Last update 10/12/2001

Eye Research Network &LensNet Vision and Blindness Prevention News Some of the advances in vision research and blindness prevention that are ongoing at institutions around the world. Read about some positive happenings and the work of many good people doing a great job to build our scientific understanding and find treatments of the future for many blinding diseases. The future is often closer than you think. Kenneth P. Mitton, Ph.D., Editor Eye Research Institute - Oakland University Rochester MI, USA

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From: Marla Piasecki <MPiasecki@BLINDNESS.org> Date: Thu, 27 Jul 2000 To:   Friends of The Foundation Fighting Blindnes From:  Tom Hoglund, Communications Director Foundation Researchers Use Gene Therapy to Restore Retinal Function in an Animal Model of Retinal Degeneration By Tom Hoglund In the July issue of Nature Genetics, Foundation-supported researchers used gene replacement therapy to treat a rodent model of retinal degeneration.  This is the first published study to show that gene replacement therapy can restore function to photoreceptor cells. These findings also demonstrate that gene replacement therapy can create missing cellular components when genetic mutations interfere with the development of a photoreceptor cell. Dr.  Gerald Chader, Chief Scientific Officer of The Foundation Fighting Blindness commented, "Previous studies have established 'proof of principle' that gene replacement therapy can dramatically slow the loss of photoreceptor cells in animal models with retinal degenerative diseases.  However, this study offers the first evidence that gene replacement therapy can also restore retinal function.  This study gives us real hope that researchers may be able to develop treatments that restore vision." In the study, a team of scientists from London (Dr.  Robin Ali and Dr Shomi Bhattacharya from the Foundation's Research Center at the Institute of Ophthalmology along with Dr.  Adrian Thrasher at the Institute of Child Health) tested gene replacement therapy in the rds mouse.  This mouse has an autosomal recessive retinal degeneration that results from mutations in the peripherin/rds gene.  Using electroretinograms (ERG), a diagnostic tool that measures photoreceptor cell function, ten-week old treated rds mice had significant ERG recordings, indicating a marked improvement in retinal function.  Untreated rds mice of the same age have no detectable ERG response. Peripherin/rds Gene Key to Photoreceptor Cell Structure The peripherin/rds gene produces a specialized protein that helps to form the outer segment discs of photoreceptor cells.  Outer segments are the finger-like structures containing hundreds of light-sensitive discs that absorb light.  These discs contain rhodopsin, the visual pigment that begins phototransduction, the process of turning light into an electrical signal.  This signal is then relayed to the visual cortex, the part of the brain that interprets visual information. Mutations in the recessive form of the rds mouse prevent the peripherin/rds gene from producing its protein product.  As a result, photoreceptor cell outer segments and their light-sensitive discs fail to form.  Phototransduction and vision are not possible without these crucial cellular components. To verify that delivery of the peripherin/rds gene resulted in the development of outer segments, the research team used a sophisticated imaging technology called electron microscopy to examine the structure of treated photoreceptor cells.  Photoreceptor cells of treated rds mice were able to generate outer segments containing light-sensitive discs.  By contrast, untreated rds mice have no outer segments. Although treated mice had fewer outer segments than normal mice, improvements in gene delivery techniques should allow researchers to treat a greater portion of the retina in the future. Limits of Gene Replacement Therapy This study offers "proof of principle" that gene replacement therapy can restore photoreceptor cell function.  It also indicates that gene therapy can restore missing photoreceptor cell components that result from genetic mutations.  However, it is important to note that gene replacement therapy is not applicable to all retinal degenerative diseases.  It is only likely to be applicable to autosomal recessive diseases and some X-linked diseases. Ribozyme Gene Therapy For autosomal dominant diseases, ribozyme gene therapy may be applicable.  In dominant forms of retinal degeneration, patients have a healthy functioning gene and a gene with a disease-causing mutation.  The mutant gene produces a dysfunctional, toxic protein that damages the photoreceptor cell.  Ribozymes are molecules containing genetically encoded information that disrupt the mutant gene's ability to produce the harmful protein.  With the diseased gene inactivated, the healthy gene can supply the photoreceptor cell with the needed protein.  In previous studies, Foundation researchers have dramatically slowed retinal degeneration in a rodent model with ribozyme therapy. It is also important to note that treatment with both gene replacement and ribozyme therapy must be administered before photoreceptor cells have died. Future Work Before the Food and Drug Administration will grant approval for gene therapy clinical trials, researchers must thoroughly test its safety and efficacy in the laboratory.  Researchers must further validate these initial findings in larger animal models with eyes that more closely resemble human eyes.  Because rodents experience a much more rapid progression of vision loss than do larger mammals, these experiments may take somewhat longer to gauge the treatments effectiveness.  Optimal doses must also be established to insure that the gene or genetic information penetrates as many photoreceptor cells as possible. The safety of the gene delivery system must be tested to make sure it does not cause a harmful immune response.  In science, gene delivery systems are called vectors.  Vectors act like a fleet of microscopic delivery trucks transporting genes into retinal cells.  Vectors are composed of genetically modified viruses.  Viruses are extremely effective at infiltrating cells.  Viral vectors are modified to remove their harmful qualities while still retaining their gene delivery capabilities.  Although new-generation vectors are thought to be safe, Foundation researchers must establish their safety in the eye. This gene therapy breakthrough and the recent report of sight restoration in a mouse model with a severe retinal degenerative disease called Leber congenital amaurosis offer the first real promise that researchers can develop light-restoring treatments for retinal degenerative diseases.	From: Marla Piasecki <MPiasecki@blindness.org> Date:  Fri, 12 Oct 2001 09:21:23 -0400 New Therapy for AMD Announced Dear Friends of The Foundation:  Below is an article reporting the long-awaited results of the Age-Related Eye Disease Study testing antioxidants and zinc in patients withAge-Related Macular Degeneration. Clinical Trial Finds Antioxidants and Zinc Beneficial in Reducing Risk of Severe AMD Patients with advanced cases of dry age-related macular degeneration (AMD) can moderately lower the risk of developing the more severe wet form of the disease and preserve vision by taking a daily dose of antioxidant vitamins and zinc.  This finding is the result of the Age-Related Eye Disease Study (AREDS), a randomized, placebo-controlled clinical trial funded by the National Eye Institute.  AREDS evaluated over 3600 men and women between the ages of 55 and 80 for an average of 6.3 years.  Published in the October issue of the Archives of Ophthalmology, AREDS also evaluated whether antioxidants and zinc might reduce cataract development but found no beneficial effect.  Dr.  Paul Sieving, Director of the National Eye Institute, stated, "Now that we know antioxidants and zinc are helpful in reducing the risk of severe disease, it is even more important for older-age Americans to have regular eye exams.  Intervening in at-risk individuals could help reduce severe disease and vision loss in millions of Americans."  Specifically, the AREDS study found that AMD patients with advanced cases of dry AMD or vision loss due to wet AMD in one eye, who took daily supplements containing vitamin C, vitamin E, beta carotene, and zinc, had a 20% chance of developing wet macular degeneration over a five-year period.  By comparison, the control group taking a placebo pill lacking any nutrients had a 28% chance of developing wet macular degeneration over a five-year period.  This finding is important because delaying the onset of wet AMD and its accompanying vision loss by several years can prolong the independence and mobility of seniors and preserve their quality of life.  What is Macular Degeneration? Macular degeneration is so named because it causes the degeneration of the macula, the central portion of the retina that helps us perceive fine visual detail.  Dry macular degeneration is first diagnosed by the appearance of fatty deposits called drusen in a layer of cells beneath the retina called the retinal pigment epithelium (RPE).  As drusen deposits accumulate and become larger, they interfere with the function of photoreceptor cells in the macula, causing a gradual loss of central vision.  In the later stages of dry AMD, drusen deposits can also cause the death of cells in the RPE, a condition called geographic atrophy.  Researchers have found that patients with extensive intermediate and large size drusen deposits are at a higher risk of developing the more severe wet form of AMD than patients with fewer or smaller drusen.  In wet AMD, abnormal, leaky blood vessels grow beneath the retina, allowing plasma and blood to seep into the macula.  Because wet AMD usually results in a rapid and devastating loss of central vision, researchers are searching for treatments that prevent or delay this form of the disease from developing.  Antioxidants and zinc, in the doses administered in the AREDS study, provide the first therapy for patients with advanced cases of dry AMD, who are at increased risk of developing wet AMD.  Dosages Vitamin companies are not yet manufacturing a supplement of antioxidants and zinc containing the dosages used in the AREDS study.  Until such a formulation becomes available, patients can purchase each nutrient separately.  The daily therapeutic dosages of each of the nutrients used in the AREDS study are as follows: vitamin C, 500 mg; vitamin E, 400 IU; beta carotene, 15 mg; and zinc, 80 mg  Contraindications  Cancer prevention studies have found that high doses of beta carotene increase the risk of developing lung cancer in cigarette smokers. These studies strongly suggest that cigarette smokers, or those with smoking histories, should avoid taking beta carotene to prevent advanced macular degeneration.  The AREDS study findings are specific to patients with advanced cases of dry macular degeneration or vision loss from wet AMD in one eye.  The study did not evaluate patients with early onset forms of macular degeneration such as Stargardt and Best disease.  Due to the nature of the severe genetic defects that cause these early onset forms of macular degeneration, there is no evidence to support the use of high doses of antioxidants and zinc.  There is also no evidence that antioxidants and zinc would offer benefit to patients with other retinal degenerative diseases such as retinitis pigmentosa.  To the contrary, a well-designed clinical trial found that a daily dose of 400 IU of vitamin E resulted in a faster progression of vision loss for patients with common forms of retinitis pigmentosa.  Lutein and Zeaxanthin  Lutein and zeaxanthin are two antioxidant nutrients found highly concentrated in the macula.  They give the macula its characteristic yellow appearance.  Lutein and zeaxanthin are thought to protect the macula from oxidative stress due to light exposure. Because lutein and zeaxanthin supplements were not available at the start of the AREDS study, these nutrients could not be included. Future clinical trials will need to evaluate these antioxidants in AMD.  Am I Candidate For This Treatment?  Only a trained ophthalmologist can determine whether you have AMD and would be a candidate to begin antioxidant and zinc therapy.  The Foundation Fighting Blindness and the National Eye Institute strongly urge adults over age 55 to have regular eye exams.  Future Treatments  AREDS is a prime example of the importance of clinical trials in determining the safety and efficacy of treatments.  With this therapy, patients can hopefully delay severe vision loss as researchers work to develop even more effective therapies for AMD.  For example, researchers recently submitted an application to the FDA to begin clinical trials testing the safety of a gene therapy treatment that inhibits blood vessel growth.  Drug treatments that block blood vessel growth are already in clinical trials.  Still other clinical trials are testing the effectiveness of low-intensity laser treatment in dry AMD to delay or prevent severe vision loss.  The Foundation is collaborating with a biotech company called Oculex to test the use of a drug delivery device that slow-releases a steroid to prevent immune complications after retinal cell transplantation. Such a device could help elevate transplantation therapies to clinical trials.  As with all retinal degenerative diseases, researchers are at last able to develop and test promising therapies.
From: Marla Piasecki <MPiasecki@BLINDNESS.org> Date: Mon, 26 Jun 2000 To:   Friends of The Foundation Fighting Blindnes Researchers Restore Vision in an Animal Model of Childhood Blindness By Tom Hoglund In a groundbreaking 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. Dr.  Jacobson to Speak at Visions 2000 For those interested in hearing more about this exciting breakthrough and the efforts to develop other treatments for retinal degenerative diseases, Dr.  Jacobson will speak at The Foundation's Visions 2000 conference to be held in Orlando, Florida on August 10-12.  Don't miss this exciting opportunity.  To register for Visions 2000, please call The Foundation at 800-683-5555.
From: Marla Piasecki <MPiasecki@BLINDNESS.org> Date: Fri, 30 Jun 2000 To:   Friends of The Foundation Fighting Blindnes From:  Tom Hoglund, Communications Director Vision Researcher First to Implant an Artificial Retina in Humans For the first time ever, researchers from a company called Optobionics surgically implanted an artificial retina into three patients who are blind from retinitis pigmentosa.  These highly-experimental prosthetic devices, made of silicone computer chips, are intended to restore ambulatory vision, thereby giving people the freedom to walk without the assistance of a cane or guide dog.  The company's device, called an Artificial Silicon Retina (ASR), is designed to function much like a photoreceptor cell in the retina.  In retinal degenerative diseases, such as RP, macular degeneration and Usher syndrome, photoreceptor cells degenerate and die.  In studies, supported by The Foundation Fighting Blindness, researchers found that, despite the loss of photoreceptors, much of the remaining nerve cell network in the retina remains relatively healthy.  This finding led researchers to begin developing computer chips that might function in place of photoreceptor cells.  The ASR is 2 millimeters in diameter and one-thousand of an inch in thickness, making it thinner than a human hair.  It contains 3500 solar cells that are designed to convert light into electrical signals. Optobionics is based out of Chicago and headed by Dr.  Alan Chow. Dr.  Chow is a  member of The Foundation Fighting Blindness' Surgical and Implant Advisory Committee.  According to Dr.  Chow, these experimental implants are part of a Food and Drug Administration approved feasibility and safety study to see whether the device can be safely implanted and whether it is well-tolerated in the human eye.  For these three operations, Dr.  Chow implanted a smaller version of the ASR device in the periphery, or side, of the retina. Dr.  Chow also hopes to gauge whether patients gain any visual perception where the chip is implanted.  The operations, performed on June 28 and 29, reportedly went well and the patients are at home recovering from the surgery.  In the past, researchers have performed very brief experiments to stimulate the retina in patients without vision.  However, this is the first time anyone has implanted a device in humans.  Although there is still a great deal of remaining research before such a device will be available to patients, news of these first-ever surgeries is a sign that artificial retinas are advancing toward clinical trials.  Several other research groups are working to develop an artificial retina. The Foundation currently supports two groups: Dr.  Eugene de  Juan and Mark Humayun of The Foundation's Research Center at Johns Hopkins University, and Drs.  Joseph Rizzo and John Wyatt, of Harvard Medical School and Massachusetts Institute of Technology, respectively.  The Foundation also supports Dr.  Richard Normann at the University of Utah, who is developing a silicon chip to be implanted in the visual cortex of the brain.

 
 

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