RP Research 1998 Year End Review
From the Foundation Fighting Blindness Newsletter
by Gerald J Chader, PhD, MD.hc
Chief Scientific Officer

Contents
Genetics
Gene Therapy
RPE Cell Transplant
Photoceptor Cell Transplants
Pharmaceutical Therapies
Summary

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This past year, I was continually struck by the explosive growth in retinal degenerative disease research. For instance, in February over 40 of the world's leading researchers in gene therapy and related fields attended a gene therapy workshop sponsored by The Foundation. Just a few short years ago, there were only a handful of scientists applying gene therapy to retinal degeneration.

In May, I needed running shoes just to keep pace with all the scientific papers presented at the Association for Research in Vision and Ophthalmology meeting held in Fort Lauderdale. This meeting made clear that legions of researchers have now joined the small cadre of Foundation scientists who first pioneered genetics and gene therapy, retinal cell transplantation and pharmaceutical therapies.

In June, The Foundation and The Wilmer Ophthalmological Institute at Johns Hopkins Medical School sponsored the first-ever international scientific symposium on age- related macular degeneration (AMD). The auditorium was packed with over 650 scientists and clinicians. Attendance for this three day meeting far exceeded anyone's expectations and underscored the increased research attention retinal degenerative diseases are now receiving.

With this increased research effort, breakthroughs are now occurring at an ever faster rate. In just twelve short months, geneticists identified several new genes causing various forms of retinitis pigmentosa (RP), macular degeneration, Leber congenital amaurosis and cone-rod dystrophy. Meanwhile, gene therapy researchers made several stunning advances, bringing us closer to clinical trials and making the hunt for disease- causing genes ever more urgent. There were also several reports ot promising new pharmaceutical agents that show potential to slow the progression of disease. On the nutritional front, Foundation researchers are testing whether a fatty acid called DHA can slow the progression of X-linked RP. In short, there are so many advances to report and so little space that I must confine my comments to the major accomplishments for each of The Foundation's research programs.

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Genetics


Conducting vision research can be like piecing together an intricate jigsaw puzzle. Sometimes scientists find missing puzzle pieces that add astonishing clarity to our understanding of retinal degeneration. This past year, Foundation researchers found an extremely important puzzle piece called the ABCR gene.

In 1997, researchers first identified mutations in the ABCR gene causing Stargardt disease, the most common early onset form of macular degeneration. Then, in January 1998, researchers identified a mutation in the ABCR gene causing an autosomal recessive form of RP. Most recently, scientists have been studying whether additional alterations in the ABCR gene are associated with AMD.

The ABCR gene is a very important discovery. That different mutations in the same gene cause either macular degeneration or RP further undermines the outdated notion that retinal degenerative diseases require separate research efforts. The ABCR gene is now the third gene Foundation researchers have identified that can contain mutations causing different retinal degenerative diseases.

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Gene Therapy


Although gene therapy has delayed retinal degeneration in an animal model, further progress toward clinical trials has been hampered by the lack of safe and effective gene delivery systems. In the past year, a new generation of gene delivery systems has shown great promise. In discusslons with several of our genetics grantees, we began to wonder just how soon gene therapy might gain FDA approval for clinical trials.

To answer this question, The Foundation held a workshop to assess gene therapy research for retinal degenerative diseases During the workshop, Dr. William Hauswirth a Foundation-funded grantee from the University of Florida, reported that ribozyme therapy, a form of gene therapy specifically for autosomal dominant diseases, dramatically halted vision loss in a rodent with the most common form of dominant RP. If ribozyme therapy proves safe and effective in larger animal models, Dr. Hauswirth will seek FDA approval for phase 1 clinical trials.

We were also very fortunate to have Dr Philip Noguchi, the FDA's Director for Cellular and Gene Therapies, in attendance. After reviewing all of the research presented at the meeting, Dr. Noguchi gave a very favorable regulatory assessment of current efforts. This vote of confidence was extremely important, as the FDA must grant approval to test gene therapy in humans. While there's still more work to be completed before clinical trials can begin, gene therapy is on the right track and advancing rapidly.

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RPE Cell Transplants


Animal model studies suggest that transplanting retinal pigment epithelial (RPE) cells, which support the function of photoreceptor cells, may halt or slow further vision loss. These promising studies spurred surgeons to test the safety of this transplant procedure in humans. News reports of these experimental transplants generated considerable excitement. While we are all hopeful this treatment will one day safely prevent vision loss, in these initial experiments patients have commonly experienced immune responses from the donor RPE cells. This past year, The Foundation funded new research studies to better understand and overcome immune complications. With better control of immune responses, researchers hope to evaluate the effectiveness of RPE transplants in a safe manner.

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Photoreceptor Cell Transplants


Photoreceptor cell transplants, which are intended to restore vision, have also been tested in humans. The good news is that the procedure appears safe. Transplanted photoreceptor cells do not seem to trigger immune responses. However, there is not yet any evidence that transplanted photoreceptor cells connect with the host retina to restore vision. Clearly, additional laboratory work is needed to establish proof of principle for this treatment. We must refine the procedure before continuing further experiments with patients. Through its transplantation grant program, The Foundation is funding projects to establish proof of principle in animal models; to develop surgical procedures that promote nerve cell connectivity; and to identity the optimal age of donor tissue. We hope these research efforts will soon overcome remaining obstacles so that clinical trials can begin.

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Pharmaceutical Therapies


One promising drug treatment pioneered by Foundation researchers is a survival factor called Axokine. Survival factors are naturally occurring substances that sustain the function of nerve cells. In animal model studies, Axokine has significantly delayed retinal degeneration. The Foundation, together with Regeneron Pharmaceuticals and the National Eye Institute, are now working to complete the pre-clinical studies necessary to gain FDA approval to test this drug in humans. Researchers are hopeful that the FDA will grant approval for a Phase I clinical trial to test the safety of Axokine in a small number of patients sometime in 1999.

The Foundation is very excited about this development. Vision researchers cannot test promising drugs without cooperation and investment from pharmaceutical and biotechnology companies. Through our Medical Therapies Trustee committee initiative, The Foundation is actively forging relationships with industry. We hope to soon witness a day when numerous drugs are being tested in clinical trials.

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Summary


In summary, retinal degenerative disease research has truly turned a corner. We are now moving along a very busy street filled with opportunities to make treatments and cures a reality. While we have not yet found treatments to stop vision loss and restore sight, we are-for the first time in my 30 years as a vision scientist-truly poised to realize these urgent goals.
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Date last modified February 13, 1999