MACULAR DEGENERATION

Antioxidant Therapy

By Michael Oubre

INTRODUCTION

Macular Degeneration, frequently called AMD (age-related macular degeneration), is the leading cause of vision loss and blindness in Americans aged 65 and older. Because older people represent an increasingly larger percentage of the population, vision loss associated with AMD is a growing problem. To illustrate, in 2004, the Archives of Ophthalmology estimated that 1.75 million Americans had significant symptoms associated with AMD. That number is predicted to reach 3 million by the year 2020. Macular degeneration is a retinal degenerative disease that causes progressive loss of central vision. The risk of developing this disease increases with age, and it most often affects people in their sixties and seventies.

http://www.blindness.org/content.asp?id=46 http://www.allaboutvision.com/conditions/amd.htm

CLINICAL DESCRIPTION

Central vision loss from AMD is caused by degeneration of the macula. The macula is the central portion of the retina responsible for perceiving fine visual detail.

Light sensing cells in the macula, known as photoreceptors, convert light into electrical impulses and then transfer these impulses to the brain.

Central vision loss from AMD occurs when photoreceptor cells in the macula degenerate.

http://www.blindness.org/content.asp?id=46

www.maculardisease.org

CLINICAL DESCRIPTION

Individuals with Macular Degeneration may first notice a blurring of central vision that is most apparent when performing visually detailed tasks such as reading and sewing. Blurred central vision may also make straight lines appear slightly distorted or warped, and as the disease progresses, blind spots form within central vision. In most cases, if one eye has AMD, the other eye will also develop the disease. The extent of central vision loss varies according to the type of AMD.

http://www.blindness.org/content.asp?id=46

WHAT THEY SEE

Typical symptoms of advanced AMD

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Where Does AMD Come From?

Many forms of macular degeneration may be linked to aging and related deterioration of eye tissue. Duke University and other researchers have noted a strong association between AMD and the presence of a variant of a gene known as complement factor H (CFH). This gene deficiency is associated with almost half of all potentially blinding cases of AMD. Information released in March 2006 from Columbia University Medical Center indicates that variants of another gene, known as complement factor B, may be involved in development of AMD. Specific variants of one or both of these genes, which play a role in the body's immune responses, have been found in 74% of AMD patients who were studied.

http://www.allaboutvision.com/conditions/amd.htm

More CFH

CFH is a key regulator in the compliment system of our immune response. Researchers discovered that the drusen clots in Dry AMD consistently contain compliment components. This phenomenon is due to the variant CFHs inability to properly control the immune system. In 2005, a researcher named Hagemen stated that the CFH variant is located in exon 2 on chromosome 1q31. It was concluded that this variant greatly increases the risk of AMD with approximate odds ratios between 2 to 1 and 3 to 1.

http://www.sciencemag.org/cgi/reprint/sci;308/5720/385.pdf http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=134370

DIAGNOSIS

Macular degeneration usually produces a slow and painless loss of vision. Early signs of vision loss associated with AMD can include seeing shadowy areas in your central vision or experiencing unusually fuzzy or distorted vision. An eye-care practitioner often detects early signs of AMD before symptoms occur. Usually this is accomplished through a retinal examination. When macular degeneration is suspected, a brief test using an Amsler grid that measures your central vision may be performed. If the eyecare practitioner detects some defect in your central vision, such as distortion or blurriness, he or she may order a fluorescein angiography to specifically examine the retinal blood vessels surrounding the macula.

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DIAGNOSIS

Along with regular examinations by an eye doctor, individuals can test their eyesight for possible Macular Degeneration symptoms with a simple home test known as the Amsler Grid. The Amsler grid, consisting of parallel and perpendicular lines, looks much like a sheet of graph paper. By focusing on a marked spot in the middle of the grid, one can assess whether the lines appear blurred or distorted.

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The AMSLER GRID

Normal Vision

Macular Degeneration

While the Amsler Grid is not a substitute for expert medical diagnosis, it does allow individuals to check their eyesight regularly for possible symptoms of macular degeneration.
http://www.blindness.org/content.asp?id=46

Risk Factors

Researchers have discovered several risk factors that appear to be associated with AMD:

Age Cigarette Smoking Early Menopause Hypertension (high blood pressure) and/or cardiovascular disease A diet high in certain vegetable fats, especially those found in snack foods like potato chips Prolonged sun exposure Heredity Race

http://www.blindness.org/disease/riskfactors.asp?type=2

Risk Factors

Age - a persons age is by far the largest risk factor for AMD. It is estimated that 25% of the population between 65 and 74 have AMD. Above age 75, 33% have AMD. Cigarette Smoking - Cigarette smoking has been implicated as a great risk factor for AMD. Two separate studies found that current and former smokers, when compared with people who never smoked, had as much as twice the risk of developing AMD.

In former smokers of one pack or more a day, the risk of developing AMD remained elevated even after having quit for more than 15 years. Nonetheless, quitting smoking greatly reduces the risk of developing cigarette-related cancers, emphysema and heart disease.

http://www.blindness.org/disease/riskfactors.asp?type=2

Risk Factors

Estrogen and Early Menopause - researchers are examining the possibility of a link between estrogen production and the onset of AMD in women. Information gathered in recent years indicates there is a higher incidence of AMD in women, and that women who experience earlier onset of menopause may be at greater risk of developing the disease.

The National Institutes of Health currently supports a large, three-part study of womens post-menopausal health issues investigating risk factors for heart disease, osteoporosis, certain types of cancers, and AMD.

Elevated Blood Pressure - results from a recent study suggest that severe AMD is associated with moderate to severe elevations in blood pressure. Patients with wet AMD were more than 4 times as likely to have moderate to severe hypertension than those without macular degeneration.

http://www.blindness.org/disease/riskfactors.asp?type=2

Risk Factors

Dietary Fat Intake - a recent study found that high intake of monounsaturated, polyunsaturated and vegetable fats was associated with a twofold-increased risk of developing Wet AMD.

These fats are commonly found in snack foods such as potato chips, French fries, cakes and commercially prepared pies. In the same study, researchers also found that individuals who consumed little food containing linoleic acid and who ate two or more servings of fish per week showed a lower risk of developing macular degeneration.

Sun Exposure - previous studies have found that UV light exposure can damage cells through a process called oxidative stress. Some researchers have theorized that UV light exposure may damage the macula and lead to AMD.

However, light exposure studies have not yet found a definitive link to the development of macular degeneration.

http://www.blindness.org/disease/riskfactors.asp?type=2

Risk Factors

Heredity - recent studies have found that specific variants of two different genes are present in most people who have AMD. Race Caucasians are much more likely to develop AMD, while African-Americans have a much smaller chance of developing the disease.

http://www.ahaf.org/SubIndex/MDR_PDF_FactSheets/Macular%20Degeneration.pdf

How to reduce risk

Some experts believe that consumption of fish (high in DHA and EPA, healthy fatty acids) and nuts may help protect people from developing AMD. Recent studies have shown that the consumption of foods rich in antioxidants may lower AMD risk. Colorful fruits and vegetables, which are rich in the carotenoids lutein and zeaxanthin, may be protective, as well.

http://www.blindness.org/disease/treatment_detail.asp?type=2&id=6

Two Types of AMD

Dry Macular Degeneration = non-neovascular

Wet Macular Degeneration = neovascular

Neovascular refers to growth of new blood vessels in an area, such as the macula, where they are not supposed to be.

http://www.allaboutvision.com/conditions/amd.htm

DRY Macular Degeneration

Dry macular degeneration accounts for about 90 percent of all cases. Yellow-white deposits called drusen accumulate in the retinal pigment epithelium (RPE) beneath the macula. Drusen deposits are composed of waste products from photoreceptor cells, and for unknown reasons, RPE tissue can lose its ability to process waste. As a result, drusen deposits accumulate in the RPE. These deposits are thought to interfere with the function of photoreceptors in the macula, causing progressive degeneration of these cells.

http://www.blindness.org/content.asp?id=46

http://www.ahaf.org/macular/about/Normal_Dry_Wet.htm

DRY Macular Degeneration

The symptoms of Dry AMD are not nearly as severe as those of Wet AMD. Vision loss due to Dry AMD occurs very slowly over the course of many years. Central vision may even remain stable between annual eye examinations. Individuals with macular degeneration do not usually experience a total loss of central vision. However, vision loss may make it difficult to perform tasks that require finely focused vision.

http://www.blindness.org/content.asp?id=46
http://www.allaboutvision.com/conditions/amd.htm

Treatments for Dry AMD

AREDS formulation The Age-Related Eye Disease Study (AREDS) a landmark investigation conducted by the National Eye Institute (NEI) determined that antioxidant supplementation can slow (but not prevent) the progression of AMD. The AREDS formulation is an over-the-counter antioxidant supplement recommended for people who are at risk of developing more advanced forms of either dry or wet AMD. The AREDS formulation includes the antioxidants beta carotene, vitamin E, and vitamin C, as well as the nutrients zinc and copper.

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Treatments for Dry AMD

AREDS researches found that people at risk of developing advanced stages of AMD, lowered their risk by about 25% when treated with a high-dose combination of vitamin C, vitamin E, beta-carotene, and zinc. The director of NEI, Dr. Paul Sieving, says, The nutrients are not a cure for AMD, nor will they restore vision already lost from the disease, but they will play a key role in helping people at high risk for developing advanced AMD keep their vision."

http://clinicaltrials.gov/ct/show/NCT00306488

The AREDS Study Summary

The AREDS study involved 4,757 participants, 55-80 years of age, in 11 clinical centers nationwide. Participants in the study were given one of four treatments: 1) zinc alone; 2) antioxidants alone; 3) a combination of antioxidants and zinc; or 4) a placebo. The benefits of the nutrients were seen only in people who began the study at high risk for developing advanced AMD -- those with intermediate AMD, and those with advanced AMD in one eye only. In this group, those taking "antioxidants plus zinc" had the lowest risk of developing advanced stages of AMD. Those in the "zinc alone" or "antioxidant alone" groups also reduced their risk of developing advanced AMD, but at more moderate rates compared to the "antioxidants plus zinc" group. Those in the placebo group had the highest risk of developing advanced AMD. Researches also found that some people with intermediate AMD may not wish to take large doses of antioxidant vitamins or zinc because of medical reasons. For example, beta-carotene has been shown to increase the risk of lung cancer among smokers.

http://clinicaltrials.gov/ct/show/NCT00306488

Emerging Treatments for Dry AMD

OT-551 = Antioxidant Eye Drops currently being developed in clinical trials

Otheras OT-551 is intended to supplement the eyes natural defense system against disease and injury. Permeating tissues at both the front of the eye (lens) and back of the eye (retina), researchers hope that OT-551 will provide antioxidant protection against cataracts and dry AMD.

http://www.blindness.org/disease/treatment_detail.asp?type=2&id=6

Emerging Treatments for Dry AMD

Encapsulated Cell Technology (ECT)

the ECT is a tiny capsule (6 mm long) implanted into the eye. The capsule contains retinal cells that have been genetically engineered to produce produce a vision-preserving protein called Ciliary Neurotrophic Factor (CNTF). The capsule delivery method is favorable because it allows CNTF to diffuse over long periods of time. The protein helps keep photoreceptors alive and healthy, thereby preserving vision. The ECT is currently in a Phase II human clinical trial for people with dry AMD.

http://www.blindness.org/disease/treatment_detail.asp?type=2&id=6 http://209.85.165.104/search?q=cache:uCEvMUxDty0J:www.nih.gov/about/researchresultsforthepublic/M acularDegeneration.pdf+CNTF+macular&hl=en&ct=clnk&cd=1&gl=us

Wet Macular Degeneration

In about 10% of cases, dry AMD progresses to a more advanced and damaging disease known as Wet Macular Degeneration. With Wet AMD, new blood vessels grow (neovascularization) beneath the retina causing a leakage of blood and fluid. This leakage causes permanent damage to light-sensitive retinal cells, which then die off and create blind spots in central vision. Wet macular degeneration tends to progress rapidly and can cause severe damage to central vision.

http://www.blindness.org/content.asp?id=46 http://www.allaboutvision.com/conditions/amd.htm

http://www.ahaf.org/macular/about/Normal_Dry_Wet.htm

WET Macular Degeneration

In some cases, if diagnosed early, laser surgery can prevent extensive central vision loss. In this type of surgery, laser beams destroy the leaky blood vessels that form beneath the macula. For laser surgery to be effective, it is critical that wet macular degeneration be diagnosed before extensive vision loss occurs. Therefore, individuals should consult with an eye doctor at the first sign of blurred or distorted central vision.

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Current Treatments for Wet AMD

Lucentis (ranibizumab) The FDA approved Lucentis in June 2006 for the treatment of wet AMD.

Lucentis (ranibizumab) is a humanized anti-VEGF antibody fragment that inhibits VEGF activity by competitively binding with VEGF.

VEGF = Vascular Endothelial Growth Factor is an important protein involved in the initiation of neovascular growth. So by inhibiting VEGF, Lucentis prevents further growth of unwanted blood vessels on macula.

A two-year study showed that 95 percent of people with wet AMD who received monthly injections of Lucentis experienced no significant loss in visual acuity. Genentech also reported moderate visual improvement in 24.8 percent of participants treated with a 0.3 mg dose of Lucentis and 33.8 percent of participants treated with a 0.5 mg dose.

http://www.blindness.org/disease/treatment_detail.asp?type=2&id=6
http://en.wikipedia.org/wiki/VEGF

http://www.agingeye.net/mainnews/lucentis.php

Current Treatments for Wet AMD

Macugen (pegaptanib) The FDA approved Macugen in December 2004 for the treatment of wet AMD.

Mucagen is an Aptamer a DNA or RNA strand that binds to a particular target (VEGF).

Mucagen, like Lucentis, is an anti-VEGF drug that prevents unwanted neovascularization.

In clinical studies, approximately 70 percent of patients treated with Macugen experienced no significant vision loss.

http://www.blindness.org/disease/treatment_detail.asp?type=2&id=6
http://cancerweb.ncl.ac.uk/cgi-bin/omd?query=aptamer&action=Search+OMD

Current Treatments for Wet AMD

Visudyne (verteporfin) and Photodynamic Therapy (PDT) this medicine contains the active ingredient verteporfin, which is a light-activated medicine. Verteporfin has no effect on its own, but in the presence of light and oxygen, it reacts with oxygen to produce a cell-killing (cytotoxic) effect. Verteporfin is used in the photodynamic treatment of eye disorders involving abnormal growth of blood vessels in the back of the eye. In this treatment, Visudyne is injected intravenously. When the drug reaches the eye, a low-intensity laser is directed to the region of blood vessel growth, activating the drug, which destroys the unhealthy vessels.

http://www.blindness.org/disease/treatment_detail.asp?type=2&id=6
http://www.tiscali.co.uk/lifestyle/healthfitness/health_advice/netdoctor/archive/100004709.html

Schematic of Visudynes action.

Notice that when Verteporfin is lightactivated, the targeted blood vessels are destroyed. In step 7, the patients eye is free of the unwanted vessels.
http://www.science.ca/images/scientists/s1-levy.jpg

Emerging Treatments for Wet AMD

AdPEDF a possible gene therapy treatment for wet AMD that is in clinical trials. The name of the treatment is adenovirus-based Pigment Epithelium Derived Factor (AdPEDF). The AdPEDF treatment involves the delivery of a gene that leads to the production of the protein PEDF, which helps keep photoreceptors healthy, thereby preserving vision.

The company believes that AdPEDF will preserve vision in people with a variety of retinal degenerative diseases including dry AMD.

siRNA (bevasiranib) is an innovative technology that silences the genes that lead to the growth of unhealthy, vision-robbing blood vessels under the retina. The treatment has showed safety and efficacy in a Phase II study. A Phase III clinical trial is planned.

http://www.blindness.org/disease/treatment_detail.asp?type=2&id=6

More Research

Complement Factor H (CFH) gene In early 2005, FFB-funded researchers identified variations in a gene known as CFH, which are implicated in as many as 50 percent of all cases of AMD. In early 2006, these same investigators found that variations in CFH along with variations in two other newly identified genes, factor B (BF) and complement component (C2), are present in 74 percent of AMD cases. Though the environmental and genetic causes of AMD are complex and not completely understood, these landmark findings confirm a genetic influence on the development of AMD. And, these genes give a clear target for the development of future, more effective therapies. Specifically, the CFH finding strongly suggests that the immune system and related inflammatory responses are key factors in the development of AMD. Future therapies may be directed toward stopping the effects of CFH variations and other related genes. Scientists believe more AMDrelated genes will be identified in the near future. FFB continues to fund genetic research for AMD, because the identification of genetic risk factors will give experts the best targets for preventions and cures.

http://www.blindness.org/disease/treatment_detail.asp?type=2&id=6

More Research

FFBs Stem Cell Consortium FFB oversees a consortium of investigators working to advance the development of stem cell therapies to regenerate retinal tissue, and restore vision in people significantly affected by AMD and other retinal degenerative diseases. Stem cell therapies also show promise as neuroprotective treatments, providing protection for the remaining, functioning photoreceptors of people affected by AMD and other diseases.

http://www.blindness.org/disease/treatment_detail.asp?type=2&id=6

More Research

Retinal transplantation A Phase II human study of retinal transplantation is in progress for people with severe vision loss, including those affected by AMD. Though the investigation is still at an early stage, researchers are making encouraging progress. The researchers are perfecting the procedure for transplanting delicate retinal tissue, minimizing tissue rejection, and testing methods to get the transplanted retinas to integrate with the recipients tissues.

http://www.blindness.org/disease/treatment_detail.asp?type=2&id=6

More Research

Artificial retinas (retinal chips) Though still in the early stage of development, artificial retinas offer hope for people who have lost all or most of their vision from advanced retinal degenerative diseases, including AMD. Most artificial retinas are being designed to replace lost photoreceptors and other retinal tissue. The artificial devices are designed to convert light into images, and send them back to the brain via the optic nerve. One device, designed by Mark Humayan, M.D., Ph.D., Doheny Eye Institute, University of California, Los Angeles, is in a human clinical trial, and is enabling patients to see light and basic shapes. This device includes a video camera, which is mounted on a pair of glasses. Images from the camera are relayed to the artificial chip, which in turn sends them to the optic nerve.

http://www.blindness.org/disease/treatment_detail.asp?type=2&id=6

Sources

http://www.blindness.org/content.asp?id=46 http://www.allaboutvision.com/conditions/amd.htm www.maculardisease.org http://www.sciencemag.org/cgi/reprint/sci;308/5720/385.pdf http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=134370 http://www.blindness.org/disease/riskfactors.asp?type=2 http://www.ahaf.org/SubIndex/MDR_PDF_FactSheets/Macular%20Degeneration.pdf http://www.ahaf.org/macular/about/Normal_Dry_Wet.htm http://clinicaltrials.gov/ct/show/NCT00306488 http://209.85.165.104/search?q=cache:uCEvMUxDty0J:www.nih.gov/about/researchresultsforthepublic/Macula rDegeneration.pdf+CNTF+macular&hl=en&ct=clnk&cd=1&gl=us http://en.wikipedia.org/wiki/VEGF http://cancerweb.ncl.ac.uk/cgi-bin/omd?query=aptamer&action=Search+OMD http://www.tiscali.co.uk/lifestyle/healthfitness/health_advice/netdoctor/archive/100004709.html http://www.science.ca/images/scientists/s1-levy.jpg