Important New Findings Reported at Vision Research Meeting
From the Foundation Fighting Blindness Newsletter
by Tom Hoglund
Science Information Manager

Each May, the Association for Research in Vision and Ophthalmology (ARVO) holds a week of meetings where basic and medical researchers present new study findings in the effort to find treatments for eye disease. Over 10,000 scientists presented over 5000 research studies. Once again, growth in retinal degenerative disease research was evident. Pharmaceutical and biotechnology companies had a much larger presence than previous years. Participation by industry is extremely encouraging. Research progress will greatly accelerate with investment from the private sector.

The following report highlights some of the most important research breakthroughs that were announced at the ARVO meeting.

Genetic research holds the key to discovering the underlying causes of vision loss. Identifying every gene that contains a diseasecausing mutation is the critical first step to understanding retinal degenerative diseases. As each mutant gene is identified, cell and molecular biologists can study how the gene normally functions in retinal cells and how a diseasecausing mutation leads to vision loss. Armed with this knowledge, scientists can develop and test experimental therapies that defeat the disease. At a meeting of The Foundation's Scientific Advisory Board, which followed ARVO, University of Texas researcher Dr. Stephen Daiger reported on the status of genetic research. Dr. Daiger, who oversees The Foundation's genetics program, noted that almost half the genes containing mutations that cause retinal degeneration are known. Due to rapid progress in genetic research, Dr. Daiger reported that most of the mutant genes causing retinal degeneration will be identified within the next three to five years.

Macular Degeneration Gene Identified
Dr. Edwin Stone, a Foundation-funded researcher from the University of Iowa, presented a study of particular importance at ARVO. Dr. Stone reported on the discovery of a mutation in a gene causing an autosomal dominant form of macular degeneration called malattia leventinese. Malattia leventinese is also known as Doyne honeycomb retinal dystrophy or dominant drusen.

Although rare, malattia leventinese closely resembles typical age-related macular degeneration (AMD). In both these diseases, yellow-white fatty deposits known as drusen accumulate beneath the macula, the center of the retina. Drusen deposits appear to interfere with the function of photoreceptor cells in the macula and lead to central vision loss.

The discovery of the malattia leventinese gene is extremely important for macular degeneration research. Scientists can now create animal models with a mutation in this gene. With an animal model of malattia leventinese, researchers can study the function of this gene and learn how a disease-causing mutation leads to the formation of drusen. This genetic discovery will lead to a much better understanding of malattia leventinese and AMD, and ultimately to treatments for these diseases.

Pharmaceutical Therapies
Apoptosis or "programmed cell death" is a genetically-controlled process that causes degenerating photoreceptor cells to die. Apoptosis is common to all retinal degenerative diseases. It is hoped that an understanding of apoptosis will lead to sight-saving drug therapies that prevent or delay photoreceptor cell death. Such treatments might offer a universal therapy for all retinal degenerative diseases.

Dr. Alan Laties, Chairman of The Foundation's Scientific Advisory Board, and Dr. Ron Wen, both of the University of Pennsylvania, are working on a promising agent that inhibits apoptosis. This substance preserves a significant number of photoreceptor cells in a rodent with a genetic mutation that causes an autosomal dominant form of retinitis pigmentosa (RP) in humans. Although further work is needed, this important finding could lead to a new sight-saving pharmaceutical therapy.

In the early 1990s, Dr. Matthew LaVail and colleagues from The Foundation's research center at the University of California, San Francisco, published pioneering work in the use of survival factors to slow the course of retinal degeneration. Survival factors are naturally occurring substances that protect photoreceptor cells from degeneration. Since publishing this groundbreaking study, survival factor research has blossomed.

This year, Dr. David Hicks and colleagues at the Hospital Center in Strasbourg, France reported that a survival factor called Glial Derived Neurotrophic Factor (GDNF) slowed photoreceptor degeneration in a rodent model. This is the first report of GDNF exhibiting sightsaving protection.

At The Foundation's Scientific Advisory Board meeting following ARVO, Dr. Paul Sieving, ViceChairman for clinical research, reported on efforts to advance a survival factor, known as Axokine, to clinical trials. Axokine is a genetically altered form of ciliary neurotrophic factor. Foundation researchers have found that Axokine slows photoreceptor cell degeneration in a variety of animal models.

Dr. Sieving reported that several Foundationsupported researchers are working with Regeneron Pharmaceuticals, the maker of Axokine, to complete the pre-clinical studies that are necessary to gain Food and Drug Administration approval to begin human clinical trials.

Gene Therapy as Drug Delivery Device
While Axokine and other survival factors show great promise, it is not yet clear how these agents will be delivered to the retina. The retina is protected from direct exposure to the blood supply, making it difficult for most drugs to reach photoreceptor cells. Therefore, survival factors cannot be delivered systemically via a pill or an intravenous injection. Presently, injection into the eye is the most effective method to deliver survival factors. Although eye injections are relatively safe, they are not the ideal way to deliver drugs.

Researchers are working to develop more effective drug delivery methods to the retina. This year at ARVO, researchers from Chiron Pharmaceuticals and the University of California at Berkeley reported stunning success using gene therapy in the delivery of a survival factor. Gene therapy is the delivery of a gene or genetic information to retinal cells to achieve a therapeutic effect.

The Chiron and Berkeley research team includes Dr. John Flannery, a member of The Foundation's Kearn Family Center in San Francisco. They used gene therapy to deliver the gene that produces the survival factor known as basic fibroblast growth factor (bFGF) to retinal cells. In addition to preserving vision in rodent models with retinal degeneration, the bFGF gene also produced this survival factor for long periods of time. Although further work is needed, gene therapy may offer a more effective, long-term drug delivery method than injection.

In a potentially groundbreaking study, Dr. Raymond Lund, Vice-Chairman of The Foundation's Scientific Advisory Board for transplantation, reported that transplanted photoreceptor cells restored vision in a rodent model with retinal degeneration. This breakthrough study establishes "proof of principle" that photoreceptor cell transplants can restore vision. This encouraging finding could re-energize the field of photoreceptor cell transplantation.

Retinal Prosthesis
Research groups from around the world are working to develop a computer chip that can restore rudimentary vision to patients with retinal degenerative diseases. Such a device, implanted on the surface of the retina, could possibly restore ambulatory vision to patients with end-stage retinal degeneration. Early experiments suggest that such an approach is feasible. However, before this high-tech visual aide can be used in humans, researchers must demonstrate that this is a device that can safely transmit meaningful images to the brain.

Several scientists presented research findings at ARVO on the design and longterm biocompatibility of a vision-producing computer chip. The Foundation also hosted a meeting for retinal prosthesis researchers to foster collaboration, exchange ideas and address future research needs.

Macular Degeneration
Dr. Peter Campochiaro, Principle Investigator of The Foundation's new research center at Johns Hopkins University, presented data on a promising new drug that prevents blood vessel growth in animal models. This drug holds promise for wet macular degeneration. Over the last few years, Dr. Eugene de Juan, also of the center, pioneered a surgical procedure for wet macular degeneration called macular translocation. This year, Dr. de Juan and several other research groups reported promising initial results with this highly experimental surgery. Dr. Martha Neuringer, a Foundation-funded researcher from the Oregon Regional Primate Research Center, presented preliminary results from nutritional studies in primates. Because primates are the only non-human species with a macula, this new research will prove extremely valuable for AMD research.

The Future
Not so long ago, Foundation researchers were alone in their mission to find treatments and cures for retinal degenerative diseases. However, this year's ARVO meeting made clear that pharmaceutical and biotechnology firms now see real opportunities to make treatments and cures a reality. Although it is difficult to predict when these experimental therapies will reach clinical trials, the question is no longer if they will reach clinical trials, but rather, how soon.
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Date last modified September 18, 1999