that researchers understand the basic biology first, said Dr. Vetter, so they know which pathways are involved. “It may require—just as with HIV or cancer treatment—that you’ve got to hit multiple pathways,” she said. “That’s manageable if we can come up with a reasonable model.”
Dying little deaths. One challenge is that the compartments of the retinal ganglion cell—the axon, synapse, dendrites and cell body—can die independently, said Dr. Nickells.4 “Each compartment has its own molecular program it can turn on that doesn’t require the previous deaths of other compartments,” said Dr. Nickells, adding that this may require agents to address the deaths of all these different compartments.
Is a silver bullet then out of the question? It probably is, according to Dr. Calkins, who argued that multiple sequential or simultaneous interventions are a more likely scenario, particularly when the disease is not caught early.
Where Best to Intervene
The response to IOP elevation and the factors promoting disease progression may be very different processes, said Dr. Vetter. She and other researchers are focused on early and middle stages of the disease.
First stop, nerve head. Dr. Cioffi suggested that focusing on early initiating events will prove most productive. “We’ve gotten better in recent years at being more sensitive to early functional and structural changes—better visual field tests for function and better ways of looking at the optic nerve and nerve fibers structurally—and so we’re picking up problems earlier and earlier,” said Dr. Cioffi. “I think we’ll learn a lot more by looking at models that mimic early disease as opposed to models that mimic late blown-out terrible disease. I believe the initial insult is at the optic nerve head and, therefore, it’s more fruitful to go after the axon.”
Downstream damage. In addition to the primary insult, however, a secondary cascade of events can cause death of retinal ganglion cells. Transsynaptic degeneration may act like dominoes, toppling connected neurons one after another. That might explain why IOP-lowering medications are sometimes ineffective in preventing progression.5
The immune system: hero or hellion? “I think that a lot of recent research has shown that neural inflammation plays a really critical role in how the neurons respond,” said Dr. Nickells. A student of Dr. Nickells’ has shown how macrophages can stimulate and help ganglion cells.
“There are resident surveillance macrophage-like cells called microglia in the nervous system,” explained Dr. Vetter. “They act very locally in terms of detecting damage and changes in the nervous system. We think that these are playing an important role at that juncture. They may not be the triggering step, but I actually think they do play an important role in this progression.”
Dr. Weinreb is a consultant for Alcon, Allergan, Merck and Pfizer. The other experts report no related financial interests.
2 Steele, M. R. et al. Invest Ophthalmol Vis Sci 2006;47:977–985.
3 Ritch, R. Can J Ophthalmol 2007;42(3):425–438.
4 Nickells, R. W. Can J Ophthalmol 2007;42(2):278–287.
5 Weinreb, R. N. Can J Ophthalmol 2007;42(3):396–398.