Macular Degeneration 101

Research Update

Biomedical research is beginning to unravel the mysteries surrounding macular degeneration and is on the verge of developing new treatments that slow or prevent the onset of this blinding disease.

Gene Therapy Trials

January 2008

Macular degeneration is a leading cause of blindness in the world. It affects people of all ages, but is particularly prevalent in the elderly. Age-related macular degeneration (AMD) is a complex disease involving genetic, environmental, and social factors including family history, cigarette smoking, and poor diet in addition to age. Loss in vision occurs when light absorbing photoreceptors in the central retina die. Intensive research is being carried out to identify factors that contribute to photoreceptor cell death. This knowledge is being used to develop preventative measures, treatments and cures for this set of blinding disorders.

Although at the present time there is no cure for macular degeneration, significant progress has been made in our understanding of macular degeneration and related retinal degenerative diseases. Genes responsible for a large number of early onset inherited macular degenerations such as Stargardt disease, Best disease, Sorby’s fundus dystrophy, and autosomal dominant macular dystrophies have been identified. This has led to a clearer understanding of the molecular and cellular basis for why mutations in these genes cause photoreceptor cell death and vision loss.

Gene therapy clinical trials have begun this past year on a hereditary retinal degenerative disease known as Leber’s Congenital Amaurosis, a severe disorder that causes blindness in children. These trials have been initiated as the result of success with animal models in which replacement of a defective gene with a normal gene has restored vision in dogs and rodent models for this disease. Success in these ongoing human clinical trials will pave the way for the application of gene therapy for the treatment of other retinal degenerative diseases including certain forms of macular degeneration.

Significant progress has been made in identifying genetic sequence variations which increase one’s risk of developing AMD. A number of such variants occur in genes that code for proteins such as complement factor H that function in the immune response. This breakthrough, together with earlier immunochemical analysis of retina tissue samples of affected individuals, has led scientists to investigate the role of inflammation in the pathogenesis of AMD.

Wet AMD involves the growth of abnormal blood vessels under the central retina known as the macula. An understanding of factors responsible for the growth of these vessels has enabled scientists to develop drug treatments which block the formation of abnormal blood vessels. Lucentis TM (ranibizumab) and related products have been reported to slow vision loss in individuals with wet AMD and remarkably in some cases improve visual acuity.

To date there are no treatments for dry AMD. Continued research on juvenile and age-related macular degeneration is needed to understand in more detail the molecular and cellular basis for these diseases, design and develop new diagnostic tools to detect AMD in its early stages before significant numbers of photoreceptors die, and develop new and improved treatments for this set of blinding diseases. The MVRF has provided over $10,000,000 for research in macular degeneration and related retinal degenerative diseases over the past 10 years. This funding has had a major impact in advancing our understanding of macular degeneration. Some examples of the research currently being funded include:

•Identification of genes responsible for early onset and age-related macular degeneration
•Defining the role of the immune system and inflammation in the pathogenesis of AMD
•Development of animal models for AMD and other retinal diseases
•Design and application of gene therapy for retinal degenerative diseases
•Identification of molecular and cellular pathways responsible for photoreceptor cell survival and cell death
•The role of neural growth factors in photoreceptor cell survival
•Isolation and application of stem cells for photoreceptor regeneration

The recent progress in understanding the genetics and biology of macular degeneration and related retinal degenerative diseases has led to optimism among scientists that rationale treatments to prevent, slow, or even cure vision loss in individuals affected by macular degeneration will be further developed in the future.

Robert Molday, Ph.D. Chairman
MVRF Board of Scientific Advisors

New Genes Linked to Age-Related Macular Degeneration

May 2006

One of the byproducts of sequencing the human genome is a series of several hundred thousand markers that we can use to link any given disease and a specific gene with a precision that was never previously possible. Over the past year studies using these markers have identified a series of genes that account for most of the genetic risk of developing Age-related Macular Degeneration (AMD).

Perhaps the most important of the recent findings was first reported in the journal Science by research groups from Yale University, Southwestern Medical Center and Duke University who found that a particular variant of a serum protein called Complement Factor H greatly increases one’s risk for developing AMD. The CFH gene encodes a protein known to regulate inflammation in the immune system. The finding is a major breakthrough since the polymorphic mutation in the CFH gene is present in a large fraction of individuals with AMD. Identification of genes linked to AMD is important since it serves as a basis for identifying people at risk for developing AMD, understanding the molecular and cellular basis for AMD, and developing treatments to slow or prevent loss in vision from AMD. The research carried out by investigators at Yale University was funded in part by the MVRF through a research grant to Dr. Colin Barnstable, a member of the MVRF Scientific Advisory Board. Recently, Dr. Anand Swaroop with funding from the MVRF has confirmed the finding of these groups that complement factor H variant is a major contributor to AMD susceptibility.

A further boost to the idea that inflammation might be related to the development of AMD has come from the finding of Dr. Rando Allikmets of Columbia University Medical Center that variants of a related complement factor, Factor B, are also found in higher frequency in AMD patients. This work, also funded by MVRF, suggests that drugs that modify the inflammatory response might have a place in therapies to delay or prevent AMD.

What causes the inflammation? Whole genome screening methods have detected several other chromosomal regions that increase the risk of developing AMD and these may be more related to the initial cause of the disease. One of these, studied by Drs. Josephine Hoh at Yale and Bernhard Weber in Germany (both funded by MVRF), is on chromosome 10 and a gene called PLEKHA1, or its next door neighbor LOC387715, appear to be important in the development of AMD. How they contribute to the disease is unknown and needs further research.

Several other genes have been described as risk factors for AMD at recent meetings and details of these will soon be published in scientific journals. These include a number of growth factors and membrane receptors — components of signals that are essential to keep cells healthy.

A recent review of many studies of AMD concluded that 60% of the disease was caused by genetic factors and 40% by environmental factors. When all the newly described AMD genes are added together, they account for essentially all the genetic component of AMD. This remarkable progress means that we now have the tools to understand what causes the disease and, more importantly, important targets for new therapeutic intervention.

Scientists Identify Genetic Variants Associated with an Increased Risk of Age-related Macular Degeneration

September 2005

Age-related macular degeneration (AMD) is a complex disease that leads to progressive loss in central vision in the elderly. It has been known for some time that genetics plays a major role in determining the susceptibility of an individual to AMD. In a major breakthrough over the past year, four research groups reported that a common genetic variant (Y402H) of the complement factor H dramatically increases one’s risk for developing AMD. Complement factor H is a key regulatory protein of the complement pathway of the innate immune system that fights microbial infections. Recently, Dr. Anand Swaroop with funding from the Macular Vision Research Foundation has confirmed the finding of these groups that the Y402H complement factor H variant is a major contributor to AMD susceptibility. In addition Swaroop’s group has recently reported that a D229G mutation in toll-like receptor 4, a protein implicated in the inflammatory response and cholesterol movement, is also associated with susceptibility to AMD. Identification of genetic variants associated with AMD such as those of complement factor H and toll-like receptor 4 is an essential first step in understanding the molecular and cellular basis for AMD and developing treatments to prevent or slow the onset of visual loss.

Gene Therapy Restores Vision in a Mouse Model for a Retinal Degenerative Disease

September 2005

In an important step toward developing a treatment for retinal degenerative diseases, an international team of researchers headed by Drs. William Hauswirth (University of Florida, U.S.), Robert Molday (University of British Columbia, Canada) and Bernhard Weber (University of Regensburg, Germany) successfully used gene therapy to restore vision in a mouse model of X-linked Juvenile Retinoschisis (RS). RS is a relatively common inherited macular degeneration that affects males early in life. It is characterized by a loss in central vision resulting from a splitting of the retina. Complications including retinal detachment and vitreal hemorrhages can occur over time leading to complete loss in vision. Normal retinal cells secrete a protein known as retinoschisin or RS1 that functions as a “glue” to maintain the cellular organization and synaptic connection of the retina. If the functional RS1 protein is not produced due to a mutation in the RS1 gene, the retinal cell layers become highly disorganized resulting in a loss in transmission of electrical signals from photoreceptors to other retinal neurons as part of the visual process. In this study funded by the Macula Vision Research Foundation, the normal human RS1 gene packaged in a viral vector was injected into the subretinal space of 15-day old mice deficient in the mouse gene. Two months after injection, the RS1 protein was expressed at normal levels and distributed throughout the retina in a pattern similar to that observed in a normal retina. The protein functioned as a cell adhesion protein to glue the cells back together and re-establish the highly organized cellular architecture of the retina. Importantly, visual function was restored as measured by electrical recordings known as electroretinograms or ERGs. A single injection was sufficient to restore retinal structure and function and prevent photoreceptor cell degeneration over the lifetime of the mice. Although more research has to be carried out, these studies provide evidence for the potential of gene therapy as a treatment for X-linked Juvenile Retinoschisis and other retinal degenerative diseases including macular degeneration. This research was supported by the Foundation Fighting Blindness and NEI as well as the MVRF.

Researchers funded by MVRF identify a key gene linked to Age-Related Macular Degeneration.

March 2005

Age-related macular degeneration (AMD) affects over 15 million people in North America. It is a complex disease in which genetics plays a crucial role. In three papers just published in Science, research groups from Yale University, Southwestern Medical Center and Duke University have identified a polymorphic mutation in the CFH gene that greatly increases one’s risk for developing AMD. The CFH gene encodes a protein known as complement factor H that regulates inflammation in the immune system. The finding is a major breakthrough since the polymorphic mutation in the CFH gene is present in a large fraction of individuals with AMD. Identification of genes linked to AMD is important since it serves as a basis for identifying people at risk for developing AMD, understanding the molecular and cellular basis for AMD, and developing treatments to slow or prevent loss in vision from AMD. The research carried out by investigators at Yale University was funded by the MVRF through a research grant to Dr. Colin Barnstable, a member of the MVRF Scientific Advisory Board. Previously, Dr. Ed Stone funded by the MVRF had shown that mutations in the fibulin 5 gene are responsible for some cases of AMD.

AMD Gene Discovered

Edwin Stone, M.D., Ph.D.
Member — Macula Vision Research Foundation Board of Scientific Advisors

As reported in The Wall Street Journal on July 22, 2004 and The New England Journal of Medicine on July 22, 2004, announced the discovery of a new age-related macular degeneration gene. It was found by a team of researchers at the Research Center for Macular Degeneration and Allied Diseases at the University of Iowa. The Center’s director and lead author of the report is Edwin M. Stone, M.D., Ph.D.

Known as fibulin-5, the gene is among the first to be discovered to play a role in the common form of the disease. It is expected to help researchers understand how age-related macular degeneration develops. It is thought that it could lead, in turn, to new medicines and preventive strategies for a disease for which few effective options are available. This discovery is pointing to new promising avenues of research.

Macular degeneration, the leading cause of irreversible vision loss in people over 60 in the Western world.

The Wall Street Journal quoted Edwin Stone, M.D., Ph.D., of the Center for Macular Degeneration at the University of Iowa and the lead author of the study, as saying, “We have a toehold on Mt. Everest.” Because of the graying of America, “it is not an understatement to say that there is an impending epidemic of blindness,” continued Dr. Stone. That expectation is adding urgency to learn more about the disease and to develop treatments.

Dr. Stone is a member of the Macula Vision Research Foundation’s Board of Scientific Advisors and the Foundation helped top support this important research.

Molecular Genetics and Gene Therapy

Macular degeneration is a heterogenesous group of diseases that affects both the young and the elderly. During the past six years, genes that are defective in many inherited, early onset forms of macular degeneration have been identified. More recently, a mutation in a gene that causes one form of age-related macular degeneration (AMD) has been discovered. Through these discoveries, it is now possible to develop gene therapy approaches to repair these genes or replace defective genes with normal genes. Recently gene therapy has been successfully used to deliver a normal gene into the retinal pigment cells of blind dogs with an inherited retinal degenerative disease. This procedure has enabled the dogs to see. Clinical trials are planned within the next two years. This discovery brings hope that gene therapy can be used to prevent and perhaps cure macular degeneration.

A new gene therapy technique, which suppresses the expression of genes, may have widespread application in a number of retinal degenerative diseases. Blood vessel growth in wet age-related macular degeneration is spurred by an over expression of a gene. Therefore, suppression of this gene may prevent abnormal blood vessel growth thereby reducing rapid vision loss associated with this form of age-related macular degeneration.

Environmental Issues

Environmental factors, including cigarette smoking, diet, blood pressure and sunlight are known to play a role in macular degeneration. Studies are underway to determine how these factors contribute to the onset of age-related macular degeneration.

Experimental Pharmaceutical Drugs

Several anti-angiogenic drugs that stop the growth of new blood vessels, are being tested by different pharmaceutical companies as a treatment for wet age-related macular degeneration. Most drugs cannot easily cross the blood/retina barrier. Therefore they must be “delivered” directly into the eye.

Drugs and Laser Therapy Treatments

Over the last 25 years, there have been a number of advances in the treatment of neovascular AMD including the use of thermal laser, photodynamic therapy (PDT) with verteporfin (Visudyne), and intravitreal injections of pegaptanib (Macugen). While each of these treatments has been shown to be modestly effective at slowing the rate of visual loss, the there has been much room for improvement. The development of Lucentis, a monoclonal antibody directed against VEGF, represents a major therapeutic improvement over existing therapies. Lucentis was approved for use in patients with choroidal neovascularization (CNV) by the Food and Drug Administration (FDA) in June 2006. Although highly effective, Lucentis requires frequent injections into the eye and is costly (about $2000 per injection). Other anti-VEGF agents are under development, as well as other drugs and treatments that use other mechanisms for controlling AMD.

Preventive Studies

Studies are underway using low-density lasers to destroy abnormal pigment (often a precursor to age-related macular degeneration) thereby reducing the rate of vision loss. If this study is 30% successful, this treatment could possibly eliminate 50% of bilateral blindness.

High-tech Intra-ocular Implants

Tests are underway to use a miniature telescope implanted in one eye as a means to improve the sight of patients with scars from age-related macular degeneration. It is not a cure - instead it is a method for projecting larger, brighter images to the retina. Two hundred patients are currently “implanted” with the device to test its safety and effectiveness. The surgery is an outpatient procedure. Many months are then devoted to follow-up and vision retraining.

Antioxidant Supplements and Zinc

Researchers from the National Institutes of Health/ National Eye Institute studied 3,640 people age 55 to 80 years old, with various stages of age-related macular degeneration, for an average of six years.

They found that taking an antioxidant supplement and zinc appears to slow the progression of vision loss from age-related macular degeneration. Those taking the antioxidant together with zinc had about a 25 percent reduced risk of age-related macular degeneration. Each person should consult his/her physician before taking vitamin supplements and use them only under a doctor’s supervision.

Diet

Eating dark, leafy green vegetables, such as collard greens, kale and spinach seemed to protect against the onset and progression of age-related macular degeneration. It is important to note that they did not prevent or cure the disease.

We are hopeful that we have introduced a positive picture of the many scientific pathways being explored to find the prevention, treatment and ultimately the cure for macular degeneration.