RP Research 1999 Year End Review
From the Foundation Fighting Blindness Newsletter
by Gerald J Chader, PhD, MD.hc
Chief Scientific Officer


Contents
Genetics
Cell Biology
Pharmaceutiacal Therapies
Gene Therapy
Transplantation
Macular Translocation Surgery
Retinal Prosthesis
Research Centers
The Future

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As Chief Scientific Officer of The Foundation Fighting Blindness, my job is to plan and manage a continually evolving research program that will advance promising experimental treatments to clinical trials. With the focus on future research, sometimes even recent scientific accomplishments all too quickly become passe However, breakthroughs should be celebrated and savored. Each advance forms a helpful new stepping-stone along the path leading to treatments and cures. As you'll see from this report, researchers placed many new stepping-stones in 1999.

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Genetics

Genetic research is the bedrock foundation of retinal degenerative disease research. In order to develop effective treatments, we must understand how a healthy gene normally functions in retinal cells and how a genetic mutation leads to vision loss. Each new genetic discovery adds a sturdy footing to support the development of treatments and cures. This past year, scientists identified several new genes causing retinal degeneration.

In June 1999, Foundation researcher, Dr. Edwin Stone of the University of Iowa found a gene with mutations causing a rare form of macular degeneration called malattia leventinese. Although rare, malattia leventinese resembles age-related macular degeneration. In both these diseases, yellow-white fatty deposits called drusen accumulate beneath the macula. Drusen deposits interfere with the function of photoreceptor cells in the macula, causing central vision loss. The discovery of this gene allows researchers to learn how a disease-causing mutation leads to the formation of drusen.

This past year, Foundation-supported researchers also discovered three new genes with mutations causing RP. In August 1999, researchers from Denmark, Germany and the Netherlands identified mutations in a gene causing an X-linked form of retinitis pigmentosa known as RP2. X-linked RP is among the most severe forms of retinal degeneration. In April and July 1999, Foundation researchers also found two new genes each causing autosomal dominant forms of RP.

In reviewing this past year's progress it is apparent that the pace of genetic research is advancing so rapidly that we can now see an end to our genetic hunt. At a recent meeting of The Foundation's Scientific Advisory Board, Dr. Steven Daiger from the University of Texas reported that most every mutant gene causing retinal degeneration will be identified within the next three to five years!

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Cell Biology

As geneticists find the genes that cause retinal degeneration, cell biologists can begin to study their function in retinal cells. This year, Foundation researcher Dr. Gabriel Travis of the University of Texas Southwestern Medical Center developed a mouse model of Stargardt disease. The Stargardt mouse has a mutation in the ABCR gene that mimics the human form of this disease.

Dr. Travis and his colleague, Dr. David Birch of the Retina Foundation of the Southwest in Dallas, found that these mice had abnormally large accumulations of fatty deposits called lipofuscin. Lipofuscin deposits are thought to be toxic to retinal cells and may well be the cause of vision loss in Stargardt disease and other forms of macular degeneration. Drs. Travis and Birch also observed that ABCR mice reared in dark environments had virtually no accumulation of lipofuscin. This important finding could mean that patients with Stargardt disease might slow the progression of vision loss by wearing sunglasses and avoiding exposure to bright light.

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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 sightsaving 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, recently uncovered an agent that inhibits apoptosis. This substance preserved 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 sightsaving pharmaceutical therapy.

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

In October, a research group led by Dr. Jose Sahel, also from Louis Pasteur University, substantially slowed vision loss in a rodent model with a rare form of retinitis pigmentosa (RP) using a commonly prescribed heart medication called diltiazem. This study represents the first time vision researchers have successfully used gene-based pharmaceutical therapy to slow the course of retinal degeneration. Gene-based pharmaceutical therapy exploits the knowledge gained from studying how a mutant gene causes cellular dysfunction and vision loss. With this knowledge, researchers can test drugs that overcome the disease process.

In this case, diltiazem, a calcium-channel blocker, was used to address a rare gene defect (beta PDE) that disrupts the photoreceptor cell's ability to traffic calcium. Researchers are applying this similar technique to other genes with mutations that cause retinal degeneration.

As you can see from this list of discoveries, 1999 was a banner year for pharmaceutical therapy research. Researchers are currently testing the safety and effectiveness of these drugs in order to gain Food and Drug Administration approval for clinical trials.

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Gene Therapy as a Drug Delivery Device

Most drugs cannot reach the retina through systemic administration. Researchers are currently working to develop effective drug delivery methods to the retina. This year, researchers from Chiron pharmaceuticals and the University of California at Berkeley reported success using gene therapy to deliver a survival factor to the retina. 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 used gene therapy to deliver the gene that produces the survival factor known as basic fibroblast growth factor (bFGF) to retinal cells. The bFGF gene produced this survival factor for long periods of time and thereby markedly preserved vision in a rodent model with RP. Although further work is needed, gene therapy should offer a more effective, long-term drug delivery method than pills or injections. Chiron Pharmaceuticals' participation is another welcome sign that industry is devoting considerable resources to the study of retinal degenerative disease.

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Transplantation

This year, an encouraging finding could reenergize the field of photoreceptor cell transplantation. Despite considerable effort, previous research studies had not found evidence that photoreceptor cell transplants could form nerve connections with the host retina to restore lost vision.

However, in a potentially groundbreaking study, Dr. Raymond Lund, Vice-Chairman of the The Foundation's Scientific Advisory Board and program leader of The Foundation's transplantation program, found that transplanted photoreceptor cells restored vision in a rodent model with retinal degeneration. This breakthrough study established "proof of principle" that photoreceptor cell transplants may ultimately restore lost vision in humans.

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Macular Translocation Surgery

With Foundation support, Dr. Eugene de Juan of Johns Hopkins University is conducting preliminary studies to test the safety and efficacy of macular translocation surgery, a highly experimental surgical procedure for the wet form of age-related macular degeneration (AMD). By partially detaching the retina and then relocating the macula away from the area of abnormal blood vessel growth, Dr. de Juan hopes to preserve, and in some cases possibly restore, central vision to patients in the early stages of the disease. If preliminary results prove promising, Dr. de Juan plans to launch full-scale clinical trials.

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Retinal Prosthesis

Vision researchers are working to develop a computer chip that can restore rudimentary vision to patients with retinal degenerative diseases. Implanted on the surface of the retina or in the visual cortex of the brain, the computer chip would receive visual information transmitted from a camera mounted on a pair of glasses. Early experiments suggest that such an approach is feasible.
Before this device can be tested in humans, researchers must overcome long-term biocompatibility issues and develop a safe and reliable power supply for the computer chip. Nonetheless, retinal prosthesis research is now reaching critical mass. This year, several new academic research groups presented study results at scientific meetings. The Foundation recently sent a delegation to meet with German researchers to plan and coordinate future clinical trials.

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Research Centers

Research centers are an integral part of The Foundation's scientific program. Research centers allow talented laboratory scientists and clinicians from many different disciplines to share ideas, pursue new directions, and collaborate on research. Research centers also possess the necessary clinical and laboratory capabilities to conduct clinical trials. As promising experimental therapies near clinical trials, the need to fund additional research centers becomes more critical.

Recently, The Foundation appointed a blue ribbon panel of distinguished scientists to review its research programs. The panel recommended that additional research centers be established. The panel also recommended that in some cases, The Foundation create centers without walls, uniting scientists with complimentary talents from different universities and cities. Acting on the panel's recommendations, The Foundation reviewed grant applications from over a dozen leading research institutions. In July, five new centers were funded. They are:
The Emory University Research Center for the Study of Inherited Retinal Degenerations in Atlanta, Georgia.

The Center for Macular Degeneration and Allied Retinal Disorders at the University of Iowa in Iowa City, Iowa.

The Wilmer Center for the Study of Retinal Degenerations and AMD at Johns Hopkins University in Baltimore, Maryland.

The Pre-clinical Medical Therapy Center at Cornell University, Duke University and North Carolina State University.

The FFB Southwest Regional Center at the University of Oklahoma Health Sciences Center, the Retina Foundation of the Southwest in Dallas, the University of Texas Southwestern Medical Center in Houston, and the University of Texas Health Science Center in Dallas.

With these five new centers, The Foundation now supports 18 research centers around the world.

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The Future

The Foundation has laid a solid scientific base upon which pharmaceutical and biotechnology firms can now build retinal degeneration research programs. With help from industry, promising experimental therapies can now advance to clinical trials. As a scientist who has devoted his career to finding treatments and cures for retinal degenerative diseases, it is exciting to catch glimpses of a near future filled with clinical trials.

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Date last modified March 12, 2000