Glaucoma Research Foundation

Catalyst For a Cure Phase Two Completed

The year 2008 marked in many ways a turning point for the Catalyst for a Cure. Completed work from the end of the second phase (2005-2007) found its way into key publications, while new work building from the second phase was begun. Of note were two papers in the Journal of Neuroscience. These described early changes in glaucoma associated with the neurochemistry of the retina and optic nerve and the persistence of retinal neurons long after those changes occur. Papers in Investigative Ophthalmology and Visual Science described how silencing the immune system in glaucoma can increase survival of the optic nerve and the use of magnetic resonance imaging to track disease progression. Finally, in another study in Investigative Ophthalmology and Visual Science, CFC investigators linked a potentially protective signal from retinal cells to a special pressure sensor that could be activated in glaucoma. These and other results were presented as part of a larger showcase of findings at the 2008 Vanderbilt Eye Institute Symposium “Neurodegeneration in Glaucoma: from Mechanisms to New Treatments”. The symposium, which was sponsored in part by the Glaucoma Research Foundation, brought together glaucoma researchers and physicians from all over the United States and Canada to share their latest investigations and novel ideas.

CFC Research Featured in Major Vision Publication

The article featured on the cover of the September, 2006 edition of vision research magazine IOVS (Investigative Ophthalmology & Visual Science) is authored by Rebecca M. Sappington, PhD, and David J. Calkins, PhD, of the GRF-funded Catalyst For a Cure (CFC) research consortium. Drs. Calkins and Sappington provided the following summary of their published findings:

In glaucoma, the response of astrocytes and microglia is generally associated with negative effects on retinal ganglion cells (RGCs). Recent work by the Catalyst For a Cure (CFC) research consortium demonstrates that microglia may actually protect RGCs from death. In a recently published paper, the CFC researchers identified interleukin-6 (IL-6) as an important factor released by microglia that can significantly reduce RGC death caused by elevated pressure. In a second newly published paper, the CFC researchers demonstrate that pressure-induced production and release of IL-6 by microglia occurs via cellular mechanisms that also underlie IL-6 production in other neurological insults and diseases. CFC studies support the notion that as a neurodegenerative disease, glaucoma shares common disease mechanisms and characteristics with other neurological injuries and disorders. In particular, the CFC has identified both IL-6 and microglia as potential targets for therapeutics aimed at promoting health and survival in glaucoma.

Three New Hypotheses Reported by Catalyst For a Cure Researchers

In December 2005, the Catalyst For a Cure (CFC) research team reported the development of three new hypotheses for how glaucoma is initiated and where new therapeutic targets can be found.

The first theory is derived from a fascinating event that occurs months or even years before nerve cells die in the retina. During the lifespan of a neuron, it continuously samples the microenvironment of its distal connections. In the case of a Retinal Ganglion Cell (RGC), this means that the cell is sampling the microenvironment of the brain by its longest process called the axon. It appears that the transport machinery or highway that RGCs use to bring neurotrophins — “food” really — back from the brain becomes dysfunctional early in the disease long before the RGC cell dies.

The second hypothesis is based on two primary observations. The CFC has found that there are distinct changes in the structure and functional state of glial cells in the glaucomatous retina. Glial cells get their name as a type of support cell or glue for the neurons, but until recently glial cells have not been adequately studied. The CFC has made an important finding that glial cells react very early in the progression of glaucoma. The most exciting aspect of these data is that changes in glial cells appear to be the earliest event reported in the progression of glaucoma occurring well before neuronal loss or even vision begins to decline.

The final favored hypothesis is based on a family of molecules that have been discovered in the last 10 years and their genes are just being discovered. The molecules are called mechanical receptors and are located throughout the brain and retina and represent a complex family of molecules. Although they have an as yet unknown function in the brain, their presence in the retina has obvious implications for a disorder where pressure is clearly a cofactor. Until this observation, the general concept was that pressure simply compressed the retina making it sick. These observations could provide a more specific mechanism for pressure-induced damage in the retina and, hence, one that could be specifically blocked therapeutically.

Catalyst For a Cure scientists present initial findings at major research meeting

In May 2005, Scientists from the Catalyst For a Cure (CFC) collaborative research program presented initial findings at the Association for Research in Vision and Ophthalmology (ARVO) annual meeting in Ft. Lauderdale, Florida. ARVO is the world’s largest research meeting devoted specifically to vision research with more than 11,000 attendees from all fields of vision research. The CFC scientists presented their work in seven different sessions where they were well received by their colleagues in the quest for a cure for glaucoma.

Monica Vetter, PhD, CFC principal investigator from the University of Utah, said, “Since our long-term goal is to develop strategies for preventing vision loss in glaucoma, it is essential to understand the molecular changes associated with glaucoma, especially at early stages of the disease.” Her enthusiastically received poster and lecture presented the first results of the CFC study comparing gene profiles during the development of glaucoma. According to Dr. Vetter, “We found consistent changes in immune response genes at an early stage of the disease, as well as evidence of changes in retinal glia, suggesting molecular pathways that could be targeted for intervention.”

January, 2005 – Nearly $1 Million in grants affirms GRF's commitment to innovative research

Grants totaling nearly $1 million were awarded in January 2005 by the Glaucoma Research Foundation, officially launching the second three-year cycle of its innovative Catalyst For a Cure (CFC) collaboration of laboratories at Johns Hopkins University, Universities of Utah and Washington, and Vanderbilt University; and funding six Pilot Projects at Cambridge University, Johns Hopkins University, W. K. Kellogg Eye Center, and the Universities of Iowa, Michigan and Wisconsin. GRF is dedicated to providing funding for cutting-edge research to improve glaucoma treatment and potentially find a cure.

December, 2004 - Catalyst For a Cure investigators report on progress

The four principal investigators in the Catalyst For a Cure (CFC) team reported third year results from their collaborative research at the 2004 CFC Dinner and Report to Donors in San Francisco. The event marked the completion of the first 3-year phase of the CFC research consortium. The scientists reported their findings and talked about the direction their research would take in the next 3-year phase, 2005 to 2007.

David Calkins, PhD, principal investigator from Vanderbilt University, emphasized that their research results indicated glaucoma is not a disease of the eye, but a disease of the central nervous system. “Glaucoma bears striking similarities to diseases such as Alzheimer’s, Parkinson’s, Lou Gehrig’s disease, and Huntington’s disease,” Dr. Calkins said. “We think it is those similarities that are going to lead us through the next three years in our search for therapeutic targets for glaucoma.”

December, 2003 – Catalyst For a Cure scientists report second-year results

Catalyst For a Cure researchers met in San Francisco to report on the results of their second year of investigations. The four scientists reported the establishment of a glaucoma model that will enable tracking the genetic changes that occur as glaucoma progresses. They also developed techniques for isolating genetic material for analysis. The researchers have created core capabilities at each research site to identify the genes responsible for the progression of glaucoma. Using gene chip technology, the CFC team verified their process for isolating and identifying genes that may play a key role in glaucoma.

2003 – Catalyst For a Cure scientists identify key targets for glaucoma research

In the first year of the Catalyst For a Cure consortium, the four principal researchers collaboratively identified important avenues for glaucoma, researched, hired and trained necessary laboratory personnel, mastered new techniques, and delivered important preliminary results.

Four key targets were established as research objectives to be tackled collaboratively:

• Study the body’s innate repair response to glaucoma in order to determine if stem cells found in the eye can be manipulated to improve the repair process and thus slow down the disease.

• Screen for molecular changes during glaucoma progression. Using this approach, complex changes in proteins that hinder the ability of eye cells to function can be revealed and targeted for therapy.

• Create a resource of tools and information that will allow researchers to move more quickly in discovering the cause and potential treatments for glaucoma. Specifically, CFC investigators will identify new genes that are uniquely found in retinal ganglion cells which progressively die in the glaucoma patient.

• Analyze the interaction between retinal ganglion cells and their surrounding support cells, called glia.

2002 - Catalyst For a Cure (CFC) collaborative research program commences

The first 3-year phase of the Catalyst For a Cure research consortium commenced in 2002. Jointly funded by the Steven and Michele Kirsch Foundation and the Glaucoma Research Foundation, the four principal CFC scientists aim to use recent breakthroughs in neuroscience, molecular biology, genetics and immunology to speed progress of treatment and a possible cure for glaucoma.

According to Dr. Martin Wax, member of the CFC advisory board, “The CFC initiative is doing something nearly unprecedented in the field of medical research. It provides research funding to young, bright scientific minds based solely on their desire and ability to apply their scientific skills to the study of a specific disorder with which they were previously unfamiliar; in this case, glaucoma.”

2001 – Compound found to protect optic nerve

Researchers at the Weizmann Institute of Science in Rehovot, Israel, conducted a study demonstrating that vaccination with a compound normally used to treat multiple sclerosis may be able to protect the optic nerve. Professor Michal Schwartz of the Weizmann Institute’s Neurobiology Department led this research.

The synthetic compound Copaxone was found to have the ability to protect the optic nerve from the effects of toxic levels of glutamate that can be produced as a result of cell death from high intraocular pressures.

These results indicate that vaccination with Copaxone may some day be a viable treatment for people with glaucoma. Since Copaxone is already approved by the FDA, scientists are hopeful human trials can begin soon.