We fund a variety of research, and here are summaries of several on-going research projects.

Here is a partial list of breakthroughs in the field of Retinal Degenerative Diseases for Fiscal Year 2001-2002:

Gene Replacement Therapy for RP
New Naturally Occurring Animal Model Discovered for Autosomal Dominant RP
New Genetic Inheritance Pattern - Bardet-Biedl Syndrome
Vitelliform Macular Dystrophy (Best disease)
AMD and Smoking
AREDS - Age-Related Eye Disease Study
Lutein and Supplements
Researchers Identify Genes Associated with Aging of the Retina
New Link to Macular Degeneration is Discovered In A Gene That Causes Other Eye Diseases
AMD and Drusen
Wet AMD
Drugs and Drug Delivery
Stem Cells
Retinal Chip Research or Visual Prosthetics

One of the major RD genetics-related breakthroughs occurred when FFB-sponsored scientists, Drs. Robin Ali and Shomi Bhattacharya of the Institute of Ophthalmology (London) along with Dr. Adrian Thrasher at the Institute of Child Health restored visual function in a rodent model of retinal degeneration using gene replacement therapy. The gene defect in this model was known to be in the peripherin/rds gene, which produces a specialized protein that is located at the rims of the outer segments in a complex with the protein ROM1. This was one of the first published studies to show that gene replacement therapy can restore function to photoreceptor cells. Previous to this finding, treatments and potential therapies only slowed the progression of disease and did not reverse it. These findings also demonstrate that gene replacement therapy can create missing cellular components when genetic mutations interfere with the development of a photoreceptor cell.

2. New Naturally Occurring Animal Model Discovered for Autosomal Dominant RP

A recent study by FFB-supported researchers Drs. Gus Aguirre and Greg Acland and their colleagues at the Scheie Eye Institute led by Dr. Sam Jacobson, describes a naturally occurring rhodopsin mutation in dogs whose disease phenotype is very similar if not identical to the phenotype in the Pro23His and other class B1 rhodopsin mutations in man.

Rhodopsin, the visual pigment of rod photoreceptors, is one of many G protein-coupled receptors involved in human disease. Numerous rhodopsin gene (RHO) mutations cause RP. Retinitis Pigmentosa caused by RHO mutations exhibits two different phenotypes. One is an early-onset disorder with rapid loss of rods uniformly across the retina. The second has a protracted natural history of vision loss and puzzling features; rod vision can be normal early in life and degeneration slowly spreads from a disease focus in one retinal region; furthermore, and independent of disease stage, there is abnormally slow recovery of rod vision after bright light exposure. Variation in severity of this second phenotype may indicate that epigenetic factors play an important role in its progression and suggests that it may be particularly amenable to preventive or ameliorative therapies.

Other than in humans, naturally occurring disease-causing RHO mutations have not been identified previously in mammals. Genetically engineered animals and mutagenized flies have been the mainstay for in vivo research and treatment attempts in the past decade. Naturally occurring hereditary retinal degenerations in dogs, termed progressive retinal atrophies (PRAs), are widespread and have provided several models of autosomal recessive and X-linked RP. Now the first autosomal dominant form of PRA, one that closely resembles the second human phenotype described above, has been described in English Mastiff dogs.

The phenotype features shared by dog and man includes a dramatically slowed time course of recovery of rod photoreceptor function after light exposure and a distinctive topographic pattern to the retinal degeneration. The canine disease offers opportunities to explore the basis of prolonged photoreceptor recovery after light in RHO mutations and determine if there are links between the dysfunction and apoptotic retinal cell death. The RHO mutant dog also becomes the large animal needed for pre-clinical trials of therapies for a major subset of human retinopathies. Evaluation of this model should advance our understanding of the pathophysiology of the disease and lead to therapies for this major subset of dominant RP.

3. New Genetic Inheritance Pattern - Bardet-Biedl Syndrome

FFB-supported researchers Drs. Richard Lewis, Nicholas Katsanis and James Lupski, Baylor College of Medicine, have uncovered an unusual pattern of disease inheritance that adds new insight into the understanding of how diseases are passed from one generation to the next. Individuals with BBS have vision loss due to RP. This study described four families suffering from Bardet-Biedl syndrome in which the signs of the disease do not occur unless two copies of the same gene are mutated and a single copy of another gene is also altered. Each gene had been associated previously with the disease.

Bardet-Biedl syndrome had been considered a classic recessive disease until these four families were studied. It was only after the first two genes known to be associated with the disorder were isolated and their DNA sequenced that the group at Baylor began to question whether the disease was truly inherited in a classic, recessive fashion according to the laws established by Mendel in the late 1800s.

The group at Baylor found that this disorder occurs in some families as a result of the inheritance of 3 mutations in 2 different genes. They call this "triallelic inheritance". In some instances the affected offspring have 2 altered copies of 1 BBS gene (either BBS2 or BBS6) and a 3rd altered copy of the other. Siblings who inherit other combinations of mutations, but without a total of 3, develop normally and exhibit no phenotype of the disease. This type of inheritance is different from the inheritance patterns of Mendelian genetics where a change in phenotype is usually a consequence of a mutation in 1 gene (autosomal dominant inheritance) or both copies of a gene (autosomal recessive inheritance). This discovery provides a link between Mendelian disorders and complex human traits. It may be the first step in understanding multifactorial diseases such as diabetes, asthma and macular degeneration.

4. Vitelliform Macular Dystrophy (Best disease)

FFB-supported Dr. Jeremy Nathans and his colleagues discovered that the Vitelliform macular dystrophy protein defines a new family of chloride channels (March 2002). This is an early onset autosomal dominant disorder where there is accumulation of lipofuscin-like material within and beneath the retinal pigment epithelium. Bestrophin - the protein product of the Vitelliform macular dystrophy gene plays a role as a channel protein. Chloride channel provides explanation for the electooculographic abnormalities in patients. Defects in this channel might create an imbalance in intracellular pH.

5. AMD and Smoking

Age-related macular degeneration (ARMD) is a degenerative condition of the macula which is the central portion of the retina. It is the most common cause of vision loss in the United States in those 50 or older, and its prevalence increases with age. AMD is caused by hardening of the arteries that nourish the retina. This deprives the sensitive retinal tissue of oxygen and nutrients that it needs to function and thrive. As a result, the central vision deteriorates.

A new study shows that AMD is 3 times as frequent among tobacco-smokers.

6. AREDS - Age-Related Eye Disease Study

In October 2001, the NEI published the results of a seven-year study -- called the Age-Related Eye Disease Study (AREDS) -that showed that a high-dose combination of vitamin C, vitamin E, beta-carotene, and zinc significantly reduces the risk of developing advanced stages of AMD by about 25 percent. These high levels of antioxidants and zinc are the first effective treatment to slow the progression of AMD. The nutrients are not a cure for AMD, nor will they restore vision already lost from the disease. But they are playing a vital role in helping people at high risk for developing advanced AMD keep their vision. In the same study, the antioxidant and zinc combination showed no significant effect on the development or progression of cataract.

7. Lutein and Supplements

Claims made about an association between lutein and eye health are speculative and should be viewed with caution. The possible benefits of lutein for the eye remain uncertain.

Certain foods contain antioxidants -- molecules that can help maintain healthy cells and tissues in the eye. One category of these antioxidants, called carotenoids, may play a role in maintaining eye health as well as overall health. One of these carotenoids -- lutein -- is concentrated in the retina and lens of the eye.

There is little definitive scientific evidence at this time to support claims that taking supplements containing lutein can decrease the risk of developing advanced age-related macular degeneration (AMD), a blinding eye disease, or cataract. There is conflicting data make it clear that the relationship between lutein and eye health needs to be examined more closely before conclusions can be drawn.

So What's Next for Lutein?

The NEI is investigating the role of nutrition -- including the effects of lutein -- in eye disease. Specifically, the NEI is:

Conducting a pilot study to see how well lutein is absorbed into the bloodstream in people over age 60. This is a first step in testing this substance as a possible treatment for AMD. The pilot study is not designed to treat AMD; its purpose is to help determine the best dose of lutein oral supplements in people over age 60. This dose of lutein can then be separately tested in humans as a possible treatment for AMD.

Supporting a study that compares the intake of lutein and zeaxanthin with the likelihood of developing AMD and/or cataract. Researchers explain that results from this study -- called the Carotenoids and Age-Related Eye Disease in Women's Health Study -- will help health professionals make dietary recommendations regarding the benefit of eating diets rich in lutein and zeaxanthin. Study results will also provide information needed to conduct clinical trials that can evaluate the effectiveness of lutein and zeaxanthin supplements on the progression of age-related eye disease.

Lutein was not part of the AREDS study because during the AREDS planning stages in the early 1990s, lutein and zeaxanthin were not commercially available.

8. Researchers Identify Genes Associated with Aging of the Retina

Foundation-supported Dr. Anand Swaroop and his colleagues at the University of Michigan used microarray technology to analyze gene expression in the aging human retina. The authors showed that aging of the human retina is associated with changes in patterns of gene expression specifically in pathways involved in stress response and energy metabolism. These studies demonstrate the utility of gene microarrays in identifying global patterns of retinal gene expression and lay the foundation for future studies defining the genetic basis of aging-associated retinal diseases, such as age-related macular degeneration.

9. New Link to Macular Degeneration is Discovered In A Gene That Causes Other Eye Diseases

Several classically inherited (Mendelian) forms of macular degeneration have been mapped and some genes have been cloned, but none thus far on the X chromosome. The X chromosome harbors several retinal disease loci, including that for cone dystrophy (COD1 and COD2), juvenile retinoschisis (XLRS), congenital stationary night blindness (CSNB), and at least five loci for retinitis pigmentosa. Recently, Foundation-supported Dr. Radha Ayyagari discovered that a gene that forms one type of retinal disease, retinitis pigmentosa, also causes a form of macular degeneration. She reported that the gene RPGR has a direct link to a form of early-onset macular degeneration that primarily affects males. The finding is important because it will ultimately help scientists understand how macular degeneration progresses, and it raises an intriguing question: How can a single gene cause two very different eye diseases, each affecting a different segment of vision? This study marks the first time any scientist has mapped a macular degeneration gene to the X chromosome. Ayyagari's next steps are to learn more about the nature of the mutation, and then to design studies that could one day lead to treatments for macular degeneration. For example, if the gene is found to create a new protein, scientists could look for ways to block it from interfering with other proteins in the retina, or, alternatively, to promote the action of necessary proteins.

10. AMD and Drusen

What are Drusen? Drusen are nodules or deposits beneath your retina in a layer is called Bruch's membrane. Drusen occur in two forms:

Hard, small (less than 63um in diameter) drusen do not increase with age and do not predispose to macular degeneration.
Soft, large (more than 63 um in diameter) drusen enlarge and become confluent with age, may predispose to macular degeneration, are more commonly seen in eyes of people with advanced macular degeneration in their other eye.

Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. The compositional similarity between drusen and other disease deposits may be significant in view of the recently established correlation between AMD and atherosclerosis. This study suggests that similar pathways may be involved in the etiologies of AMD and other age related diseases.

11. Wet AMD

AMD is classified as either the wet (neovascular) or dry form. About 10% of patients who suffer from macular degeneration have wet AMD. This type occurs when new vessels form to improve the blood supply to oxygen deprived retinal tissue. However, the new vessels are very delicate and break easily, causing bleeding and damage to surrounding tissue. With choroidal neovascularization, abnormal blood vessels stemming from the choroid (the blood vessel-rich tissue layer just beneath the retina) grow up through the retinal layers. Imagine the abnormal blood vessels as weeds creeping up through the cracks of a sidewalk. These new vessels are very fragile and break easily, causing blood and fluid to pool within the layers of the retina. As the vessels leak, they disturb the delicate retinal tissue, causing the vision to deteriorate. The severity of the symptoms depends on the size of the CNVM and its proximity to the macula. Patients' symptoms may be very mild such as a blurry or distorted area of vision, or more severe, like a central blind spot.

Many companies (both pharmaceutical and biotech) are interested in developing treatments for wet AMD. Some of the more promising treatments are listed below.

• FDA Considers Approval for First Gene Therapy Clinical Trial for Retinal Degeneration Dr. Peter Campochiaro, Director of The Foundation's Research Center at the Wilmer Eye Institute, Johns Hopkins Medical School, presented data before the U.S. Food and Drug Administration's Recombinant DNA Advisory Committee (RAC) to gain approval to begin the first-ever clinical trial to test the safety of a gene therapy treatment for wet macular degeneration. The RAC committee is responsible for approving gene therapy clinical trails.

In laboratory experiments with rodents that exhibit abnormal blood vessel growth, Dr. Campochiaro and colleagues used gene therapy to deliver the gene that encodes pigment epithelium-derived factor (PEDF) to the retina. PEDF, originally developed by Dr. Gerald Chader, Chief Scientific Officer of The Foundation, is a protein created by retinal pigment epithelial cells. In previous experiments, PEDF has been found to inhibit blood vessel growth, slow photoreceptor cell degeneration and prolong cell life. In these recent experiments, blood vessel growth was inhibited by as much as 90% in rodent models of blood vessel growth.

Dr. Campochiaro is developing this gene therapy treatment in collaboration with GenVec, Inc., a biotechnology firm from Gaithersburg, Maryland. GenVec invited The Foundation Fighting Blindness to give public comment before the RAC committee to underscore the importance of developing therapies for retinal degenerative diseases. Harriet Finkelstein, Vice Chair of The Foundation's Board of Trustees, recounted her father's personal struggle with macular degeneration and the urgent need to save the sight of millions of Americans that suffer from all retinal degenerative diseases.

A decision by the RAC committee is expected in the near future.

• In May, Alcon Research, Ltd. reported preliminary results from its Phase II clinical trials demonstrating that anecortave acetate, a modified steroid and one of its key drugs under development, preserves or improves vision in patients with the wet form of age-related macular degeneration (AMD). These results were based on a six-month analysis of an ongoing 24-month trial. Alcon Research, Ltd. is conducting two Phase II studies in the US and Europe to assess the safety and efficacy of anecortave acetate for the treatment of AMD as a single therapy or with photodynamic therapy (PDT). The single-therapy trial is being conducted at 18 sites with 128 patients enrolled for 24 months; the study with PDT was a six-month study with 136 patients at 11 sites. Anecortave acetate is delivered around the back of the eye, where it diffuses across the choroid into the macular portion of the retina. In the single-therapy study, anecortave acetate treatments were administered every six months.

• Eyetech is currently conducting Phase II/III pivotal clinical trials in age-related macular degeneration (AMD) at over 100 of the world's leading medical centers. These clinical trials are to evaluate the safety and efficacy of Eyetech's lead product, an anti-VEGF aptamer. Studies suggest that Vascular Endothelial Growth Factor (VEGF) causes the abnormal blood vessel growth and/or leakage that causes AMD and DME. Eyetech's anti-VEGF aptamer may inhibit the biological pathway that causes vision loss in AMD and DME. Eyetech's compound may result in stabilized and/or better vision and an enhanced quality of life for patients suffering from AMD, DME and related retinal diseases.

• Bausch & Lomb's Retisert implant, which exudes a steroid into the eye for up to three years and is being used for diabetic retinopathy and macular degeneration.

• Eli Lilly has the only pill among the new drugs; used to prevent worsening eye disease in diabetics.

• RhuFab is an anti-VEGF monoclonal antibody fragment developed by Genentech for the potential treatment of the wet form of age-related macular degeneration (AMD). RhuFab is currently being evaluated in a Phase Ib/II study for patients with wet AMD. This research is in very early stages and it is still not known if this product is safe or effective.

Although the new drugs being tested for the treatment of wet AMD vary, most of them, like rhuFab, zero in on a growth promoting protein called vascular epidermal growth factor, or VEGF as it appears to be an especially important trigger of damaging blood vessels in both forms of blindness.

12. Drugs and Drug Delivery

Although Foundation researchers have discovered several promising drug therapies, further progress has been hampered by an inability to safely deliver drugs to the retina. Most drug compounds cannot cross the blood/retina barrier, making systemic administration impossible. Last year, The Foundation sponsored a meeting to further spur the development of novel drug delivery systems. The May meeting of the Association for Research in Vision and Ophthalmology (ARVO) provided evidence that The Foundation's efforts are working. Several new and existing research teams presented hopeful work. With safe drug delivery devices, a number of promising drug therapies should enter clinical trials.

13. Stem Cells

ARVO provided the clearest picture yet of stem cell research. There were many studies evaluating the steps necessary to biologically coax stem cells taken from various adult sources to become fully functioning photoreceptor cells. Adult retinal stem cells share some but not all biologic properties with photoreceptor cells. During the course of human development, various genes instruct a stem cell to mature into a certain cell type in the body. For a retinal stem cell to mature into a functional photoreceptor cell, one of the most complex cell types in the human body, requires that a number of developmental genes function properly. Thus, for adult retinal stem cells to become a viable transplantation source, Foundation researchers must document and then replicate this complex biological process. ARVO witnessed a number of researchers beginning to research this process.

14. Retinal Chip Research or Visual Prosthetics

Obviously this past year retinal chip research generated considerable media excitement.

At ARVO Dr. Alan Chow of Optobionics presented unpublished findings from a Phase I clinical trial testing the safety of the company's Artificial Silicon Retina, a highly experimental device designed to mimic photoreceptor cell function. The Foundation is pleased to learn that the six patients in this study have not experienced complications from the device. We anxiously await published study data that can objectively evaluate and verify the subjective claims made by the patients regarding small improvements in vision. Nonetheless, it is very encouraging to see this research field reach clinical trials.
Foundation-supported researchers at the University of Southern California have implanted a microelectronic retinal prosthesis into a patient who is blind from retinitis pigmentosa. This experimental surgery is part of a Food and Drug Administration (FDA) approved Phase 1 clinical trial to test the safety of a permanently implanted retinal prosthesis. Dr. Humayun performed the first surgery on February 19, 2002. Two more pre-selected patients will receive these devices in the near future. Once it has been determined that a permanently implanted device is safely tolerated, then larger scale clinical trials, testing the effectiveness of the device, can begin.
Dr. Joe Rizzo at the Massachusetts Eye and Ear Infirmary is also beginning testing in humans.

These high-tech medical devices might one day restore ambulatory vision, allowing patients with end-stage retinitis pigmentosa, macular degeneration and Usher syndrome to regain their independence and mobility. At this time, data concerning the effectiveness of these devices are not yet available. Nonetheless, it is extremely encouraging to witness several research groups begin clinical trial testing of a retinal prosthetic device.

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Macular Disease Foundation