Last month EyeNet began a two-part examination of new theories in glaucoma pathogenesis and treatment. This month we look at the specifics of neuroprotective agents, as researchers face many opportunities—and many questions: Will the ideal intervention involve sequential or simultaneous therapies? Will treatments be easy for patients to use? Will they address mechanisms specific to retinal ganglion cells? Will they avoid inflammatory responses?
Challenges of Drug Development
Approved only for lowering intraocular pressure, today’s glaucoma medications may also have neuroprotective properties, but none has definitively demonstrated that in humans. Neuroprotection was simply not a part of their initial therapeutic rationale or their subsequent approval by the FDA, said Robert N. Weinreb, MD, director of the Hamilton Glaucoma Center and professor of ophthalmology at the University of California, San Diego. Because each IOP-lowering medication has distinct biological properties, it is difficult to know how or whether they also provide neuroprotection independent of their IOP effects. One such medication, brimonidine, has been under study to answer that question, but results are not yet available.
As agents are reviewed for their neuroprotective properties, noted Dr. Weinreb, some criteria must be considered:
- Does the drug have a specific receptor target in the retinal nerve cells or the optic nerve?
- Does activation of the drug’s targets trigger pathways that enhance neuronal survival or decrease neuronal damage in animal models?
- Can it actually reach the retina or optic nerve in pharmacologically effective concentrations?
- Has neuroprotection been demonstrated in an appropriately designed clinical trial—a randomized, controlled study in patients?
A number of agents have been tested in the lab and have demonstrated potential for clinical neuroprotection, said Dr. Weinreb. In cell culture models, many have enhanced the viability of cultured retinal ganglion cells. And in experimental models, a significant number of drugs have demonstrated neuroprotective properties.
Clinical trials. But the last criterion—human trials—is an incredibly expensive hurdle, said George A. Cioffi, MD, professor of ophthalmology at Oregon Health & Science University and chairman of the Devers Eye Institute in Portland. There are two reasons why.
1. Study size and duration. Glaucoma is a very slowly progressing disease. At birth, the human eye has approximately one million retinal ganglion cells and optic nerve fibers, and it is estimated that healthy individuals lose fewer than 20 cells per day, said Dr. Weinreb. With glaucoma, that loss multiplies severalfold but still is not always noticeable, he said. Therefore, progressive glaucomatous injury is difficult to detect, and clinical trials must then be lengthy and enroll many patients.
2. Definition of study endpoints. Study goals remain problematic, said Dr. Weinreb, because regulatory agencies equate glaucoma progression with standard visual field loss. Thus far, they have not permitted a surrogate to serve as an endpoint, he said, such as a selective functional test or change in the optic disc or retinal nerve fiber. Dr. Cioffi believes this will change as researchers get better at detecting structural and functional changes. “As we convince regulatory agencies that these are good barometers of disease, we’ll be able to test drugs much faster,” he said.
Memantine: The first neuroprotector? One glutamate receptor antagonist, memantine, is a good example of these challenges. Approved by the FDA in 2003 to treat Alzheimer’s disease, it is the only drug demonstrating glaucoma neuroprotection in primates. In monkeys, it protected against optic nerve fiber loss, neuronal shrinkage within the central visual pathway and visual function loss.1 These results may be due to its ability to mitigate excitotoxicity and the release of excess glutamate into the extracellular space, which causes ganglion cells to die by apoptosis from secondary damage.2
Human trials of memantine for open-angle glaucoma have produced confusing and disappointing results. Progression of disease in studies last year appeared to be lower in patients receiving the higher dose of the drug compared to those receiving a low dose. But in January Allergan announced that final analysis of a memantine phase 3 trial revealed that overall the drug did not perform any better than a placebo.
Despite these inconclusive results, Dr. Cioffi remains optimistic about the memantine trials. “Going into such studies we don’t know if we are testing the right drug, but we’re going to learn something from each trial, including the memantine trial,” he said, pointing to the large number of patients—2,000—who were followed for four years with state-of-the-art structure and function measures. “That’s a huge step for us in glaucoma,” he added. “It sets the stage and teaches us how to do these things better in the future.”
New Theories, New Targets
In the past few years, researchers have begun to formulate new theories about the role of neurodegeneration in glaucoma. Some of the most exciting work has focused on three ideas, best encapsulated as axonal degeneration, gliosis and pressure injury.
1. Axonal degeneration. A precursor to eventual vision loss, changes begin to occur months or even years before retinal nerve cells die. Retinal ganglion cells (RGCs) sample the microenvironment of the brain via the axon. However, the transport machinery used to bring nourishment from the brain to the RGCs becomes dysfunctional—long before the cells die—as first shown by the lab of Donald J. Zack, MD, PhD, at Johns Hopkins University.4 The axon also provides the functional connection that allows the retina to communicate with the brain. So if the axon becomes damaged, the retina cannot send visual information to the brain, even if the RGC is still alive, explained Monica L. Vetter, PhD, professor of neurobiology and anatomy at the University of Utah in Salt Lake City.
Researchers have also discovered that deficits in transport have early, middle and late-stage components. “This allows researchers to break down the progression and home in on particular models involved in each stage,” said David J. Calkins, PhD, associate professor of ophthalmology and visual science at Vanderbilt University in Nashville.
The drug minocycline has been shown to improve retrograde transport and morphology of the optic nerve. If delivered at stages well before evidence of disease, it can suppress activation of microglia, said Dr. Vetter. This shows that axonal changes are coupled with activation of microglia. “We wanted to capture this window before microglia get activated and cranky,” she said, acknowledging that the picture is considerably more complex than this, likely involving many cellular players.
2. Gliosis. Dr. Calkins added that recent research continues to unearth the multiple roles of glial cells—both at the onset and in the progression of the disease. Thought of in the past as only support cells for the neurons, glial cells have begun to earn greater respect in recent years. For example, researchers have found that, in response to pressure at the optic head, glial cells release proteins that may be toxic to neurons. In fact, changes in glial cells are the earliest known event in the progression of glaucoma, happening well before vision loss occurs. This makes them another potential therapeutic target.4
Two other main models exist for how glial changes affect RGCs, said Robert W. Nickells, PhD, professor of ophthalmology and visual science at the University of Wisconsin in Madison. “Cells may pump out neuropeptides that affect vascular flow, creating a kind of microischemic event at the optic nerve head,” he said. “Or the cells themselves may become stressed, losing their ability to accommodate the axons they’re surrounding.”
In any event, some of the first changes that can be seen in the level of gene expression or morphology are glial changes, said Dr. Vetter. In early stages of the mouse model, she said, there are changes in gene expression, where you can start to see axonal changes. There is clear optic nerve pathology, but the retinal ganglion cells are still there until late in the game. Studies by the lab of Philip J. Horner, MD, at the University of Washington in Seattle, document that the ganglion cells persist for a long time, detectable by the expression of a general neuronal marker.5 “There is still the potential for rescue because the cells are simply quiescent or atrophied—not gone,” said Dr. Vetter. In addition to other factors, loss of neurotrophic support may eventually contribute to cell body death. “But apoptosis is not the driving force for quite a while in this disease,” she added.
3. Pressure injury. Designed to sense pressure, a family of molecules called mechanicoreceptors is located throughout the brain and retina. These molecules might allow cells in the retina and optic nerve to respond directly to ocular pressure. “This could be similar to how neurons in the spinal cord respond to pressure from walking, sitting and keeping balance,” said Dr. Calkins. Pressure injury may overload the cells with calcium, which can cause a direct degenerative cascade, he said. Researchers suggest that the molecules sensing pressure might be the factor translating pressure into neuronal damage. If so, blocking the pressure-sensitive calcium channel might restore contact with the brain.
Dr. Vetter and other researchers express excitement about these and other theories concerning glaucoma and neuroprotection. “We do feel that we’ve learned enough to have some candidate pathways to target, and we’re hopeful that in the next couple of years we’ll be able to figure out—along with a number of other excellent labs—which ones are responding.”
Dr. Weinreb is a consultant for Alcon, Allergan, Merck and Pfizer. The other experts report no related financial interests.
1 Hare, S. et al. Invest Ophthalmol Vis Sci
2 Nickells, R. W. Can J Ophthalmol
4 Pease, M. E. et al. Invest Ophthalmol Vis Sci
5 Buckingham, B. P. et al. Progressive Ganglion Cell Degeneration Precedes Neuronal Loss in a Mouse Model of Glaucoma. J Neurosci
2008, in press.
Glaucoma Research Foundation
The valuable work of three of the re-searchers interviewed for this two-part story, Drs. Vetter, Calkins and Horner, as well as researcher Nicholas Marsh-Armstrong, PhD, who contributed the images, is sponsored by the Glaucoma Research Foundation. For more information, visit www.glaucoma.org.