July 15, 2000

Researchers Restore Vision In an Animal Model of Childhood Blindness

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Researchers Restore Vision In an Animal Model of Childhood Blindness

By Tom Hoglund
Information Officer, Foundation Fighting Blindness
July 2000
In a ground breaking study published in the July issue of The Proceedings of the National Academy of Sciences, researchers rapidly restored lost vision in a mouse model of Leber congenital amaurosis (LCA) using oral doses of a chemical compound derived from vitamin A. LCA is a group of severe, early-onset, autosomal recessive retinal degenerative diseases causing rapid vision loss at birth or during very early childhood. This finding represents the first time researchers have restored vision in an animal model of retinal degeneration.
In this study, Dr. Krzysztof Palczewski of the University of Washington, Dr. Samuel Jacobson of The Foundation’s Research Center at the Scheie Eye Institute of the University of Pennsylvania, and their colleagues orally administered doses of a chemical called 9- cis-retinal to 8- to 12-week old mice with a form of LCA. Using electroretinograms (ERG), a diagnostic tool that measures visual function, the researchers found that treated mice experienced a profound restoration of vision. By comparison, untreated mice of the same age have severely depressed ERG readings indicating very little vision.
Commenting on this study, Dr. Gerald Chader, Chief Scientific Officer of The Foundation Fighting Blindness said, “That Drs. Palczewski and Jacobson were able to restore lost vision in an animal model with a severe retinal degenerative disease offers hope that we may be able to develop sight-restoring treatments for other forms of retinal degeneration before retinal cells die. With advances in genetic research, we are at last able to understand the causes of vision loss and develop treatments that overcome a gene defect.”
LCA Can be Caused by a Block in the Visual Cycle
As light enters our eyes, the retina turns it into an electrical signal through a biochemical process called phototransduction. This signal is then relayed to the visual cortex of the brain, where visual perception occurs. The visual cycle allows us to continually process light energy so that we can see again and again throughout our lives.
In 1997, Foundation researchers discovered disease-causing mutations in a gene called RPE65 that account for an estimated 10 percent of all LCA cases. The RPE65 gene product is abundantly expressed in a layer of cells adjoining the neural retina called the retinal pigment epithelium (RPE). RPE cells support the function of photoreceptor cells in the retina by providing essential nutrients and eliminating digested waste products. As part of the visual cycle, RPE cells convert vitamin A into a chemical that combines with a molecule found in rod photoreceptor cells to form rhodopsin. Rhodopsin is the visual pigment in rod photoreceptor cells that initiates phototransduction.
In 1998, after cloning the RPE65 gene, Foundation-supported researchers next developed a mouse model of LCA that disrupts the function of the gene. This mouse model, known as the RPE65 mouse, enabled researchers to study the specific cause of vision loss in LCA at the cellular and molecular level. Through this animal model, it was determined that the RPE65 gene product is critical to the visual cycle and phototransduction.
A mutation in the RPE65 gene disrupts the visual cycle, thus preventing the formation of rhodopsin and the process of phototransduction. Without rhodopsin, photoreceptor cells cannot function, and vision loss ensues. Further investigation of the RPE65 mouse revealed that, although vision loss occurs rapidly, photoreceptor cells do not immediately degenerate and die. This finding led researchers to test treatments that might compensate for the defective gene. By making the chemical 9-cis-retinal directly available to RPE cells, the researchers successfully overcame the effects of the dysfunctional RPE65 gene, allowing the mouse’s retina to produce an artificial rhodopsin that restored vision.
Where do We Go from Here?
Although this study was of a short duration, it holds exciting possibilities for patients with LCA resulting from mutations in the RPE65 gene. With “proof of principle” now established for this treatment, Drs. Palczewski, Jacobson and colleagues are conducting further experiments to better evaluate the safety and efficacy of this treatment. Researchers must determine how long the vision improvement lasts and if there is any long-term toxicity. Another important issue is how early and how late in the disease process one can successfully intervene. Because there is some interval between the time retinal function is lost and photoreceptor cells die, it needs to be predetermined whether older patients are suitable candidates for such a treatment. Modern techniques of clinical evaluation should allow for these questions to be addressed in patients. Considerable work will thus need to be completed in the laboratory and clinic before clinical trials can begin.
Lastly, because this treatment specifically addresses the RPE65 gene defect, LCA patients must first be genetically identified to determine whether they are future candidates for this therapy. Besides RPE65, there are four other genes with mutations that each cause LCA. Unfortunately, LCA patients with these other gene defects would not be expected to benefit from this treatment. Although additional work must be completed before clinical trials can begin, The Foundation Fighting Blindness suggests that patients with LCA consider being evaluated at a Foundation Research Center to confirm an RPE65 diagnosis. To locate the nearest Foundation Research Center, please call 800-683-5555.
Genetic Research Holds the Key
This study demonstrates the critical importance genetic research plays in retinal degenerative disease research. The ability to develop effective therapies for all genetic diseases depends on first identifying a gene with disease-causing mutations. Once the gene is identified, researchers can develop genetically engineered animal models that mimic the disease. These animal models can be used as living laboratories to understand the gene’s function and how a mutation in the gene leads to disease. With this knowledge, researchers can develop treatments that compensate for the cellular dysfunction that results from genetic diseases. Aided by breathtaking advances in genetic research, vision scientists can now begin to understand and treat the entire spectrum of retinal degenerative diseases.

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