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8/12/2019 ARMD Study

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MACULAR DEGENERATION

Antioxidant Therapy

By Michael Oubre


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INTRODUCTION Macular Degeneration, frequently called AMD (age-related maculardegeneration), is the leading cause of vision loss and blindness in

Americans aged 65 and older.Because older people represent an increasingly larger percentage of thepopulation, vision loss associated with AMD is a growing problem.To illustrate, in 2004, the Archives of Ophthalmology estimated that 1.75million Americans had significant symptoms associated with AMD. Thatnumber is predicted to reach 3 million by the year 2020.Macular degeneration is a retinal degenerative disease that causesprogressive loss of central vision.The risk of developing this disease increases with age, and it most oftenaffects people in their sixties and seventies.

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


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CLINICAL DESCRIPTION

Central vision loss from AMD is caused bydegeneration of the macula .The macula is the central portion of the retinaresponsible 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 whenphotoreceptor cells in the macula degenerate .

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


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www.maculardisease.org


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CLINICAL DESCRIPTION

Individuals with Macular Degeneration may first noticea blurring of central vision that is most apparent whenperforming visually detailed tasks such as reading andsewing.Blurred central vision may also make straight linesappear slightly distorted or warped, and as the diseaseprogresses, blind spots form within central vision.In most cases, if one eye has AMD, the other eye willalso develop the disease. The extent of central visionloss varies according to the type of AMD.



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WHAT THEY SEE

Typical symptoms ofadvanced AMD


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Where Does AMD Come From?Many forms of macular degeneration may be linked to aging andrelated deterioration of eye tissue.

Duke University and other researchers have noted a strongassociation between AMD and the presence of a variant of a geneknown as complement factor H (CFH). This gene deficiency isassociated with almost half of all potentially blinding cases of

AMD.Information released in March 2006 from Columbia UniversityMedical Center indicates that variants of another gene, known ascomplement factor B , may be involved in development of AMD.Specific variants of one or both of these genes, which play a rolein the body's immune responses, have been found in 74% of AMD

patients who were studied.

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


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More CFH

CFH is a key regulator in the compliment system of ourimmune response.Researchers discovered that the drusen clots in Dry

AMD consistently contain compliment components.This phenomenon is due to the variant CFHs inabilityto properly control the immune system.

In 2005, a researcher named Hagemen stated that theCFH variant is located in exon 2 on chromosome 1q31.It was concluded that this variant greatly increases therisk of AMD with approximate odds ratios between 2 to1 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
http://www.sciencemag.org/cgi/reprint/sci;308/5720/385.pdfhttp://www.sciencemag.org/cgi/reprint/sci;308/5720/385.pdf


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DIAGNOSIS Macular degeneration usually produces a slow and painless lossof vision.

Early signs of vision loss associated with AMD can include seeingshadowy areas in your central vision or experiencing unusuallyfuzzy or distorted vision.

An eye-care practitioner often detects early signs of AMD beforesymptoms occur. Usually this is accomplished through a retinalexamination.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 centralvision, such as distortion or blurriness, he or she may order afluorescein angiography to specifically examine the retinal blood

vessels surrounding the macula.http://www.blindness.org/content.asp?id=46


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The AMSLER GRID


Normal Vision Macular Degeneration

While the Amsler Grid is not a substitute for expert medicaldiagnosis, it does allow individuals to check their eyesight regularlyfor possible symptoms of macular degeneration.


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Risk Factors

Researchers have discovered several risk factors thatappear 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


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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 beenimplicated as a great risk factor for AMD. Two separatestudies found that current and former smokers, whencompared 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 formore than 15 years. Nonetheless, quitting smoking greatlyreduces the risk of developing cigarette-related cancers,emphysema and heart disease.



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Risk Factors Estrogen and Early Menopause - researchers are examining thepossibility of a link between estrogen production and the onset of

AMD in women. Information gathered in recent years indicates thereis a higher incidence of AMD in women, and that women whoexperience earlier onset of menopause may be at greater risk ofdeveloping the disease. The National Institutes of Health currently supports a large, three-part

study of womens post -menopausal health issues investigating riskfactors for heart disease, osteoporosis, certain types of cancers, and

AMD.Elevated Blood Pressure - results from a recent study suggest thatsevere AMD is associated with moderate to severe elevations inblood pressure. Patients with wet AMD were more than 4 times aslikely to have moderate to severe hypertension than those withoutmacular degeneration.



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Risk Factors Dietary Fat Intake - a recent study found that high intake ofmonounsaturated, polyunsaturated and vegetable fats wasassociated 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 samestudy, researchers also found that individuals who consumed littlefood containing linoleic acid and who ate two or more servings of fishper week showed a lower risk of developing macular degeneration.

Sun Exposure - previous studies have found that UV lightexposure can damage cells through a process called oxidativestress. Some researchers have theorized that UV light exposuremay 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


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Risk Factors

Heredity - recent studies have found that specificvariants of two different genes are present in mostpeople who have AMD.Race Caucasians are much more likely to develop

AMD, while African-Americans have a much smallerchance of developing the disease.

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


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How to reduce risk

Some experts believe that consumption of fish(high in DHA and EPA, healthy fatty acids) andnuts may help protect people from developing

AMD.Recent studies have shown that theconsumption of foods rich in antioxidants maylower AMD risk. Colorful fruits and vegetables,which are rich in the carotenoids lutein andzeaxanthin, may be protective, as well.

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


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DRY Macular Degeneration Dry macular degeneration accounts for about 90 percent of allcases.

Yellow-white deposits called drusen accumulate in the retinalpigment epithelium (RPE) beneath the macula.Drusen deposits are composed of waste products fromphotoreceptor cells, and for unknown reasons, RPE tissue canlose its ability to process waste. As a result, drusen deposits

accumulate in the RPE.These deposits are thought to interfere with the function ofphotoreceptors in the macula, causing progressive degenerationof these cells.



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


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DRY Macular Degeneration The symptoms of Dry AMD are not nearly as severe asthose of Wet AMD.

Vision loss due to Dry AMD occurs very slowly over thecourse of many years. Central vision may even remainstable between annual eye examinations.Individuals with macular degeneration do not usually

experience a total loss of central vision. However, visionloss may make it difficult to perform tasks that require finelyfocused vision.



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Treatments for Dry AMD AREDS formulation The Age-Related Eye DiseaseStudy (AREDS) a landmark investigation conducted by

the National Eye Institute (NEI) determined thatantioxidant supplementation can slow (but not prevent) theprogression of AMD.The AREDS formulation is an over-the-counter antioxidantsupplement recommended for people who are at risk of

developing more advanced forms of either dry or wet AMD.The AREDS formulation includes the antioxidants betacarotene, vitamin E, and vitamin C, as well as the nutrientszinc and copper.



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Treatments for Dry AMD AREDS researches found that people at risk ofdeveloping advanced stages of AMD, lowered their risk

by about 25% when treated with a high-dosecombination of vitamin C, vitamin E, beta-carotene,and zinc.The director of NEI, Dr. Paul Sieving, says, Thenutrients are not a cure for AMD, nor will they restorevision already lost from the disease, but they will play akey role in helping people at high risk for developingadvanced AMD keep their vision."

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


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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 withadvanced 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 "zincalone" 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 totake large doses of antioxidant vitamins or zinc because of medical reasons. Forexample, beta-carotene has been shown to increase the risk of lung cancer amongsmokers.



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Emerging Treatments for Dry AMD

OT-551 = Antioxidant Eye Drops currentlybeing developed in clinical trials Otheras OT -551 is intended to supplement the

eyes natural defense system against disease andinjury.

Permeating tissues at both the front of the eye(lens) and back of the eye (retina), researchershope that OT-551 will provide antioxidant protectionagainst cataracts and dry AMD.



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Emerging Treatments for Dry AMDEncapsulated 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 proteincalled Ciliary Neurotrophic Factor (CNTF).

The capsule delivery method is favorable because it allowsCNTF 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://209.85.165.104/search?q=cache:uCEvMUxDty0J:www.nih.gov/about/researchresultsforthepublic/MacularDegeneration.pdf+CNTF+macular&hl=en&ct=clnk&cd=1&gl=us
http://www.blindness.org/disease/treatment_detail.asp?type=2&id=6http://www.blindness.org/disease/treatment_detail.asp?type=2&id=6


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Wet Macular Degeneration In about 10% of cases, dry AMD progresses to a moreadvanced and damaging disease known as Wet Macular

Degeneration.With Wet AMD, new blood vessels grow(neovascularization) beneath the retina causing a leakageof blood and fluid. This leakage causes permanent damageto light-sensitive retinal cells, which then die off and createblind spots in central vision.Wet macular degeneration tends to progress rapidly andcan cause severe damage to central vision.



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WET Macular Degeneration

In some cases, if diagnosed early, laser surgery canprevent extensive central vision loss. In this type ofsurgery, laser beams destroy the leaky blood vesselsthat form beneath the macula.For laser surgery to be effective, it is critical that wetmacular degeneration be diagnosed before extensive

vision loss occurs. Therefore, individuals shouldconsult with an eye doctor at the first sign of blurred ordistorted central vision.



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Current Treatments for Wet AMD Lucentis (ranibizumab) The FDA approved Lucentis inJune 2006 for the treatment of wet AMD.

Lucentis (ranibizumab) is a humanized anti-VEGF antibodyfragment that inhibits VEGF activity by competitively bindingwith VEGF.

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

A two-year study showed that 95 percent of people with wet AMDwho received monthly injections of Lucentis experienced nosignificant loss in visual acuity. Genentech also reported moderatevisual improvemen t in 24.8 percent of participants treated with a 0.3mg dose of Lucentis and 33.8 percent of participants treated with a0.5 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


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Current Treatments for Wet AMD

Macugen (pegaptanib) The FDAapproved Macugen in December 2004for 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 drugthat prevents unwanted neovascularization.

In clinical studies, approximately 70 percentof patients treated with Macugen experiencedno 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


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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, butin the presence of light and oxygen, it reacts with oxygen toproduce a cell-killing (cytotoxic) effect.Verteporfin is used in the photodynamic treatment of eye disordersinvolving abnormal growth of blood vessels in the back of the eye.

In this treatment, Visudyne is injected intravenously. When thedrug reaches the eye, a low-intensity laser is directed to the regionof blood vessel growth, activating the drug, which destroys theunhealthy 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


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https://reader010.{domain}/reader010/html5/0617/5b25d4ab00fd3/5b25d4bb0ff27.jpg

Notice that whenVerteporfin is light-

activated, the targeted blood vessels are

destroyed. In step 7,the patients eye is freeof the unwanted

vessels.

Schematic of

Visudynes action .


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Emerging Treatments for Wet AMDAdPEDF a possible gene therapy treatment for wet AMD that isin clinical trials. The name of the treatment is adenovirus-basedPigment Epithelium Derived Factor (AdPEDF). The AdPEDFtreatment involves the delivery of a gene that leads to theproduction of the protein PEDF , which helps keep photoreceptorshealthy, 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 silencesthe genes that lead to the growth of unhealthy, vision-robbingblood vessels under the retina. The treatment has showed safetyand efficacy in a Phase II study. A Phase III clinical trial isplanned.



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More Research Complement Factor H (CFH) gene In early 2005, FFB-funded researchersidentified variations in a gene known as CFH, which are implicated in as many as50 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 notcompletely understood, these landmark findings confirm a genetic influence onthe development of AMD. And, these genes give a clear target for the developmentof 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 CFHvariations and other related genes.

Scientists believe more AMD related genes will be identified in the near future.FFB continues to fund genetic research for AMD, because the identification ofgenetic risk factors will give experts the best targets for preventions and cures.



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More Research FFBs Stem Cell Consortium FFB oversees a consortium ofinvestigators working to advance the development of stem cell

therapies to regenerate retinal tissue , and restore vision inpeople significantly affected by AMD and other retinaldegenerative diseases.Stem cell therapies also show promise as neuroprotectivetreatments, providing protection for the remaining, functioning

photoreceptors of people affected by AMD and other diseases.



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More Research Retinal transplantation A Phase II human study ofretinal transplantation is in progress for people withsevere vision loss, including those affected by AMD.Though the investigation is still at an early stage,researchers are making encouraging progress. Theresearchers are perfecting the procedure for

transplanting delicate retinal tissue, minimizing tissuerejection, and testing methods to get the transplantedretinas to integrate with the recipients tissues.



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More Research Artificial retinas (retinal chips) Though still in the early stage ofdevelopment, artificial retinas offer hope for people who have lost all ormost of their vision from advanced retinal degenerative diseases,

including AMD.Most artificial retinas are being designed to replace lost photoreceptorsand other retinal tissue. The artificial devices are designed to convert lightinto images, and send them back to the brain via the optic nerve.One device, designed by Mark Humayan, M.D., Ph.D., Doheny EyeInstitute, University of California, Los Angeles, is in a human clinical trial,

and is enabling patients to see light and basic shapes . This deviceincludes a video camera, which is mounted on a pair of glasses. Imagesfrom the camera are relayed to the artificial chip, which in turn sendsthem to the optic nerve.



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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.pdfhttp://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=134370


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



http://209.85.165.104/search?q=cache:uCEvMUxDty0J:www.nih.gov/about/researchresultsforthepublic/MacularDegeneration.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

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