RxPG News : ARMD

Deficiency of the Dicer enzyme in retinal cells linked to age-related macular degeneration

Sun, 06 Feb 2011 16:45:23 PST

( from http://www.rxpgnews.com ) A team of researchers, led by University of Kentucky ophthalmologist Dr. Jayakrishna Ambati, has discovered a molecular mechanism implicated in geographic atrophy, the major cause of untreatable blindness in the industrialized world.

Their article, "DICER1 Deficit Induces Alu RNA Toxicity in Age-Related Macular Degeneration," was published online by the journal Nature on Feb. 6 (DOI: 10.1038/nature09830).

Concurrent with this discovery, Ambati's laboratory developed two promising therapies for the prevention of the condition. This study also elaborates, for the first time, a disease-causing role for a large section of the human genome once regarded as non-coding "junk DNA."

Geographic atrophy, a condition causing the death of cells in the retina, occurs in the later stages of the "dry type" of macular degeneration, a disease affecting some 10 million older Americans and causing blindness in over 1 million. There is currently no effective treatment for geographic atrophy, as its cause is unknown.

Ambati's team discovered that an accumulation of a toxic type of RNA, called Alu RNA, causes retinal cells to die in patients with geographic atrophy. In a healthy eye, a "Dicer" enzyme degrades the Alu RNA particles.

"We discovered that in patients with geographic atrophy, there is a dramatic reduction of the Dicer enzyme in the retina," said Ambati, professor and vice chair of the Department of Ophthalmology and Visual Sciences and the Dr. E. Vernon and Eloise C. Smith Endowed Chair in Macular Degeneration Research at the UK College of Medicine. "When the levels of Dicer decline, the control system is short-circuited and too much Alu RNA accumulates. This leads to death of the retina."

Alu elements make up a surprisingly large portion — about 11 percent by weight — of the human genome, comprising more than 1 million sequences. However, their function has been unknown, so they have been called "junk" DNA or part of the "dark" genome. The discovery of Alu's toxicity and its control by Dicer should prove of great interest to other researchers in the biological sciences, Ambati says.

Ambati's team developed two potential therapies aimed at preventing geographic atrophy and demonstrated the efficacy of both approaches using laboratory models. The first involves increasing Dicer levels in the retina by "over-expressing" the enzyme. The second involves blocking Alu RNA using an "anti-sense" drug that binds and degrades this toxic substance. UK has filed patent applications for both technologies, and Ambati's group is preparing to start clinical trials by the end of this year.

Response from the scientific community has been enthusiastic.

"These findings provide important new clues on the biological basis of geographic atrophy and may provide avenues for intervention through preventing toxic accumulation of abnormal RNA products," said Dr. Paul Sieving, director of the National Eye Institute.

"Ambati's latest research provides important mechanistic insights in geographic atrophy, and identification of this novel pathway may result in new therapeutic targets for a major cause of blindness," said Dr. Napoleone Ferrara, a member of the National Academy of Sciences and Lasker-DeBakey awardee who is a researcher at Genentech.

This work has "widespread implications" for future study, said Dr. Stephen J. Ryan, president of the Doheny Eye Institute and member of the Institute of Medicine.

"The authors have opened an important line of research with real possibilities for future therapeutic intervention for patients with geographic atrophy," Ryan said.

Quit smoking to save your eyes

Fri, 01 Jan 2010 11:09:08 PST

( from http://www.rxpgnews.com ) A UCLA study finds that even after age 80, smoking continues to increase one's risk for age-related macular degeneration (AMD), the leading cause of blindness in Americans over 65.

The American Journal of Ophthalmology publishes the findings in its January edition.

"The take-home message is that it's never too late to quit smoking," said lead author Dr. Anne Coleman, professor of ophthalmology at the Jules Stein Eye Institute at UCLA. "We found that even older people's eyes will benefit from kicking the habit."

AMD causes progressive damage to the macula, the center of the retina that allows us to see fine details. When the macula degenerates, people experience darkness or blurring in their central vision, preventing them from being able to read, drive and recognize faces.

After age, smoking is the second most common risk factor for AMD. This study sought to determine whether age influences the effects of smoking on AMD risk.

Coleman and her colleagues followed a group of 1,958 women who underwent retinal photographs at five-year intervals, starting with a baseline exam at age 78. Four percent, or 75 of the women, smoked.

The researchers compared the retinal images at ages 78 and 83 to check for the appearance of AMD, and evaluate whether smoking affected the women's likelihood of developing the disease.

"Age is the strongest predictor for AMD, yet most of the research in this field has been conducted in people younger than 75," explained Coleman. "Our population was considerably older than those previously studied. This research provides the first accurate snapshot of how smoking affects AMD risk later in life."

Overall, women who smoked had 11 percent higher rates of AMD than other women their same age. In women over 80, however, those who smoked were 5.5 times more likely to develop AMD than women their age who did not smoke.

"We saw a slightly higher rate of AMD in women after age 80, but the rate was dramatically higher in older women who smoked," said Coleman. "The bottom line is that AMD risk increases with age. And if you smoke, your risk of developing the disease rises even more."

Cigarette smoking has been hypothesized to increase AMD risk by reducing serum antioxidant levels, altering blood flow to the eyes and decreasing retinal pigments.

"This study provides yet another compelling reason to stop smoking and suggests that it is never too late to quit," said Dr. Paul Sieving, director of the National Eye Institute.

Post Menopausal Hormones - reduces risk of macular degeneration

Mon, 14 Apr 2008 13:52:27 PST

( from http://www.rxpgnews.com ) Women who take postmenopausal hormones appear to have a lower risk of developing advanced stages of the eye disease age-related macular degeneration, especially if they had also taken oral contraceptives in the past, according to a report in the April issue of Archives of Ophthalmology, one of the JAMA/Archives journals.

Age-related macular degeneration (AMD) is the leading cause of vision loss and blindness among older adults, affecting 1.75 million Americans, according to background information in the article. “Although genetics plays a key role in susceptibility to AMD, environmental factors, such as smoking, are also important,” the authors write. “Evidence of higher rates of AMD in women than in men and links between AMD and cardiovascular disease suggested a role for estrogen in the etiology” or development of the condition.

Diane Feskanich, Sc.D., of Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues assessed estrogen-related factors such as postmenopausal hormone use, past use of oral contraceptives, ages at first period and menopause and childbirth history in 74,996 post-menopausal women in the Nurses’ Health Study. Between 1980 and 2002, 554 of the women developed early (beginning-stage) AMD and 334 women developed neovascular (more advanced, involving the formation of new blood vessels) AMD.

“Current postmenopausal hormone users had a notable 48 percent lower risk of neovascular AMD compared with those who had never used postmenopausal hormones, although risk did not decline linearly with longer durations of use,” the authors write. “Risk was lowest for postmenopausal hormone users who had used oral contraceptives in the past.”

In contrast, risk of early AMD was 34 percent higher among current postmenopausal hormone users and oral contraceptive use was not associated with early AMD risk. “The higher risk of early AMD among postmenopausal hormone users was unexpected and in apparent conflict with the observed inverse association for neovascular AMD,” the authors write. Women who had given birth had a 26 percent lower risk of early AMD.

“Taken together, these findings suggest a role for estrogen in the pathogenesis of AMD that requires further research in specific early and late signs of disease,” they conclude.

Higher fish consumption have a reduced risk of advanced age-related macular degeneration

Mon, 14 May 2007 20:33:58 PST

( from http://www.rxpgnews.com ) Individuals who have higher dietary intake of foods with omega-3 fatty acids and higher fish consumption have a reduced risk of advanced age-related macular degeneration, while those with higher serum levels of vitamin D may have a reduced risk of the early stages of the disease, according to two reports in the May issue of Archives of Ophthalmology, one of the JAMA/Archives journals.

Age-related macular degeneration (AMD) occurs when the macula, the area at the back of the retina that produces the sharpest vision, deteriorates over time. It is the most common cause of blindness among older adults in the United States, affecting more than 7 million individuals older than 40 years, according to background information in the articles. The prevalence of AMD is likely to increase as the population ages. There is currently no known way to prevent the condition, but research has begun to identify potentially modifiable risk factors and nutrient-based treatments.

The Age-Related Eye Disease Study Research Group assessed 4,519 individuals who were age 60 to 80 when they enrolled in 1992 through 1998. At that time, photographs were taken of their retinas to determine if they had AMD, and if so, to which of four stages the condition had progressed. The participants also completed a food frequency questionnaire that measured how often they consumed foods rich in certain vitamins, minerals and other nutrients, such as omega-3 fatty acids commonly found in tuna, salmon and other fish.

A total of 1,115 participants did not have any symptoms of AMD at the beginning of the study, and were compared with those who did, including 658 individuals with neovascular (severe) AMD. "Dietary total omega-3 long-chain polyunsaturated fatty acid intake was inversely associated with neovascular AMD, as was docosahexaenoic acid," or DHA, a fatty acid that previous evidence suggests affects the retina, the authors write. "Higher fish consumption, both total and broiled/baked, was also inversely associated with neovascular AMD." Eating more than two medium (4-ounce) servings of fish per week or more than one medium serving of broiled or baked fish was associated with the lowest risk for advanced AMD.

Omega-3 fatty acids may influence processes involved in the development of blood vesselâ and nerve-related diseases of the retina, the authors write. For instance, DHA may protect the retina by influencing which genes turn on and off, while fatty acids overall may eventually form compounds that promote cell survival and proper blood vessel function, reduce inflammation and maintain energy balance.

"These results and those from other observational analytic investigations suggest that modifying diet to include more foods rich in omega-3 long-chain polyunsaturated fatty acids could result in a reduction in the risk of having neovascular AMD," the authors conclude. Clinical trials would provide further information about whether diet changes or supplements could prevent the development of advanced AMD.

In a related study, Niyati Parekh, Ph.D., R.D., of the University of the Medicine and Dentistry of New Jersey, New Brunswick, and the University of WisconsinâMadison, and colleagues analyzed data from 7,752 individuals (including 11 percent with AMD) who were part of the National Health and Nutrition Examination Survey, a large study designed to represent the entire U.S. population. Participants were enrolled in the study between 1988 and 1994. They had physical examinations that included blood and urine samples, photographs of the retinas, and interviews and questionnaires regarding sociodemographics, lifestyle habits and food intake.

"Levels of serum vitamin D were inversely associated with early AMD but not advanced AMD," the authors write. When participants were split into five groups based on level of vitamin D in the blood, those in the highest group had a 40 percent lower risk of early AMD than those in the lowest group. "Milk intake was inversely associated with early AMD. Fish intake was inversely associated with advanced AMD."

Vitamin D may reduce the risk of AMD by reducing inflammation or by preventing the growth of new blood vessels in the retina, which contributes to some forms of AMD, the authors speculate. "This study provides evidence that vitamin D may protect against AMD," the authors conclude. "However, at this time there is insufficient epidemiologic evidence of the relationship between vitamin D level and AMD to make recommendations regarding optimum serum vitamin D levels or milk and fish intake to protect against AMD or its progression. The results of the present research warrant further investigation for confirmation of the vitamin D-AMD association in other population studies."

HTRA1 gene linked to aggressive 'wet' age-related macular degeneration

Thu, 23 Nov 2006 21:13:40 PST

( from http://www.rxpgnews.com ) A gene variant that increases the risk of developing the aggressive "wet" form of age-related macular degeneration (AMD), the most common cause of blindness in people over age 50, is reported in two recent articles in Science by researchers at Yale School of Medicine.

AMD causes light-sensitive cells in the retina to break down, resulting in progressive loss of central vision. Of the two forms of AMD, the "dry" is more common than the "wet" form. Wet macular degeneration can rapidly lead to blindness, while the dry AMD progresses more slowly.

Last year, Josephine Hoh, associate professor in the Departments of Epidemiology & Public Health and Ophthalmology at Yale and senior author on one of the two new studies, identified a gene for dry AMD and found that both wet and dry AMD are associated with a variant in the complement factor H (CFH) gene on chromosome 1.

Hoh now reports they have found a single nucleotide polymorphism (SNP)—a one-base change in the sequence—of the regulatory part of the HTRA1 gene on chromosome 10 that leads to greatly increased risk of developing the wet form of AMD.

According to Hoh, buildup of abnormal blood vessels in Caucasian patients is compounded by development of large waste deposits called drusen. Chinese patients, she said, develop little to no drusen and progress directly to wet AMD. This study demonstrates that these two major genes, CFH and HTRA1, in two different biological pathways, each affect the risk for a distinct component of the AMD phenotype: CFH influences the drusen of dry AMD, whereas HTRA1 influences blood vessel development, the hallmark of the wet disease type. When the two processes are combined, it leads to the composite characteristics that are seen in some cases of AMD.

Hoh, her collaborators in Hong Kong, and her colleagues at Yale including Michael Snyder and Colin Barnstable in the Departments of Molecular, Cellular and Developmental Biology and Molecular Biophysics and Biochemistry, and Ophthalmology, did trans-racial gene mapping by comparing genomes between precisely defined populations to find the incidence of SNP in a Chinese population—96 with AMD and 130 with normal vision.

"We found that patients with the HTRA1 SNP were 10 times more likely to have wet AMD than those without this gene variant," said Hoh. "While this is only preliminary work, it points to possible directions for future treatment of wet AMD."

Hoh also worked on a replication study led by Kang Zhang at the University of Utah School of Medicine that found a link between the same SNP and AMD. Zhang and his team studied 581 Caucasian patients with AMD and 309 with normal vision. These patients had wet AMD as well as a large amount of drusen.

To confirm the association, the Utah team also examined several donor eyes and measured the expression of the gene and the encoded protein. They found that the expressions were elevated in the eyes of patients who carry HTRA1.

"The marker we have identified is very much associated with AMD, but no one has ever pinpointed the clinical features of the gene. We need to conduct further analysis in order to understand the biological mechanisms," said Hoh.

Yellow plant pigments lutein and zeaxanthin reduce risk of age-related macular degeneration

Tue, 15 Aug 2006 11:41:00 PST

( from http://www.rxpgnews.com ) Women younger than age 75 years who eat diets rich in the yellow plant pigments lutein and zeaxanthin may have a reduced risk of developing the eye disease age-related macular degeneration, according to a report in the August issue of Archives of Ophthalmology, one of the JAMA/Archives journals.

Age-related macular degeneration (AMD) occurs when the macula, the area at the back of the retina that produces the sharpest vision, deteriorates over time. The condition is the leading cause of blindness in aging Americans, according to background information in the article. There is no cure for AMD and limited treatment options are available to slow its progression, so research on preventive measures is essential. Previous studies have suggested a potential link between AMD and lutein and zeaxanthin, plant pigments known as carotenoids and found in leafy green vegetables, corn, egg yolks, squash, broccoli and peas. These compounds may reduce the risk of AMD by absorbing blue light that could damage the macula, by preventing free radicals from damaging eye cells and by strengthening eye cell membranes.

Suzen M. Moeller, Ph.D., University of Wisconsin, Madison, and colleagues with the Carotenoids in Age-Related Eye Disease Study (CAREDS) Research Study Group, assessed the effects of dietary lutein plus zeaxanthin in 1,787 women ages 50 to 79 years in Iowa, Wisconsin and Oregon. The women with the highest and lowest dietary intakes of lutein and zeaxanthin in the Women's Health Initiative, a large study of postmenopausal women that began between 1994 and 1998, were recruited to participate in CAREDS. At the beginning of the study, participants filled out a questionnaire to evaluate what their diets were like 15 years before the beginning of the study. Blood samples were taken to assess levels of carotenoids and color photographs of the retina were used to determine the presence and progression of AMD.

A higher intake of lutein plus zeaxanthin was associated with a lower risk of intermediate-stage AMD in women younger than age 75 years who had a stable intake of the carotenoids over the 15-year period and did not have previous AMD or a chronic disease, such as cardiovascular disease, diabetes or hypertension, that might alter their dietary habits. However, no significant difference was observed in the overall group of women or when comparing lutein and zeaxanthin levels in the blood to AMD occurrence. There was a weak association between dietary lutein plus zeaxanthin and advanced-stage AMD in all the women and in women younger than age 75 years.

The lack of a link between intake of carotenoids and AMD in the overall study group could be due to several factors, including the fact that the older women who participated in the study may have been more likely to have consumed higher levels of fruits and vegetables during their lifetimes than other older adults who have already died. Many nutrients may work together to provide protection against AMD, and the study may not have measured other dietary deficits that influence risk, the authors write.

"This exploratory observation is consistent with a broad body of evidence from observational and experimental studies that suggests that these carotenoids may protect against AMD," they conclude. "Still, given the numerous analyses performed in this study, our results could be due to chance. More conclusive evidence from long-term prospective studies and clinical trials is needed to determine whether the intake of macular carotenoids themselves, or as markers of broader dietary patterns, can protect against intermediate AMD or delay progression in individuals who have early stages of the disease.

Hormone Therapy Does Not Affect Age-Related Vision Loss

Wed, 12 Jul 2006 05:59:00 PST

( from http://www.rxpgnews.com ) Postmenopausal hormone therapy does not appear to increase or decrease the overall risk of AMD among women, although combination hormones may slightly reduce the chances of developing certain risk factors or types of the condition, according to a report in the July issue of the Archives of Ophthalmology, one of the JAMA/Archives journals.

Mary N. Haan, M.P.H., Dr.P.H., University of Michigan, Ann Arbor, and colleagues studied 4,262 women age 65 years and older who were part of the Women's Health Initiative Sight Exam Study, part of the larger Women's Health Initiative clinical trial of hormone therapy. Of those, 1,627 were in the estrogen-only group of the study, with 48.1 percent taking hormones and 51.9 percent taking placebo. The other 2,635 women were in the combination hormone trial; 52.3 percent of those participants were taking estrogen plus progestin pills and 47.7 percent received placebo. Participants underwent eye assessments and retinal photography at the beginning of the study, between April 2000 and June 2002.

After an average of five years of follow-up, 21 percent of the women had developed AMD. Neither combination nor estrogen-alone therapy was found to be associated with developing AMD. Among women in the combination trial only, active hormone therapy was associated with a slightly reduced risk of developing soft drusen-deposits in the eye that may precede AMD-and also lower odds of having neovascular AMD, a less common form of the condition in which blood vessels grow underneath the retina, impairing vision.

"We conclude that treatment with hormones does not influence the occurrence of early AMD," the authors conclude. "As an exception, a possible protective effect was found for soft drusen or neovascular AMD in relation to combined equine estrogens plus progestin."

Eating Fish Protects Against Macular Degeneration

Wed, 12 Jul 2006 05:53:00 PST

( from http://www.rxpgnews.com ) In a study, Brian Chua, B.Sc., M.B.B.S., M.P.H., Westmead Millennium Institute and Vision Co-operative Research Centre, Syndney, Australia, and colleagues examined the association between dietary fat intake and AMD risk in 2,895 Australians age 49 years or older, beginning in 1992-1994. At the beginning of the study and again five years later, participants had a comprehensive eye exam that included photographs of the retina. They also filled out a questionnaire with data about food types and portion sizes consumed, including specific information about margarines, butters, oils and supplements.

Of the 2,335 participants who participated in the five-year follow-up, 158 had developed early AMD and 26 late-stage AMD. After adjusting for other factors that may influence risk, including smoking, age, sex and vitamin C intake, those in the group with the highest intake of polyunsaturated fat had a 50 percent reduced chance of developing early AMD compared with those who ate the least. Those who ate fish once a week had reduced risk of early AMD by 40 percent compared with those who ate fish less than once per month, and those who ate fish three or more times per week also had reduced risk for late-stage AMD. Contrary to previous studies showing an increased risk for AMD with higher unsaturated fat intake, no link was found between AMD and consumption of butter, margarine or nuts, which all contain high levels of unsaturated fats.

"To explain our findings, we suggest that insufficient essential fatty acid intake could result in abnormal retinal metabolism and cell renewal," the authors write. "Studies have shown cardioprotective benefits of monounsaturated fatty acids in the Mediterranean diet and that diets high in n[omega]-3 fatty acids, particularly docosahexaenoic acid, derived largely from fish, may protect against retinal oxidation and degeneration. Our finding that at least weekly fish consumption was protective against incident early age-related maculopathy provides support for this hypothesis."

Research Highlights Risk Factors For Age-Related Vision Loss

Wed, 12 Jul 2006 05:50:00 PST

( from http://www.rxpgnews.com ) Eating fish frequently may be associated with decreased chances of developing age-related macular degeneration, while smoking nearly doubles the risk for this common cause of vision loss and hormone therapy appears to have no effect, according to three articles in the July issue of the Archives of Ophthalmology, one of the JAMA/Archives journals.

Age-related macular degeneration (AMD) occurs when the macula, the area at the back of the retina that produces the sharpest vision, begins to deteriorate. The condition affects approximately 30 percent of Americans age 75 years and older, with 6 to 8 percent developing advanced cases, according to background information in one of the articles. It is the most prevalent cause of vision loss and blindness in the elderly population. Researchers have hypothesized that many of the risk factors for cardiovascular disease, including atherosclerosis or blocked arteries, may also contribute to the development of AMD, possibly by affecting blood flow to the eye.

In the first study, Johanna M. Seddon, M.D., Sc.M., of the Massachusetts Eye and Ear Infirmary, Boston, and colleagues studied genetic and environmental risk factors for AMD in 681 elderly male twins. The men underwent an examination by an ophthalmologist, filled out a food questionnaire and participated in a telephone interview to assess other risk factors, including demographics, smoking, alcohol consumption and physical activity habits. AMD was diagnosed using photographs of the inner eye.

Of the 681 men, 222 (average age 75.9 years) had intermediate or late-stage AMD and 459 (average age 74.5 years) had no AMD or were in the very early stages. Those who currently smoked had a 1.9-fold increased risk of AMD and those who had smoked in the past had a 1.7-fold increased risk. Those who ate more fish and more omega-3 fatty acids (found in salmon and other fish), were less likely to have AMD. The greatest reduction in risk was seen among individuals who ate two or more servings of fish per week. The benefits of eating more omega-3 fatty acids were most apparent among those who consumed less linoleic acid, an omega-6 fatty acid, suggesting that the proper balance of fats is key, the authors write.

"About a third of the risk of AMD in this twin study cohort could be attributable to cigarette smoking, and about a fifth of the cases were estimated as preventable with higher fish and omega-3 fatty acid dietary intake," they conclude. "Age-related macular degeneration is a common eye disease in older persons, smoking is a common avoidable behavior and dietary habits are modifiable; therefore, a proportion of visual impairment and blindness due to AMD could be prevented with attention to healthy lifestyles."

FDA approves ranibizumab for the treatment of wet age-related macular degeneration

Thu, 06 Jul 2006 02:23:00 PST

( from http://www.rxpgnews.com ) The Food and Drug Administration (FDA) today approved Lucentis (ranibizumab injection) for the treatment of patients with neovascular (wet) age-related macular degeneration (AMD). Lucentis is the first treatment which, when dosed monthly, can maintain the vision of more than 90 percent of patients with this type of AMD. Lucentis is a new molecular entity (NME), meaning it contains an active substance that has never before been approved for marketing in any form in the United States. Lucentis will be the first FDA--approved product to provide prescription information in the new format for prescription drug package inserts, to provide professionals and consumers clear and concise prescription information.

"This approval is of great importance for the 155,000 Americans who are diagnosed each year with AMD, a common cause of severe and irreversible vision loss in older adults," said Dr. Andrew von Eschenbach, Acting Commissioner of Food and Drugs. "At a time when our elderly population is rapidly increasing, this product preserves quality of life for those affected by this disease, helping them to regain the ability to participate in everyday activities such as reading and driving."

AMD, a retinal disease causing severe and irreversible vision loss, is a major cause of blindness in individuals older than 55 years. Untreated, the majority of eyes affected with wet AMD may become functionally impaired. Wet AMD, which accounts for 10 percent of all AMD, is responsible for 80 percent of the associated vision loss.

The vision loss in wet AMD is caused by the growth of abnormal leaky blood vessels that eventually damage the area of the eye responsible for central vision. Lucentis is designed to block new blood vessel growth and leakiness, which ultimately lead to disease progression and such vision loss.

Lucentis, a biologic product, administered by injection into the eye, was shown to be safe and clinically effective in three multicenter, randomized studies of patients representative of the population usually affected with AMD. In clinical trials, nearly 95 percent of the participants who received a monthly injection maintained their vision at 12 months compared to approximately 60 percent of patients who received the control treatment.

Approximately one-third of patients in these trials had improved vision at 12 months. In a single study carried out for 24 months, these findings have been maintained with continued monthly dosing. The most commonly reported adverse events included conjunctival hemorrhage, eye pain, floaters, increased eye pressure and inflammation of the eye. Serious adverse events were rare and often related to the injection procedure including endophthalmitis (severe inflammation of the interior of the eye), intraocular inflammation, retinal detachment, retinal tear, increased eye pressure and traumatic cataract.

High Body Mass Index Increase the Genetic Risk of AMD

Sat, 01 Jul 2006 17:41:00 PST

( from http://www.rxpgnews.com ) Current cigarette smoking was associated with a fivefold increased risk and high BMI (30 or higher) was associated with a twofold higher risk of AMD. The homozygous risk genotype (CC) plus smoking conferred a tenfold higher risk of AMD, compared with non-smokers with the non-risk (TT) genotype, while the risk genotype plus higher BMI increased risk of AMD almost sixfold. Gene plus environment risk scores provided an area under the receiver operating characteristic (ROC) curve of 0.70-0.75. The attributable risks for the combination of genes and environment were 69% to 73%.

Subjects in this study were Caucasians who had either advanced AMD (574 people) or no evidence of AMD (280 individuals), based on ocular examination and ocular photographs. DNA samples were obtained from the genetic repository of the Age-Related Eye Disease Study, a National Institutes of Health (NIH) clinical trial for which Johanna M. Seddon, M.D., director of the Epidemiology Unit at MEEI and an associate professor of ophthalmology at Harvard Medical School, was clinic director at MEEI. DNA samples were genotyped at the Broad Institute Center for Genotyping and Analysis, Boston, Mass. and statistical analyses were done in the Epidemiology Unit at MEEI.

These findings convey an important message. Although we cannot change our genotype, we can alter or modify our risk of getting AMD by controlling our weight and not smoking, said Dr. Seddon. There is no question that genetic factors play an important role in this disease. However, individuals with the risk genotype may be more motivated to adhere to healthy lifestyles such as not smoking, maintaining a normal weight, getting exercise, eating an antioxidant rich diet, as well as fish, and getting exercise.

AMD is the leading cause of irreversible visual impairment and blindness among persons aged 60 and older. With the elderly population steadily growing, the burden related to this loss of visual function will increase. Limited treatment options exist for the late stages of the disease and prevention remains a promising approach for addressing this public health concern.

Ranibizumab Approved for Wet Age-Related Macular Degeneration

Sat, 01 Jul 2006 16:41:00 PST

( from http://www.rxpgnews.com ) The Food and Drug Administration (FDA) approved Lucentis (ranibizumab injection) for the treatment of patients with neovascular (wet) age-related macular degeneration (AMD). Lucentis is the first treatment which, when dosed monthly, can maintain the vision of more than 90 percent of patients with this type of AMD. Lucentis is a new molecular entity (NME), meaning it contains an active substance that has never before been approved for marketing in any form in the United States. Lucentis will be the first FDA--approved product to provide prescription information in the new format for prescription drug package inserts, to provide professionals and consumers clear and concise prescription information.

"This approval is of great importance for the 155,000 Americans who are diagnosed each year with AMD, a common cause of severe and irreversible vision loss in older adults," said Dr. Andrew von Eschenbach, Acting Commissioner of Food and Drugs. "At a time when our elderly population is rapidly increasing, this product preserves quality of life for those affected by this disease, helping them to regain the ability to participate in everyday activities such as reading and driving."

AMD, a retinal disease causing severe and irreversible vision loss, is a major cause of blindness in individuals older than 55 years. Untreated, the majority of eyes affected with wet AMD may become functionally impaired. Wet AMD, which accounts for 10 percent of all AMD, is responsible for 80 percent of the associated vision loss.

The vision loss in wet AMD is caused by the growth of abnormal leaky blood vessels that eventually damage the area of the eye responsible for central vision. Lucentis is designed to block new blood vessel growth and leakiness, which ultimately lead to disease progression and such vision loss.

Lucentis, a biologic product, administered by injection into the eye, was shown to be safe and clinically effective in three multicenter, randomized studies of patients representative of the population usually affected with AMD. In clinical trials, nearly 95 percent of the participants who received a monthly injection maintained their vision at 12 months compared to approximately 60 percent of patients who received the control treatment.

Approximately one-third of patients in these trials had improved vision at 12 months. In a single study carried out for 24 months, these findings have been maintained with continued monthly dosing. The most commonly reported adverse events included conjunctival hemorrhage, eye pain, floaters, increased eye pressure and inflammation of the eye. Serious adverse events were rare and often related to the injection procedure including endophthalmitis (severe inflammation of the interior of the eye), intraocular inflammation, retinal detachment, retinal tear, increased eye pressure and traumatic cataract.

New genetic discovery explains 74 percent cases of age-related macular degeneration

Mon, 06 Mar 2006 17:31:00 PST

( from http://www.rxpgnews.com ) A new study, led by researchers at Columbia University Medical Center, pinpoints the role that two genes Factor H and Factor B play in the development of nearly three out of four cases of age-related macular degeneration (AMD), a devastating eye disease that affects more than 10 million people in the United States.

Findings indicate that 74 percent of AMD patients carry certain variants in one or both genes that significantly increase their risk of this disease.

Published in Nature Genetics, the research is a continuation of work published last year by the same team in the Proceedings of the National Academy of Sciences.

Led by Rando Allikmets, Ph.D., the Acquavella Associate Professor in Ophthalmology, Pathology and Cell Biology at Columbia University Medical Center, the research team included collaborating groups headed respectively by Gregory Hageman, Ph.D., professor of ophthalmology and visual sciences at the University of Iowa Roy J. and Lucille A. Carver College of Medicine, and by Michael Dean, Ph.D., at the National Cancer Institute of the National Institutes of Health.

The PNAS study showed that several variants in the Factor H gene significantly increase the risk of developing AMD. Factor H encodes a protein that helps shut down an immune response against bacterial or viral infection, once the infection is eliminated. People with these inherited risk-increasing variations of Factor H are less able to control inflammation caused by infectious triggers, which may spark AMD later in life.

Though the effect of Factor H on AMD is large, variation in this gene alone does not fully explain who gets AMD and who doesn't. As described in the PNAS paper, about one-third (29 percent) of people with a Factor H risk variant had not been diagnosed with AMD.

The investigators decided to look for additional culprits and focused on genes in the same immune response pathway that contains Factor H.

Their genetic analysis of 1,300 people quickly identified Factor B as the major modifier of the disease. The discovery makes good biological sense: while Factor H is an inhibitor of the immune response to infection, Factor B is an activator. Because of the complementary roles of the these two genes, a protective Factor B variation can protect against AMD, even if one carries a risk-increasing variant of Factor H, and vice versa.

As described in Nature Genetics, the two genes explained nearly three out of four AMD cases: 74 percent of the subjects with AMD had either the Factor H or Factor B risk variant (or both), but no protective variants of either gene.

"I am not aware of any other complex disorder where nearly 75 percent of genetic causality has been identified," said Dr. Rando Allikmets, who is senior author of the paper.

"These findings are significant because they absolutely confirm the roles of these two genes and, consequently, the central role of a specific immune response pathway, in the development of AMD. We confirmed this association not just statistically and genetically but, most importantly, pinpointed the biological origin of the disease," added Dr. Allikmets. "In just a few short years, we've gone from knowing very little about what causes AMD to knowing quite a lot. We now have clear targets for early therapeutic intervention."

Though the new paper explains much of the genetic risk, the specific triggers that set off the immune response and subsequent inflammation are still unknown. Researchers at Columbia University Medical Center and the University of Iowa are now searching for specific viral and bacterial culprits.

"It is my sincere pleasure to work with this talented team and to be involved in these important studies that identify the genetic basis for the role of the complement system a pathway that my colleagues and I identified a number of years ago in this truly devastating disease," said Dr. Hageman.

More than 50 million people worldwide are estimated to have irreversible blindness as a result of macular degeneration, making it the most common cause of blindness for those over 60. It's estimated that 30 percent of the population will have some form of AMD by the time they reach the age of seventy-five. The disease is marked by a progressive loss of central vision due to degeneration of the macula--a region of the retina and the area responsible for fine, central vision.

Just two genes, Factor H and Factor B, cause blindness in millions

Mon, 06 Mar 2006 16:56:00 PST

( from http://www.rxpgnews.com ) Just two genes cause blindness in millions of older people across the globe, a discovery that scientists say could aid the development of new treatments for the condition.

Nearly three-quarters of people in the world suffer from age-related macular degeneration (AMD) a most common cause of blindness. AMD is marked by a progressive loss of central vision due to degeneration of the macula - a region of the retina responsible for fine, central vision.

Researchers at New York's Columbia University studied 1,300 people and found that this common cause of blindness was linked to just two genes - Factor H and Factor B. While Factor H is an inhibitor of the immune response to infection, Factor B is an activator, the online edition of BBC News reported.

"I am not aware of any other complex disorder where nearly 75 percent of genetic causality has been identified," lead researcher Rando Allikmets said.

Factor H controls the production of a protein that helps shut down the body's immune response to infection once it has been successfully fought off.

People with these inherited variants of Factor H are less able to control inflammation caused by infectious triggers, which may spark AMD in later life, they said.

The researchers found 74 percent of the people with AMD had either the Factor H or Factor B risk factor or both - but no protective variants of either gene.

"These findings are significant because they absolutely confirm the roles of these two genes and, consequently, the central role of a specific immune response pathway, in the development of AMD," Allikmets said.

"In just a few short years, we've gone from knowing very little about what causes AMD to knowing quite a lot. We now have clear targets for early therapeutic intervention," Allikmets said.

The researchers are now searching for the specific triggers that set off the immune response, and subsequent inflammation.

Antioxidants reduce risk of age-related macular degeneration

Wed, 28 Dec 2005 18:23:00 PST

( from http://www.rxpgnews.com ) A diet with a high intake of beta carotene, vitamins C and E, and zinc is associated with a substantially reduced risk of age-related macular degeneration in elderly persons, according to a study in the December 28 issue of JAMA.

Age-related macular degeneration (AMD) is a degenerative disorder of the macula, the central part of the retina, and is the most common cause of irreversible blindness in developed countries, according to background information in the article. Late-stage AMD results in an inability to read, recognize faces, drive, or move freely. The prevalence of late AMD steeply increases with age, affecting 11.5 percent of white persons older than 80 years. In the absence of effective treatment for AMD, the number of patients severely disabled by late-stage AMD is expected to increase in the next 20 years by more than 50 percent to 3 million in the United States alone. Epidemiological studies evaluating both dietary intake and serum levels of antioxidant vitamins and AMD have provided conflicting results. One study (called AREDS) showed that supplements containing 5 to 13 times the recommended daily allowance of beta carotene, vitamins C and E, and zinc given to participants with early or single eye late AMD resulted in a 25 percent reduction in the 5-year progression to late AMD.

Redmer van Leeuwen, M.D., Ph.D., of Erasmus Medical Centre, Rotterdam, the Netherlands, and colleagues investigated whether antioxidants, as present in normal daily foods, play a role in the primary prevention of AMD. Dietary intake was assessed at baseline in the Rotterdam Study (1990-1993) using a semiquantitative food frequency questionnaire. Follow-up continued through 2004. The Rotterdam Study included inhabitants aged 55 years or older from a middle-class suburb of Rotterdam, the Netherlands. Of 5,836 persons at risk of AMD at baseline, 4,765 had reliable dietary data and 4,170 participated in the follow-up.

Average follow-up of participants was 8.0 years. During this period, 560 persons (13.4 percent) were diagnosed as having new AMD, the majority of whom had early-stage AMD. A significant inverse association was observed for intake of vitamin E, iron, and zinc. After adjustment, a 1-standard deviation increase in intake was associated with a reduced risk of AMD of 8 percent for vitamin E and 9 percent for zinc. An above-median (midpoint) intake of beta carotene, vitamins C and E, and zinc, compared with a below-median intake of at least 1 of these nutrients, was associated with a 35 percent reduced risk of AMD, adjusted for all potential confounders. In persons with a below-median intake of all 4 nutrients, the risk of AMD was increased by 20 percent. Adding nutritional supplement users to the highest quartile of dietary intake did not change the results.

"This study suggests that the risk of AMD can be modified by diet; in particular, by dietary vitamin E and zinc. A higher intake of vitamin E can be achieved by consumption of whole grains, vegetable oil, eggs, and nuts. High concentrations of zinc can be found in meat, poultry, fish, whole grains, and dairy products. Carrots, kale, and spinach are the main suppliers of beta carotene, while vitamin C is found in citrus fruits and juices, green peppers, broccoli, and potatoes. Based on this study, foods high in these nutrients appear to be more important than nutritional supplements. Until more definitive data are available, this information may be useful to persons with signs of early AMD or to those with a strong family history of AMD. Although in need of confirmation, our observational data suggest that a high intake of specific antioxidants from a regular diet may delay the development of AMD," the authors conclude.

VISION - VEGF Inhibition Study in Ocular Neovascularization Exploratory Analysis

Sat, 08 Oct 2005 05:57:00 PST

( from http://www.rxpgnews.com ) Age-related macular degeneration (AMD) is the leading cause of blindness in older patients in the developed world. Vascular endothelial growth factor is one of the key mediators stimulating the abnormal blood vessel growth and leakage characteristic of the exudative (wet) form of the condition. Pegaptanib sodium (Macugen) is a new treatment for exudative AMD, and has been shown to stabilize vision in approximately 70 percent of cases.

The researchers performed an exploratory analysis of the outcomes of patients with early exudative lesions at week 54 in clinical trials of pegaptanib sodium in the landmark VISION (VEGF Inhibition Study in Ocular Neovascularization) study. The patients were divided into two groups. The researchers found that at week 54, 76 percent of patients in group 1 receiving pegaptanib lost fewer than 15 letters or three lines of vision on the ETDRS eye chart, compared with 50 percent of patients undergoing usual care. In group 2, that proportion was 80 percent and 57 percent, respectively. A number of patients treated with pegaptanib even regained some sight. In addition, patients who underwent usual care for AMD were 10 times more likely to experience severe vision loss than those treated with pegaptanib.

The study found that early detection and treatment of age-related macular degeneration with pegaptanib sodium may enable AMD patients to maintain and, in some cases, regain vision. As a result, the Jules Stein Eye Institute is launching a prospective, open-label, multi-center trial to evaluate the efficacy and safety of pegaptanib in 40 patients with early onset of AMD.

Potential role of amyloid-beta in the pathogenesis of age-related macular degeneration

Tue, 27 Sep 2005 01:21:00 PST

( from http://www.rxpgnews.com ) Age-related macular degeneration (AMD) is the main cause of blindness in patients over the age of 60. In these AMD patients, choroidal neovascularization (CNV) is the most common cause of visual loss. The earliest clinically visible abnormality in AMD are extracellular deposits, called drusen. However, it was unclear which component of drusen contributes to AMD.

Recent data demonstrated that amyloid-beta (Abeta) deposition was found in drusen from eyes with AMD.

In a paper appearing online on September 15 in advance of print publication of the October 1 issue of the Journal of Clinical Investigation, Takeshi Yoshida and colleagues from the University of Tokyo show that Abeta contained in drusen plays an important role in the pathogenesis of AMD. These results suggest that approaches for clearing Abeta deposition might be an effective strategy against the development of AMD.

FDA Approval to be filed for Ranibizumab as Treatment of Wet ARMD

Fri, 09 Sep 2005 17:25:00 PST

( from http://www.rxpgnews.com ) Genentech, Inc. (NYSE: DNA) announced today plans to file a complete Biologics License Application (BLA) for the investigational drug Lucentis (ranibizumab) in December 2005. In addition, the company announced that it is in discussion with the U.S. Food and Drug Administration (FDA) regarding plans to initiate a Phase IIIb clinical study of Lucentis for patients with wet age-related macular degeneration (AMD). The study is anticipated to begin before the end of 2005. One-year Phase III data from the MARINA study presented at the annual meeting of the American Society of Retina Specialists in July showed Lucentis improved vision in patients with wet AMD.

"We recognize the significant unmet medical needs of those with wet AMD and hope to make Lucentis available to patients by seeking FDA approval as quickly as possible," said Hal Barron, M.D., Genentech senior vice president, development and chief medical officer. "We are encouraged by the magnitude of the benefit observed in the one-year Lucentis MARINA data and are excited about this new Phase IIIb trial, which will help provide more information about the safety profile of Lucentis and the treatment regimen for this chronic disease."

The Phase IIIb SAILOR (Safety Assessment of Intravitreal Lucentis for AMD) study is being designed to evaluate the safety of two different doses (0.3 mg and 0.5 mg) of Lucentis in a broad wet AMD population. Patients will receive Lucentis once a month for three months with criteria-based re-treatment options. Genentech anticipates that patients with wet AMD who have not received prior treatment for their disease or who continue to have active disease despite treatment with FDA-approved therapies may be eligible to enroll in SAILOR. The study will be conducted at more than 100 sites in the United States and enroll approximately 5,000 patients.

Genentech has also recently been notified that the FDA did not grant the company's request for fast-track designation, which allows for a rolling BLA submission. The FDA's decision will not affect the timing for BLA submission in December or the potential to obtain priority review for Lucentis.

Phase III MARINA Results
In July, Genentech announced positive preliminary Phase III data on Lucentis from a study of 716 patients with wet AMD. In addition to meeting the studys primary efficacy endpoint of maintaining vision in patients with wet AMD, 25 percent (59/238) of patients treated with 0.3 mg of Lucentis and 34 percent (81/240) treated with 0.5 mg of Lucentis improved vision by a gain of 15 letters or more compared to approximately 5 percent (11/238) of patients in the control group as measured by the Early Treatment of Diabetic Retinopathy (ETDRS) eye chart. Nearly 40 percent (188/478) of Lucentis-treated patients achieved a visual acuity score of 20/40 or better at 12 months compared to 11 percent (26/238) in the control group. At 12 months, patients treated with Lucentis gained an average of seven letters in visual acuity compared to study entry, while those in the control group lost an average of 10.5 letters.

An analysis of the one-year data showed that adverse events were similar to those seen in earlier trials of Lucentis. Common side effects occurring more frequently in the Lucentis arms than in the control group were mild to moderate and included conjunctival hemorrhage, eye pain and vitreous floaters. Serious ocular adverse events occurring more frequently in Lucentis-treated patients were uncommon (<1 percent

Smoking and Age Related Macular Degeneration (AMD)

Wed, 07 Sep 2005 18:06:00 PST

( from http://www.rxpgnews.com ) Smoking greatly increases your chance of developing age-related macular degeneration (AMD), which leads to severe and irreversible sight-loss, according to an article published in the Royal College of Ophthalmologist's journal Eye this week (published online 7th September 2005).

AMD is the most common cause of visual impairment in the western world; over 200,000 people suffer from the disease in the UK alone. Treatments are costly and at best only slow an inevitable progression. This means that the identification of any modifiable risk factor - such as smoking - is of great importance.

Simon Kelly and colleagues reviewed 17 studies of the association between smoking and AMD and found that in 13 of these smokers were significantly more likely to develop AMD than non-smokers. They also suggest that heavier smokers are at higher risk, and that the risk is lower for ex-smokers - indicating that the negative effects can be at least partly reversed by giving up.

Kelly and colleagues also present, in a separate paper, evidence from a survey at Bolton Hospital NHS trust suggesting that the general public remain largely unaware that smoking can lead to loss of vision. Importantly, their findings also indicate that fear of blindness may provide as much of a motivation to quit as that of well-established smoking-related conditions such as lung cancer and heart disease.

The strength of evidence presented in Kelly's review, and the conclusions of the subsequent clinical study, leave little doubt that action should be taken to raise awareness of the link between smoking and sight loss.

Cogan Award to macular degeneration scientist

Thu, 01 Sep 2005 01:23:00 PST

( from http://www.rxpgnews.com ) The Association for Research in Vision and Ophthalmology (ARVO) announced today that Joshua L. Dunaief, MD, PhD, has been selected to receive the 2006 Cogan Award during ARVO's Annual Meeting to be held in Fort Lauderdale, Fla., in May 2006.

The Cogan Award recognizes a researcher 40 years of age or younger at the time of nomination who has made important contributions to research in ophthalmology or visual science directly related to disorders of the human eye or visual system, and who also shows substantial promise for future research. Dunaief was selected to receive the award for his innovative investigations of iron metabolism and oxidative damage in the pathogenesis of age-related macular degeneration (AMD), including contributions from both human tissues and mice models of the disease.

Dunaief is an Assistant Professor of Ophthalmology at the Scheie Eye Institute's F.M. Kirby Center for Molecular Ophthalmology in Philadelphia, Pa. He received his doctorate and his medical degree from Columbia University in New York, N.Y., and served his residency in ophthalmology at the Wilmer Eye Institute at Johns Hopkins University in Baltimore, Md. He is a past recipient of the Research to Prevent Blindness Career Development Award and the Steinbach AMD Research Foundation Award. He serves as a reviewer for a number of publications including Investigative Ophthalmology & Visual Science and Journal of Neuroscience.

Age-related maculopathy (ARM) gene discovered

Wed, 17 Aug 2005 01:54:00 PST

( from http://www.rxpgnews.com ) University of Pittsburgh researchers have discovered a gene linked to age-related maculopathy (ARM), the leading cause of untreatable blindness in the elderly. Their discovery suggests a simple test might be able to identify those at risk for what is commonly known as macular degeneration (AMD) and may lead to the development of more effective preventive strategies.

Researchers report that variations of a gene called PLEKHA1 are strongly associated with a person's risk of developing ARM. The results, a culmination of 15 years of research, will be published in the September issue of the American Journal of Human Genetics and are currently available online.

The discovery of the gene came about through the team's efforts to map the genes of 612 families affected by ARM and an additional 323 individuals without a history of macular degeneration. Pooling data from a number of gene mapping studies, researchers were able to identify multiple locations on the chromosomes where there are common gene variants among people with ARM. Specifically, researchers found that a region on one of these chromosomes, chromosome 10, was the one most likely to contain a major gene that influences the risk of ARM. Further analysis of chromosome 10 found that a variation in PLEKHA1 to be strongly associated with a person's risk of developing ARM.

Earlier this year, researchers from Rockefeller University, Yale University, The National Eye Institute, Duke University, Vanderbilt University, University of Texas Southwestern, and Boston University used similar methods to identify the first gene variant thought to be a major contributor to ARM, complement factor H (CFH) on chromosome 1. The Pittsburgh study confirms involvement of this gene and, for the first time, shows that the association results also accounted for findings from previous genetic studies of AMD families. Importantly, the new study found that having both CFH and PLEKHA1 indicate a greater risk for macular degeneration.

"CFH was the first piece of the puzzle," said Michael Gorin, M.D., Ph.D., professor of ophthalmology, University of Pittsburgh School of Medicine, and professor of human genetics, University of Pittsburgh Graduate School of Public Health. "To fully understand the pathology of macular degeneration, we knew we needed to expand our investigation to find all of the genes that play a part in this condition. PLEKHA1 is an important second piece, and we'll keep searching for the rest of the pieces until we get this solved."

By identifying a number of genetic variants for ARM, researchers hope to use this information to develop a simple set of DNA tests to identify individuals who are at increased risk of this sight-robbing condition. Additionally, they hope to develop new preventive strategies and a better understanding of how ARM occurs.

An important clue to understanding the cause and mechanism of ARM was revealed through this discovery. PLEKHA1, like CFH, is involved in the cellular processes related to inflammation, which supports the hypothesis that damage caused by ARM is, in part, due to inflammation.

ARM is the leading cause of untreatable blindness in the elderly and despite recent advances in the treatment of some forms of this condition, it continues to be a serious threat to vision with no known cure. An estimated 200,000 Americans develop a severe form of AMD each year, making it the leading cause of blindness in people aged 65 and older. As many as 30 percent of individuals over the age of 75 have evidence of macular degenerative changes.

Role of melanin in preventing macular degeneration

Sat, 30 Jul 2005 01:49:00 PST

( from http://www.rxpgnews.com ) Two studies from an unusual research partnership at the University of Chicago appear to have resolved a long-standing dispute about the role of melanin in the eye. The studies, one published in the Proceedings of the National Academy of Sciences (PNAS) and one early online in the Journal of the American Chemical Society (JACS), also suggest a new way to prevent a common cause of blindness.

Chemist James Norris, Ph.D., and retina surgeon Kourous Rezai, M.D., combined resources to show that melanin, a pigment found throughout the human body, acts like a neutralizing sponge inside cells in the retina to soak up and destroy reactive oxygen species. Reactive oxygen species, or free radicals, energized by light, are thought to play a major role in macular degeneration, the leading cause of blindness in people over the age of 60.

"We now have the first persuasive evidence that melanin plays an important protective role within the eye," said Norris, professor in the Department of Chemistry and the Institute for Biophysical Dynamics at the University of Chicago and one of the senior authors of both papers. "Although melanin contains its own intrinsic free radical, we found that it absorbs a far more damaging form of free radical, converting its destructive energy into harmless heat before it can hurt the retina."

An estimated 1.75 million Americans have decreased vision from age-related macular degeneration (AMD), with about 200,000 new cases each year. The incidence of AMD is expected to double within the next 25 years as the number of older persons continues to increase. The disorder is far more prevalent among whites than among black persons.

It causes gradual loss of central vision by damaging the retinal pigment epithelial (RPE) cells that lie underneath the macula, the small region of the retina responsible for fine detail at the center of the field of vision. Without RPE cells, the photoreceptors, which are the light detectors, also die. Patients lose the ability to see detail and soon they can't read.

"This is a devastating disease," said Rezai, director of the vitreoretinal service at the University of Chicago. "We do not have a cure for this disease. We can only treat the secondary complications, such as growth of abnormal blood vessels."

"Since we don't know how to replace or repair the dead or damaged retinal cells," he said, " we need to find ways to protect them."

Because people stop producing new RPE cells after birth, these cells have to last a lifetime. They live, however, in a toxic environment. Oxygen concentrations at the back of the eye are very high. At the same time the eye is constantly bombarded with light energy, which interacts with oxygen and can lead to the production of harmful free radicals which can damage cell membranes and DNA. "It's amazing," noted Norris, "that the eye lasts as long as it does."

"To prevent the damage," Rezai said, "we need to understand exactly how it happens." He grows human RPE cells in culture in his lab, but "until now, we have had no direct way to measure the production of most dangerous free radicals. They are too small and too fast."

Norris studies photosynthesis, in which energy from sunlight is converted into electrochemical energy, a process with many parallels to vision. To study the early steps, he uses a tool called electron paramagnetic resonance (EPR). EPR is similar to magnetic resonance imaging except that it measures the spin of electrons rather than of protons.

Because photochemical reactions happen extremely fast, the Norris laboratory has one of the world's few high-speed EPR spectroscopy devices, able to record actions that occur in nanoseconds, about 1,000 times faster than standard EPR.

"Free radicals are dangerous chemicals and dangerous chemistry takes place rapidly," said Norris. "This lets us see some of it."

Norris and Rezai have another valuable asset, an ambitious student, interested in chemistry and medicine, experienced with EPR and looking for a project. This was a unique opportunity for Brandon-Luke Seagle, a third-year student in the College at the time. His knowledge of chemistry and medicine enabled him to be the link between Rezai's cells and Norris's techniques. He is the first author on both papers.

Using Rezai's cells, Norris's technology and Seagle's leg work, the team was able to capture convincing and dramatic evidence that melanin protects the retinal cells. In the PNAS paper (21 June 2005), they show that increased melanin aggregation and radical migration within melanin aggregates can protect RPE cells from free-radical damage and help prevent cell death. In the JACS paper (17 August 2005, but available online) they demonstrate how melanin actually scavenges the harmful free radicals produced by high-energy blue or ultraviolet light as it flows into the eye, soaking them up and neutralizing their effects.

"We now have molecular-based evidence to support the epidemiologic data that points to the protective effects for melanin," said Rezai, who is testing ways to boost melanin levels, first in cells grown in culture and, if that appears promising, in animal models.

Chromosome region for macular degeneration pinpointed

Wed, 27 Jul 2005 01:43:00 PST

( from http://www.rxpgnews.com ) Age-related macular degeneration is the leading cause of blindness in older adults, yet researchers are still in the dark about many of the factors that cause this incurable disease.

But new insight from University of Florida and German researchers bout a genetic link between rhesus monkeys with macular degeneration and humans could unlock secrets about the earliest stages of the disease, when severe vision loss could still be stopped.

The researchers pinpointed a chromosome region and genetic markers for macular degeneration in humans and rhesus monkeys, findings recently published in the online edition of the journal Experimental Eye Research. Linking the disease in monkeys to the disease in humans allows researchers to study how it progresses in the animals, which could lead to better treatments and even a cure.

"Stopping the development of the disease is something the monkeys will help us do that we can't do with humans," said William W. Dawson, a UF professor of ophthalmology and physiology and a co-author of the study. "This is a big step forward in dealing with the disease."

The researchers studied seven genetic sites in the monkeys that correspond to human chromosomes linked to macular disease. One of those areas, the findings confirm, contains genes that predict age-related macular degeneration in humans and rhesus monkeys. Dawson and other researchers have suspected for years that the disease was very similar in humans and monkeys, but these findings finally establish that. This discovery, he said, will allow researchers to delve deeper into what causes the disease and could be the first step toward repairing the genetic defects linked to it.

According to the National Eye Institute, nearly 2 million Americans have advanced age-related macular degeneration, a disease that develops when a small, light-detecting part of the retina called the macula breaks down. Seven million more Americans have an intermediate form of the disease, and millions more are expected to develop it within the next 15 years.

The disease causes nodule-like specks to build up in the eye, chipping away central vision over time. But Dawson said most people don't even realize something is wrong until they detect changes in their vision. The disease can be controlled, but there is no known way to reverse the vision loss it causes.

Knowing more about the earliest predictors of macular degeneration could help doctors treat the disease before extensive vision loss occurs and may even prevent it in some people. The early risks associated with macular degeneration have been difficult for researchers to study in humans, and as a result, doctors know little about this aspect of the disease, Dawson said.

"It's difficult to follow closely the aging of a human over a specific period of time," he said. "People wouldn't tolerate a controlled (living) environment for weeks and years."

One of the biggest problems researchers have faced is determining how much of a role genetics plays versus lifestyle and environmental factors such as blue light, part of the spectrum of natural visible light. Frequent exposure to blue light rays has been linked to macular degeneration. If the disease is going to be treated early, Dawson said researchers must know the significance of these factors.

Aside from studying early environmental risks, the next step for researchers is to map the specific genes at work, said Dawson, who worked on the study with German geneticist Jorg Schmidtke. But because more than one gene is likely involved, this task will not be easy, Dawson said.

Dr. Johanna M. Seddon, a Harvard Medical School associate professor and director of the epidemiology unit of the Massachusetts Eye and Ear Infirmary, said studies conducted on 840 human twins have shown that genetics plays a significant role but not the only role. Even diet plays a big part, she said. Her own research with the National Eye Institute has shown that taking certain vitamins and minerals can reduce the risk of developing the disease by 25 percent over five years.

"With the increasing number of people living beyond the age of 85, it heightens the importance of this disease and the concern about (what will happen) if we don't come up with a better way to treat this," she said.

That's where Dawson thinks the monkeys can help. They age three to four times faster than humans, making it easier to track the progression of the disease. The monkeys also can remain in a controlled environment to test nongenetic factors, and their families can be studied more extensively.

Although most rhesus monkeys never show signs of macular degeneration, between 30 percent and 70 percent of the monkeys Dawson's team studied do. That's because these primates are the descendents of 50 monkeys brought to live on a Puerto Rican island just before World War II. The free-ranging monkeys on the island have multiplied to near 1,500, but because the rhesus monkeys are not native to the area, they could mate only with each other. This inbreeding has predisposed the monkeys to various genetic diseases, such as age-related macular degeneration.

Unlike most other animals, a rhesus monkey's eyes have the same complex structure as a human eye, making them a model study subject. They're so similar, he said he sometimes slips images of rhesus monkey eyes into presentations for medical residents to see if anyone notices the difference.

"I haven't been caught yet," he said. "Only the most expert would detect the differences."

Eye Saver Easy Reading Light Bulb useful in macular degeneration

Wed, 27 Jul 2005 01:39:00 PST

( from http://www.rxpgnews.com ) For years, there has been much research and development to improve poor eyesight, including the use of scratch-resistant and radiation-blocking lenses. Now, a revolutionary product for eye correction focuses specifically on the needs of those in working environments, called the Eye Saver Easy Reading Light Bulb.

Barton Pasternak, Executive Vice President of Westinghouse Lighting Corporation realized the need for more light on work surfaces. He consulted with Dr. Scott Smith of NASA's Marshall Space Flight Center, Huntsville, Ala. and Dr. Forrest Marshall, Chief Executive Officer of medical product development at Marshall Research, LLC.

Smith used his knowledge of deep space telescope optics to further enhance the Eye Saver, and Pasternak shifted his focus from developing a reflective insert on lamp shades to creating optimum lighting with a single light bulb. Pasternak also teamed with Dr. Marshall, whose research focused on developing innovative light bulbs to make seeing easier under working conditions.

The Eye Saver provides 40 percent more surface illumination on work and reading surfaces, compared to a standard incandescent light bulb, and includes a frosty finish that reduces eyestrain by lowering glare. With an average lifetime of 2000 hours, twice as long as a standard bulb, this product is suitable for people of all ages and is specifically ideal for duties requiring high light, including reading, writing, sewing, and crafting.

Such technology is particularly useful for those afflicted with macular degeneration, a common eye disease causing deterioration of the macula, the central area of the retina, and low vision, the loss of visual sharpness. Age-related macular degeneration is the number one cause of vision loss and legal blindness in American adults over the age of 60, according to the non-profit organization, Macular Degeneration Partnership.

The Eye Saver falls in line with recommendations made by Rensselaer Polytechnic Institute's Lighting Research Center, the world's largest university-based center for lighting education and research. The center believes light fixtures close to task areas and bulbs with high light output are the best ways to combat the effects of low vision. Additionally, the Discovery Fund for Eye Research recognizes the Eye Saver as a useful source for enhancement of lighting due to eye disease.

The Eye Saver can be purchased through eye care professionals and retailers around the country. Meanwhile researchers at NASA and other institutions work to develop even new and more powerful vision-enhancing products.

FDA Approves Anecortave Acetate Suspension for Age-Related Macular Degeneration

Wed, 25 May 2005 11:05:00 PST

( from http://www.rxpgnews.com ) Alcon, Inc. (NYSE:ACL) announced today that the U.S. Food and Drug Administration (FDA) has issued an approvable letter for its New Drug Application (NDA) for RETAANE(R) 15 mg (anecortave acetate suspension). RETAANE(R) suspension is an investigational treatment for preserving the vision of patients with wet age-related macular degeneration (AMD).

Alcon said it will meet with the FDA to discuss the approvable letter, the clinical studies submitted with the NDA and other ongoing clinical studies for RETAANE(R) suspension to determine the steps necessary to gain final approval for the wet AMD indication.

"We believe that RETAANE(R) suspension has a positive impact on the vision of patients with AMD. As part of our mission to preserve and restore vision, we are continuing with all of our development efforts for this drug, which we believe will ultimately lead to approval," said Stella Robertson, Ph.D. and vice president, ophthalmology research and development.

About RETAANE(R) Suspension

RETAANE(R) suspension is an investigational treatment for maintaining vision in patients with wet AMD. The drug is an angiostatic cortisene that inhibits the abnormal growth of blood vessels, a process scientifically known as angiogenesis. Angiostatic cortisenes are derived from the steroid class and engineered to remove chemical groups responsible for side effects, such as the development of cataracts and elevated intraocular pressure leading to glaucoma, while preserving potency against angiogenesis.

RETAANE(R) suspension is administered with a blunt-tipped, curved cannula to deliver the drug behind the eye without puncturing the eyeball. This method of delivery avoids the risk of intraocular infection and retinal detachment, the most common side effects associated with injecting therapeutic agents directly into the eye. In addition, RETAANE(R) suspension requires less frequent dosing (once every six months) compared to some other investigational drugs, which are injected into the eye as often as 9 to 12 times a year. No clinically relevant side effects related to the medication or application procedure were reported in the study.

Alcon has conducted extensive clinical research into RETAANE(R) suspension over the last five years. The company has reported clinical study results from two pivotal studies that formed the basis of its clinical package for its NDA. The first study demonstrated that after one year 79 percent of patients treated with RETAANE(R) suspension maintained their vision, compared to 53 percent of those who received a sham application. The second study demonstrated that after one year the visual outcomes in patients who received RETAANE(R) suspension were not statistically different from those of patients who received photodynamic therapy with Visudyne(R).

Variation in immune response gene causes age-related macular degeneration

Sat, 30 Apr 2005 01:26:00 PST

( from http://www.rxpgnews.com ) Age-related macular degeneration, the leading cause of blindness in the elderly, occurs when a common inherited gene variation is triggered, possibly by an infection, according to a new study led by researchers at Columbia University Medical Center and the University of Iowa, with an international research team.

The gene, known as Factor H, encodes a protein that regulates immune defense against infection caused by bacteria and viruses. People who have an inherited variation in this gene are less able to control inflammation caused by these infections, which may spark age-related macular degeneration (AMD) later in life, the study finds.

Published in this week's Proceedings of the National Academy of Sciences, the results suggest that targeting the molecules involved in immune system response may provide powerful new therapies for treating and preventing AMD.

"We now understand the genetic variation that is behind age-related macular degeneration and are beginning to target the trigger that sets the process in motion," said Rando Allikmets, Ph.D., Acquavella Associate Professor in the department of ophthalmology and the department of pathology & cell biology at Columbia University College of Physicians and Surgeons. "By targeting the molecules involved in inflammation and its regulation we believe we can begin to develop therapies and diagnostic tools that could help countless people keep their sight."

Potential therapies could involve delivering healthy Factor H directly to the eye to short-circuit the disease process; extracting stem cells from the eye so they could be reengineered and re-implanted; or partial transplantation of the liver - the body's main source for Factor H.

Other research has recently established the link between the Factor H gene and AMD by scanning the human genome for variations in gene sequences, but this new research is the first to examine the roots of AMD from a biological perspective and to explore the role that immune response plays in triggering the disease.

More than 50 million people worldwide are estimated to have irreversible blindness as a result of macular degeneration, making it the most common cause of blindness for those over 60. It's estimated that 30 percent of the population will have some form of AMD by the time they reach the age of seventy-five. The disease is marked by a progressive loss of central vision due to degeneration of the macula--a region of the retina and the area responsible for fine, central vision.

The study was conducted in two parts biology and genetics. Dr. Allikmets, senior author on the paper, led the genetic analysis in the study, in collaboration with principal investigator Gregory Hageman, Ph.D., professor of ophthalmology and visual sciences at the University of Iowa Roy J. and Lucille A. Carver School of Medicine, who conducted the biological research. An international team of researchers was engaged in the project including scientists at the National Cancer Institute, the National Institutes of Health (NIH), the University of California at Santa Barbara (UCSB), and Queens University, Belfast, United Kingdom.

Dr. Allikmets began his career focusing on a different disease cancer. As an investigator for the National Cancer Institute, in 1997 Allikmets discovered the ABCR gene (also known as ABCA4), as the first gene involved in a substantial, but small fraction of age-related macular degeneration. This discovery set him on the path of pursuing research in the area of AMD genetics, and he joined Columbia University Medical Center in 1999 to pursue this groundbreaking research.

The researchers examined 900 AMD patients and 400 healthy controls and noticed that half of all AMD patients have an inherited pattern of genetic variants in the Factor H gene known as a haplotype that make them more susceptible to AMD. Different haplotypes in the Factor H gene in about one third of the population provide varied degrees of protection from acquiring AMD.

The Iowa team also examined a large collection of donated eye samples and observed that the activation of the immune system results in the formation of drusen - pockets of inflammation that are the precursors to AMD.

The new findings link variations on the Factor H gene which was found to be accumulated in drusen - directly to the process leading to AMD. The study found that compared to control subjects, patients with AMD were more likely to have single nucleotide polymorphisms that weaken the ability of Factor H to inhibit the immune response known as the alternative complement cascade - thus making them more susceptible to inflammation and the disease.

While it would seem that "anti-inflammatory" drugs could mitigate the inflammatory onslaught, the researchers say most do not work on this leg of the complement system.

The genetic pre-disposition to AMD exists in approximately half of the Caucasian population. But not everyone who has this genetic variant gets AMD, so what causes this mechanism to activate?

"We believe inflammation from infections might kick start the process that leads to AMD," said Dr. Hageman. "The variation in Factor H strengthens the immune response, keeping infections under control early, but ironically that may contribute to a chronic disease like AMD later in life." The Columbia and Iowa scientists were able to make this connection in large measure by studying a rare form of kidney disease called MPGN II. Patients with this condition often share the same kind of eye lesions as individuals with AMD. And, in fact, a genetic determinant of the two diseases had been previously linked to the same chromosome - chromosome 1. Thus, Factor H was thought to be a prime suspect in both diseases.

"It has been always assumed that AMD must have environmental triggers that turn on or aid the pathological process. Our research suggests that the trigger is a specific inducer of the alternative complement pathway, such as an infection, systemic disease, a vaccination, or another unusual agent. Interestingly, countries where the vaccination rate is highest also experience an elevated rate of AMD," said Dr. Allikmets.

The researchers continue to conduct new studies based on their results to further understand the triggers for this gene.

"This is an area for epidemiologists to study, but as our research progresses we should eventually be in a position to suggest treatment that could keep many people from going blind," he said.

Common painkillers may play a role in preventing or slowing the progression of macular degeneration

Wed, 27 Apr 2005 01:34:00 PST

( from http://www.rxpgnews.com ) Rheumatoid arthritis patients treated with anti-inflammatory drugs are 10 times less likely to develop age-related macular degeneration (AMD), the most common form of blindness in people over 55, researchers at the University of British Columbia and University of Saskatchewan have found.

The study, recently published in the Neurobiology of Aging, is a joint effort of neurologist Dr. Patrick McGeer of UBC and rheumatologist Dr. John Sibley of the U of S.

The scientists found that that rheumatoid arthritis patients being treated with anti-inflammatory drugs were 10 times less likely to develop (AMD) than unaffected individuals in the United States, Australia, the Netherlands and the United Kingdom.

"Age-related macular degeneration is like Alzheimer's disease of the eye, with retinal deposits called drusen acting like amyloid deposits in the brain found in Alzheimer's," says McGeer, a UBC professor emeritus in the Kinsmen Laboratory of Neurological Research and expert in the use of non-steroidal anti-inflammatory drugs (NSAIDS).

The scientists reviewed 993 rheumatoid arthritis patients in Saskatchewan aged 65 years or older who, on average, had been living with the condition since age 51. Only three had developed AMD, where about 30 cases could be expected in a similarly-aged group from the general populace.

"It was natural for us to look at the rheumatoid arthritis population," says Sibley, a U of S professor of medicine and head of the division of rheumatology. "They have been followed closely for more than 40 years with particular attention paid to retinal changes because medication widely used for rheumatoid arthritis can create visual problems."

It is already accepted that NSAIDS reduce the incidence of bowel cancer. Fifteen years ago, McGeer and Sibley found the first of a growing body of evidence that NSAIDS may also help reduce the incidence of Alzheimer's. However, Sibley says this is the first time a link has been identified between anti-inflammatories and macular degeneration.

The researchers emphasize that further study is required to confirm their findings, but if they are corroborated, anti-inflammatories would be the first approach for this intractable disease. Related questions such as optimum dosage and when to begin treatment need to be answered. Also, since NSAIDS can have side effects such as stomach upset, ulcers and stress on kidneys, they are not appropriate for everyone and criteria for high-risk patients that would benefit from their use will need to be defined.

Macular degeneration is the most common cause of severe vision loss in Canada, especially among the elderly, according to the Canadian National Institute for the Blind. It causes one in three cases of reported vision loss. The condition causes light-sensitive cells in the macula, or central portion of the retina, to degenerate. The macula is responsible for perceiving fine visual detail. Early signs of macular degeneration include blurring of vision when performing detailed tasks like reading or sewing.

AMD is the most common form of the disease and causes permanent loss of central vision. There are two forms of AMD wet and dry with more than 85 per cent of cases being the dry form, for which there is no effective treatment.

Smoking doubles risk of age related macular degeneration

Wed, 13 Apr 2005 01:37:00 PST

( from http://www.rxpgnews.com ) The risk of macular degeneration increases with age and is the most common cause of blindness in the UK, affecting around 200,000 elderly people.

The findings are based on a representative sample of over 4,000 people, aged 75 and older, from 49 general practices across Britain.

The participants all underwent a series of detailed eye tests and were asked about their smoking habits, and if they had given up, how long ago. After taking into account other risk factors, such as alcohol consumption and cardiovascular disease, the results showed that current smokers were twice as likely to be visually impaired as non-smokers.

Those who had kicked the habit more than 20 years previously were not at risk.

Based on the numbers of people in the UK who are blind or who are partially sighted as a result of macular degeneration, the authors calculated that smoking was likely to have caused up to 30,000 cases.

"An increased risk of [age related macular degeneration], which is the most commonly occurring cause of blindness in the United Kingdom, is yet another reason for people to stop smoking and governments to develop public health campaigns against this hazard," conclude the authors.

New Collaboration to discover genes responsible for Macular Degeneration

Fri, 01 Apr 2005 17:01:00 PST

( from http://www.rxpgnews.com ) ParAllele BioScience, Inc. announced today its joint collaboration agreement with the University of Iowa Cell Biology and Functional Genomics Laboratory, the UI Department of Ophthalmology and Visual Sciences and the UI Center for Macular Degeneration to accelerate the discovery of genes associated with age-related macular degeneration (AMD). The research initiative will be led by Gregory Hageman, Ph.D., professor at the UI Carver College of Medicine.

AMD is the leading cause of irreversible vision loss in the developed world, affecting 15 to 20 percent of individuals over the age of 60, or an estimated 50 million individuals.

"The molecular events leading to the development of AMD are poorly understood and no pharmacological treatment has been shown to be effective in preventing, arresting or reversing the loss of vision associated with early AMD," Hageman said.

Recent genome-wide linkage analyses have revealed loci on multiple chromosomes with the potential to harbor major AMD-associated genes. "We choose to collaborate with ParAllele because of their ability to comprehensively analyze those regions for both common and rare mutations that may be AMD-associated," he added. "Our long range goal is to identify new pathways and therapeutic targets that will hasten the development of pharmaceutical agents capable of delaying the onset and/or progression of AMD."

Hageman's studies are funded by the National Eye Institute at NIH and additional corporate entities.

"The agreement is an exciting opportunity for us to combine ParAllele's strengths in pharmacogenomics and high throughput gene mutation discovery with the acknowledged leadership of Dr. Hageman and his Institute in the field of AMD-associated pathways," said Nick Naclerio, CEO of ParAllele BioScience, Inc.

Gene variation could be responsible for age-related macular degeneration

Sun, 27 Mar 2005 02:22:00 PST

( from http://www.rxpgnews.com ) Half of all cases of age-related macular degeneration, the leading cause of blindness among the elderly, could be caused by a variation in a particular gene, according to UT Southwestern Medical Center researchers involved in a multicenter study.

The National Eye Institute study which will appear in an upcoming edition of the journal Science and is available online links a mutation in the gene Complement Factor H to an increased risk of age-related macular degeneration (AMD).

Macular degeneration is a complex disease that is the leading cause of blindness in Americans over the age of 50. By age 75, an estimated 30 percent of Americans have some manifestation of AMD.

The macula is an area in the center of the retina where light is focused and changed into nerve signals to compose an image in the brain. This central or "macular" vision enables us to read, drive and do things requiring fine, sharp, straight-ahead vision.

"We've identified a gene that is implicated in the pathogenesis of AMD," said Robert Ritter, a UT Southwestern research scientist involved in the Science study. "It provides a starting point for future investigations that will help us understand what takes place during the breakdown of the visual process."

Scientists have long suspected a genetic role in the disease but previously were only able to narrow the culprit gene's location to one region of a particular chromosome.

"We know that one of the most significant factors in determining who gets macular degeneration is family history," said Dr. Albert Edwards, the study's lead author and an assistant professor of ophthalmology at UT Southwestern when he conducted his research. "A positive family history can increase a person's chances of developing macular degeneration several fold compared to people in the general population."

In the study, researchers analyzed genetic data from more than 200 patients who were at high risk for developing AMD or who already had AMD in one or both eyes, and from more than 130 healthy participants without a known family history of the disease. The genetic mutation of Complement Factor H was present in half of those with AMD or at high risk for the disease.

Researchers from the UT Southwestern Eugene McDermott Center for Human Growth and Development provided genotyping, technical advice and assistance.

"This is an important study that gives us new insight into a disease that impacts a growing population of aging Americans," said Dr. Helen Hobbs, director of the center and chief of Clinical Genetics at UT Southwestern. "Genetic studies such as this provide the basis for clinicians to identify those at risk and may lead to better treatment options."

These findings may help researchers develop new preventive and therapeutic strategies for managing AMD.

"By finding genes, we can understand where the biological pathways are and the processes involved in the disease," said Dr. Edwards, who is now the president of the Institute for Retina Research at Presbyterian Hospital of Dallas. "Once we determine which genes are responsible for macular degeneration, we can screen the population and manipulate biological pathways to develop treatments."

Genetics important in age-related macular degeneration

Tue, 15 Mar 2005 01:57:00 PST

( from http://www.rxpgnews.com ) Genes play a substantial role in the development of age-related macular degeneration (AMD), one of the leading causes of irreversible blindness among older individuals, according to an article in the March issue of Archives of Ophthalmology, one of the JAMA/Archives journals.

About ten million people in the United States have signs of AMD, two million with decreased vision related to advanced AMD and eight million with earlier stages of the disease, according to background information in the article. Despite the public health impact of AMD, however, the relative roles of genes and environment in the development of AMD remain unclear. The authors state that classic twin studies, which compare the occurrence of a trait or disease in monozygotic (MZ, commonly called identical) twins versus dizygotic (DZ, commonly called fraternal) twins provide one of the most powerful methods for determining heritability (the relative contribution of genes versus environment).

Johanna M. Seddon, M.D., Sc.M., of Harvard Medical School, Boston, and colleagues surveyed 840 male twins from the National Academy of Sciences-National Research Council World War II Veteran Twin Registry born between 1917 and 1927. Two hundred and ten MZ and 181 DZ complete twin pairs and 58 singletons, whose twin were no longer living or were unavailable for the study, completed a survey and underwent an examination for AMD. The results were then statistically analyzed to determine the relative roles of genes, common shared environment and specific (unique to the individual) environment.

Of the 840 twins, 331 had no signs of macular degeneration, 241 had early signs, 162 had intermediate AMD and 106 had advanced AMD, the researchers found. There were no differences in the prevalence rates of AMD in MZ versus DZ twins. There were differences in whether the severity of AMD was the same for both twins depending on whether the twins were identical or fraternal, however. "Among pairs in which one or both twins had AMD, 55 percent of MZ pairs were classified as concordant (at the same level of severity) whereas 25 percent of DZ pairs were concordant for AMD," the authors write. "For advanced disease, the corresponding concordance rates were 18 percent for MZ twin pairs and 6 percent for DZ twin pairs."

"Genetic factors play a substantial role in the etiology [the cause of a disease] of AMD and associated macular characteristics, explaining 46 to 71 percent of the variation in the overall severity of the disease," the researchers found. "Environmental factors unique to each twin were estimated to account for 19 to 37 percent of the variation in AMD grade [level of severity] and 28 to 64 percent of the variation in the specific macular measures."

"In summary, based on what is, to our knowledge, the largest twin study of AMD to date and the only population based twin registry in the United States among elderly individuals, we quantified substantial genetic influences on AMD, contributed new information about the heritability of advanced AMD, and established an important environmental contribution," the authors conclude. "This twin study underscores the need for a multifactorial approach that incorporates genetic, environmental, and biologic factors in the study of the pathogenesis and clinical management of this increasingly prevalent cause of blindness."

Gene Variation implicated for Age-Related Macular Degeneration (ARMD)

Fri, 11 Mar 2005 16:28:00 PST

( from http://www.rxpgnews.com ) Half of all cases of age-related macular degeneration, the leading cause of blindness among the elderly, could be caused by a variation in a particular gene, according to UT Southwestern Medical Center researchers involved in a multicenter study.

The National Eye Institute study - which will appear in an upcoming edition of the journal Science and is available online - links a mutation in the gene Complement Factor H to an increased risk of age-related macular degeneration (AMD).

Macular degeneration is a complex disease that is the leading cause of blindness in Americans over the age of 50. By age 75, an estimated 30 percent of Americans have some manifestation of AMD.

The macula is an area in the center of the retina where light is focused and changed into nerve signals to compose an image in the brain. This central or "macular" vision enables us to read, drive and do things requiring fine, sharp, straight-ahead vision.

"We've identified a gene that is implicated in the pathogenesis of AMD," said Robert Ritter, a UT Southwestern research scientist involved in the Science study. "It provides a starting point for future investigations that will help us understand what takes place during the breakdown of the visual process."

Scientists have long suspected a genetic role in the disease but previously were only able to narrow the culprit gene's location to one region of a particular chromosome.

"We know that one of the most significant factors in determining who gets macular degeneration is family history," said Dr. Albert Edwards, the study's lead author and an assistant professor of ophthalmology at UT Southwestern when he conducted his research. "A positive family history can increase a person's chances of developing macular degeneration several fold compared to people in the general population."

In the study, researchers analyzed genetic data from more than 200 patients who were at high risk for developing AMD or who already had AMD in one or both eyes, and from more than 130 healthy participants without a known family history of the disease. The genetic mutation of Complement Factor H was present in half of those with AMD or at high risk for the disease.

Researchers from the UT Southwestern Eugene McDermott Center for Human Growth and Development provided genotyping, technical advice and assistance.

"This is an important study that gives us new insight into a disease that impacts a growing population of aging Americans," said Dr. Helen Hobbs, director of the center and chief of Clinical Genetics at UT Southwestern. "Genetic studies such as this provide the basis for clinicians to identify those at risk and may lead to better treatment options."

These findings may help researchers develop new preventive and therapeutic strategies for managing AMD.

"By finding genes, we can understand where the biological pathways are and the processes involved in the disease," said Dr. Edwards, who is now the president of the Institute for Retina Research at Presbyterian Hospital of Dallas. "Once we determine which genes are responsible for macular degeneration, we can screen the population and manipulate biological pathways to develop treatments."

Gene variant increases risk of age-related macular degeneration

Fri, 11 Mar 2005 02:04:00 PST

( from http://www.rxpgnews.com ) Researchers at Duke University Medical Center and Vanderbilt University Medical Center have pinpointed the first major gene that determines an individual's risk for developing age-related macular degeneration (AMD). The chronic, progressive disease -- which affects as many as 15 million people in the United States -- is the leading cause of visual impairment and legal blindness in the elderly.

A common variant of the gene, called complement factor H (CFH), explains approximately 43 percent of the risk of AMD among older adults, the researchers estimated. The team identified the disease-related gene after screening 182 families affected by AMD and 495 other individuals with the condition.

The researchers will report their findings in a forthcoming issue of Science (published online March 10, 2005, in Science Express).

The genetic advance sheds light on the mechanisms underlying the disease and could lead to new avenues for treatment, the researchers said. The finding might also yield methods for identifying those patients at the greatest risk for developing the condition before symptoms arise, when therapies and changes in lifestyle might be most effective in slowing the disease progression.

"Macular degeneration is an important cause of blindness and loss of independence in the elderly," said Margaret Pericak-Vance, Ph.D., director of the Duke Center for Human Genetics and senior author of the report. "This gene opens the door to a whole new understanding of the factors that contribute to this disease.

"The finding may ultimately lead to new methods for identifying those at high risk for macular degeneration and suggests new pathways for drug development," she added.

AMD causes progressive impairment of central vision, and is the most common cause of legal blindness in Americans over the age of 55. The disease causes damage to the retina, a thin layer of nervous tissue that lines the inside of the eye. The primary site of damage occurs in the central retina, a portion called the macula.

The retina functions like film in a camera, explained ophthalmologist Eric Postel, M.D., of the Duke University Eye Center. Without proper retinal function, images cannot be captured and sent to the brain. The macula is critical for fine, detailed vision. In patients with severe AMD, progressive blurring and loss of central vision due to damage of the macula may leave people unable to perform everyday activities such as driving, reading, writing checks and recognizing faces, he said.

"Fifteen million people in the United States have AMD and 1.5 million have the most severe form," said Postel, the head clinician on the study. "By the year 2030, as the baby boomer generation ages, the number of people with AMD is expected to double."

AMD exists in two forms: the "dry" form and more severe "wet" form. In the dry form, degeneration of the macula can cause slow, progressive vision loss over the course of months to years. While there is no cure, vitamin supplements have been shown to slow the disease in some individuals with this milder form.

In ten percent of patients, the disease progresses to the wet form in which abnormal blood vessels under the macula leak blood and fluid causing rapid damage and a precipitous loss of vision. Patients with wet AMD can receive several treatments to prevent further vision loss -- including laser surgery and recently approved injections of a drug into the eye.

However, available therapies usually can only stall the disease progression, Postel said. None effectively reverse the course of the disease.

While the underlying causes of AMD had remained largely unknown, risk factors include age, smoking, high blood pressure, obesity and diet, said Pericak-Vance. In addition to such environmental factors, evidence from family and twin studies had indicated a significant genetic contribution to the disease, she added.

Earlier studies by the Duke and Vanderbilt teams and others had linked AMD risk to a particular region on chromosome 1. To identify the gene responsible, the researchers examined two independent data sets: the first contained 182 families including members with and without AMD and the second contained 495 individuals with AMD and 185 unrelated individuals not affected by the disease.

The researchers zeroed in on a smaller region of chromosome 1 with a strong association to the disease in both data sets. Further DNA sequencing of the CFH gene that is within that region revealed that individuals with one or more copies of a particular gene variant were more likely to have AMD compared to those with other versions of the gene, they reported. When the researchers restricted the analysis to individuals with the more severe, wet form of AMD, the association between the gene variant and the disease became even stronger.

The researchers estimated that the CFH variant may be responsible for up to 43 percent of all cases of AMD.

Earlier studies had suggested that CFH may play a role in protecting blood vessels from inflammation and damage, a function which might explain its role in AMD, the researchers said.

"We knew that chronic inflammation played a role in macular degeneration, but we didn't know if that was a primary cause of the disease or a secondary symptom," said Jonathan Haines, Ph.D., of Vanderbilt Center for Human Genetics Research and first author on the report. "The finding that complement factor H is an important contributor to the disease suggests that inflammation may be a more important aspect of the disease than had previously been appreciated."

Given that the gene plays such a large role in AMD, further studies of CFH and the cellular components with which it interacts might lead to a rapid increase in understanding of the biology of the disease, the researchers added. That information, in turn, should allow scientists to advance on new treatments and preventive therapies.

Major role of genes in age-related blindness disease

Fri, 11 Mar 2005 02:00:00 PST

( from http://www.rxpgnews.com ) By combining the tools of high-throughput biology and statistical genetics, scientists at Rockefeller University, Yale University School of Public Health and the National Eye Institute have identified a gene that confers susceptibility to age-related macular degeneration (AMD), the most common cause of vision loss in the United Sates for those over 60. Reported in the March 10 issue of Science Express, the finding opens the door for new investigations of the role of genes in developing AMD and possible treatments for this disease.

"We have shown that a variant, or polymorphism, of the complement factor H gene, which alters a protein whose normal function is to regulate the immune system's attack of foreign invaders and abnormal cells, is involved in the development of AMD," says senior co-author Jürg Ott, Ph.D., professor and head of the Laboratory of Statistical Genetics at Rockefeller. "We believe this polymorphism is a strong risk factor for the disease."

The gene variant, known as a single nucleotide polymorphism (SNP), derives from a single letter difference in the genetic sequence of DNA. Some of these differences may change a gene's protein products in ways that may confer susceptibility to -- or protection from -- diseases. In this case, the complement factor H (CFH) SNP associated with AMD encodes for a different amino acid, as histidine substitutes for tyrosine at a specific position. The CFH gene lies in a region of human chromosome 1 that had been linked previously to AMD through family studies by other researchers.

The research team was led by senior co-author Josephine Hoh, Ph.D., an assistant professor in the Division of Chronic Disease Epidemiology at Yale's School of Public Health. Before joining Yale in 2003, Hoh was a research assistant professor in Ott's lab.

For the research reported in Science Express, Hoh used DNA taken from blood samples collected for the National Eye Institute-sponsored Age-Related Eye Disease Study (AREDS). The AREDS was designed to learn more about the natural history and risk factors of AMD and cataract and evaluate the effect of high doses of antioxidants and zinc on the progression of these conditions.

AMD is the leading cause of blindness in the developed world, and most sufferers are older than 60. It causes a loss of the central visual field necessary for detailed sight, reading, driving, sports participation and watching TV and movies. A characteristic of AMD (both the "dry" and wet forms) is the build up of fatty deposits called drusen in the macula, the central region of the retina.

Hoh and colleagues analyzed DNA from 96 unrelated patients with an advanced form of AMD and 50 healthy people who had little or no drusen deposits in their retinas.

The controls were chosen to be older than those with AMD. The study was carefully designed by matching other potential factors such as ethnicity, gender and smoking to ensure the only differences between the two study groups was disease status and genetic background

The researchers genotyped more than 116,000 SNPs using the most advanced microarray technology and compared the frequency of each of the 116,000 SNPs in the two groups, patients and controls.

Under the superevision of Hoh and Ott, Ott lab member Robert Klein, Ph.D., the first author of the paper, played a major role during course of the project, which include genotyping and analyzing the data generated by the microarray.

"Robert's unique background of molecular and computation biology was crucial to the success of this project," says Hoh.

Biochemical analysis of drusen by other researchers has shown that the deposits are largely composed of lipids, but a small portion of the drusen are components of the immune system called complement. The complement system is a collection of related proteins that are the body's front-line defense system -- the innate system -- that attacks foreign invaders while usually avoiding any attacks against healthy cells, the "self." And one of the known properties of factor H is that it regulates the activation of complement components.

The researchers examined the eyes of four patients with AMD and found complement debris in the drusen, as well as in eye components called Bruch's membrane and the intercapillary pillars. Other researchers also have detected complement components in the drusen of humans.

"The polymorphism produces a change in a specific amino acid in the complement factor H protein, which is located in the region that interacts with C-reactive protein and heparin," says Hoh. C-reactive protein is associated with heart disease and high cholesterol levels and both C-reactive protein and heparin are associated with AMD.

Gene for age-related macular degeneration discovered

Thu, 10 Mar 2005 02:26:00 PST

( from http://www.rxpgnews.com ) Researchers at Yale School of Medicine have identified a gene for age-related macular degeneration (AMD) on a region of chromosome 1, leading the way for targeted treatment for this widespread eye disease that causes blindness in millions of people.

The study, led by Josephine Hoh, assistant professor in the Department of Epidemiology and Public Health (EPH) at Yale School of Medicine, will be published online in the March 10 issue of Science Express. Hoh and colleagues from Yale, Rockefeller University and the National Eye Institute, used a highly interdisciplinary approach to conclude that the gene for a substance known as complement factor H (CFH) on chromosome 1 is associated with AMD.

"This is the first study to identify a common variant of the specific gene being associated with AMD," said Hoh. "Caucasian AMD patients are at least four times more likely to have one particular alteration in the CFH gene that produces a different form of the CFH protein compared to individuals without the disease."

AMD is a debilitating eye disease affecting about 15 million people in the United States. It destroys vision by attacking an area of the retina called the macula, particularly in people age 60 or older. The macula is the most sensitive region of the retina, enabling fine-detail vision, reading, driving and leisure tasks such as playing sports and watching movies and television. As part of the normal aging process, yellowish waste deposits called drusen accumulate around the macula, but in individuals with AMD, the drusen are larger and more numerous, killing cells necessary for the nourishment of adjacent retinal photoreceptor cells. As these photoreceptors die in and around the macula, central vision is lost. Peripheral vision is not impaired by AMD.

There are two forms of AMD, the more common "dry" form and the less common "wet" form. The wet form can rapidly lead to blindness, while the dry form progresses more slowly. Both are associated with the same variant in the CFH gene.

Hoh and her team used new genetic analysis and microscopic imaging technologies to find the genetic variant of the AMD gene. "What sets our study apart from previous research is that we used many more genetic markers to find the specific gene and variation," said Hoh. "Past research has involved collecting family data that pinpoint a region on chromosome 1, but failed to find the specific gene. We analyzed the DNA of unrelated patients with AMD and compared their genetic profile to that of AMD-free controls. In this sea of DNA information, we applied computation-intensive, statistical analyses and were able to find the differences between the two groups. Subsequently, the gene association has been confirmed by at least three independent studies with results pending publication."

"This work is not only important for the gene we have found, but also highlights the value in new paradigms for whole genome analysis for chronic diseases," Hoh added. "I believe that in order to find genes responsible for diseases, you have to use a totally different approach, instead of an educated guess. Our findings support greater use of this technique."

A 'Mouse Model' to Test Potential Therapies for Age-Related Macular Degeneration

Mon, 07 Mar 2005 08:01:00 PST

( from http://www.rxpgnews.com ) The mouse model, which was reported in the March 4, 2005 online edition of the Proceedings of the National Academy of Sciences, "now permits the testing of potential therapies for the "dry" version of age-related AMD and STGD in an animal model," said the study's co-senior author David S. Williams, Ph.D., UCSD professor of pharmacology and neurosciences. Currently there is no known treatment or cure for the disorder.

AMD affects about 11 million Americans, with dry AMD accounting for about 90 percent of all AMD. STGD strikes about 30,000 children and young adults in the U.S. Macular degeneration is caused by the deterioration of the central portion of the retina, the inside back layer of the eye that records images and sends them via the optic nerve from the eye to the brain.

The retina's central portion, known as the macula, is responsible for focusing central vision in the eye, and it controls the ability to read, drive a car, recognize faces or colors, and see objects in fine detail.

The UCSD-Utah scientists said that the AMD and STGD forms of macular degeneration are characterized by high levels of debris called lipofuscin that accumulates in the retinal pigment epithelium ( RPE ) and results in its degeneration together with photoreceptor cells. Vision loss follows.

Noting that scientists have recently linked mutations in a gene called ELOVL4 to AMD and STGD, the UCSD-Utah investigators developed mice with a mutant form of ELOVL4, which caused the mice to develop significant lipofuscin accumulation and photoreceptor and RPE death in a pattern closely resembling the human counterpart.

There have been other reports of mouse models of AMD, but these models have not replicated the symptoms of dry AMD. Dry AMD accounts of 90 percent of all AMD, while "wet" AMD is relatively minor and involves neovascularization of the back of the retina.

A Kentucky group developed a model called Cc1-2 which comes close to modeling wet AMD. Another model is a transgenic mouse that expresses a mutant form of the lysosomal enzyme cathepsin D. While this model showed localized atrophy of the retina, it was the periphery of the retina that was most affected.

The only other model is a knockout mouse for the Abca4 gene. Mutations in the equivalent gene in humans result in a recessive form of STGD. However, this mouse does not undergo retinal degeneration.

Self-management training benefits macular degeneration patients

Wed, 12 Jan 2005 02:15:00 PST

( from http://www.rxpgnews.com ) A 12-hour self-management program for individuals with advanced age-related macular degeneration (AMD) leads to lasting improvements in mood and function, especially in depressed patients, and decreases the development of clinical depression in AMD patients over time, according to a University of California, San Diego (UCSD) Shiley Eye Center study published in the January 2005 Archives of Ophthalmology.

In this study, individuals who participated in a structured group session designed to educate patients and assist them with skills to successfully live with the vision loss caused by AMD were assessed six-months after they completed the program. The same cohort was the subject of a paper published in the November 2002 Archives of Ophthalmology, based on testing results immediately following their participation in the program.

The 2002 study showed significant improvement in quality of life, mood and function in patients immediately following completion of the program.

This study is a six-month follow-up assessment of the self-management group and a control group of patients who did not participate in the program. Benefits of reduced distress and improved function were still seen in those who had participated in the self-management program compared with the control group. And, the incidence of depression in the control group had grown to more than twice that of the self-management group, indicating that the program "seemed to have a remarkable influence on preventing new cases of depression," according to the study's authors.

"Too often the vision loss that results from this incurable disease is accompanied by anxiety, hopelessness and depression," said Stuart I. Brown, M.D., director of UCSD's Shiley Eye Center and Chair of Ophthalmology at UCSD. "As we continue to seek effective treatments and cures for AMD, we have made it an immediate priority to help patients develop the confidence and skills to continue leading fulfilling lives despite their impaired vision."

Because of the increasing number of patients with age-related AMD associated with the growing number of people over age 65, the Shiley Eye Center developed the 12-hour program to bring AMD patients together in groups, led by health professionals, to share their experiences and frustrations, and to learn how to live with the condition. The program combines basic education about the disease with specific problem-solving sessions and projects to help participants overcome barriers and remain self-sufficient, according to Barbara Brody, M.P.H., clinical professor of ophthalmology at UCSD and director of Community Ophthalmology, at the Shiley Eye Center, and first author of the paper.

These sessions include helping patients discuss their disease and describe their limitations to others, which is often difficult for AMD patients, said Brody.

AMD is the leading cause of vision loss in older adults. Caused by the degeneration of cells and in some forms, blood vessel leakage, in the macula, the area responsible for central vision, the AMD patient loses central vision but retains peripheral vision.

For this study, 231 volunteers ranging in age from 60 to 99, all with advanced AMD, were randomly assigned to either the self-management group, a group that listened to lectures on tape, and a group that was placed on a waiting list but received no intervention. All patients were assessed for emotional and functional status; about 24 percent of the patients had major or minor depression.

The 86 patients who participated in the self-management program attended six two-hour sessions designed "to increase patients' expectations of successfully dealing with the effects of advanced AMD," according to the study's authors. "Low vision aids and services were discussed. Problem-solving skills training, including goal setting, action plans, new ways to think about their situations, role playing, and modeling of the behaviors to be changed, was provided in an enjoyable and stimulating manner." The program also teaches exercises specially designed for AMD patients to build confidence in their physical abilities.

Even after six months, the data indicate that this relatively simple intervention may protect against depression that often occurs in AMD patients, and improves the AMD patients' function, self-efficacy and emotional status, compared with the control patients in the two other groups.

"The most important feature of the study is that it achieved maintenance of benefits at 6-months. This is unusual. The biggest problem in the behavioral intervention literature is maintenance of benefit over time," said Robert M. Kaplan, Ph.D., Chair of the Department of Health Services at the UCLA School of Public Health.

Brown and Brody hope to see such programs offered more widely to AMD patients, especially as this disease becomes more common.

"We believe that the combined effects interrupted the overwhelming sense of loss and empowered participants to feel less helpless and more hopefulbased on new information and new skills to achieve small and then bigger successes that fostered engagement in personally meaningful activities," they conclude.

Pegaptanib provides benefit for neovascular age-related macular degeneration

Thu, 30 Dec 2004 02:19:00 PST

( from http://www.rxpgnews.com ) Results from two concurrent, prospective, double-blind, multi-center clinical trials show that pegaptanib (Macugen), an anti-vascular endothelial growth factor therapy, is an effective treatment for neovascular age-related macular degeneration (AMD), according to a paper in the Dec. 30 issue of the New England Journal of Medicine. Macugen was approved by the Food and Drug Administration on Dec. 17.

AMD is the leading cause of irreversible, severe loss of vision in people 50 years and older in the developed world and remains an area of unmet medical need. The neovascular or wet form of the disease represents about 10 percent of the overall disease prevalence, but is responsible for 90 percent of the severe vision loss. In wet AMD, abnormal blood vessels grow under the central retina and cause a progressive loss of central vision, interfering with driving, reading and other everyday tasks. As the population ages, almost 1 million people over the age of 55 years in the United States are expected to develop AMD in the next five years, making it a major public health issue in an increasing population of older persons.

The paper in the New England Journal of Medicine details two clinical trials that were held at 117 sites in the Unites States, Canada, Europe, Israel, Australia and South America. Patients were eligible for inclusion if they were 50 years of age or older and had subfoveal choroidal neovascularization caused by AMD and a range of best corrected visual acuity of 20/40 to 20/320 in the study eye and of 20/8000 or better in the other eye. Of the 1,208 patients randomly assigned to treatment in the two studies, (297 patients were assigned to receive 0.3 mg of pegaptanib; 305 patients, 1.0 mg of pegaptanib; 302 patients, 3.0 mg of pegaptanib; and 304 patients, sham injections), 1,190 received at least one study treatment. Treatments were given by injection into the eye.

According to lead author, Evangelos Gragoudas, M.D., Director of Retina Services at the Massachusetts Eye and Infirmary and Professor of Ophthalmology at Harvard Medical School, pegaptanib produced a statistically significant and clinically meaningful benefit in the treatment of wet AMD.

"Overall, a reduced risk of visual-acuity loss was observed with all doses as early as six weeks after treatment was begun, with evidence of an increasing benefit over time up to week 54," the authors write. "Pegaptanib reduced the chance of not only the loss of 15 letters or more of visual acuity (considered a moderate loss) but also a loss of 30 letters or more (six lines on the eye chart, which is considered a severe loss.) In addition, treatment with pegaptanib reduced the risk of progression to legal blindness in the study eye, promoted stability of vision, and in a small percentage of patients, resulted in more visual improvement at week 54 than among those receiving sham injections."

The authors conclude that treatment with pegaptanib provide a statistically significant and clinically meaningful benefit in a broad spectrum of patients with neovascular AMD, regardless of the size or angiographic subtype of the lesion or the baseline visual acuity. The rate of injection-related adverse events represents a potentially modifiable risk but necessitates vigilance, the authors caution.

The Massachusetts Eye and Ear Infirmary (MEEI) in Boston participated in these clinical trials. In addition, researchers and physicians at MEEI -- Drs. Anthony P. Adamis (formerly of MEEI), Evangelos Gragoudas (MEEI) and Joan Miller (MEEI) -- were among the first to study the role of vascular endothelial growth factor (VEGF), which causes abnormal blood vessel growth in eye disease. Their experimental studies showed that levels of VEGF protein were increased in eyes that developed abnormal new blood vessels, and that VEGF-blocking drugs were able to prevent the growth of these abnormal blood vessels. Others, including Harvard's Dr. Lloyd Paul Aiello of the Joslin Diabetes Center, Dr. Patricia D'Amore of the Schepens Eye Research Institute and Dr. Lois Smith of Children's Hospital, corroborated the importance of VEGF in neovascular eye disease. These studies formed the basis for the drug development and clinical trials of anti-VEGF therapies, including pegaptanib, and demonstrate the importance of translational research, in order to transform scientific discoveries into new therapies for patients.

Pegaptanib differs from current treatments, which are directed at the results of the disease. Current treatments, which employ a drug and laser, are able to slow vision loss, but have not been widely applicable to all patients. Pegaptanib is the first treatment designed to target the source of the disease and blocks the pathological form of a chemical called VEGF, which is produced in the eye of patients with wet AMD.

The results of the two studies provide validation of the aptamer-based therapy in the treatment of human disease and support ongoing investigations into the use of VEGF antagonists in patients with diabetic retinopathy and retinal-vein occlusion, which are other disorders associated with elevated levels of intraocular VEGF.

Growing epidemic of wet AMD

Wed, 27 Oct 2004 02:40:00 PST

( from http://www.rxpgnews.com ) Retina specialists and ophthalmologists are encouraged by promising new scientific approaches that could have the potential to reduce the devastating effects of wet AMD for patients and offer the medical community a new paradigm of care, according to presentations made at the 2004 Annual Meeting of the American Academy of Ophthalmology in New Orleans.

Many experts consider AMD, the leading cause of blindness in Americans over age 50, as a growing public health epidemic. Diagnoses for AMD are expected to double by 2020.

"The epidemic of AMD is fueled by the aging Baby Boomers, the fact that people are living longer, and the increasing incidence of the disease," said presenter Paul Sternberg Jr., M.D., Chairman of the Vanderbilt Eye Institute. "Fortunately, new approaches to treating the disease may soon become available with several therapies in late-phase clinical trials or pending FDA approval showing great promise for stabilizing wet AMD and preserving vision."

Saving Eyes, Saving Lives: The Physical and Emotional Impact of Vision Loss

AMD is a chronic, progressive disease that results in the loss of central vision. As the disease advances, simple tasks such as reading, writing NEW ORLEANS, LA, October 25, 2004 As more Americans age, the threat of blindness is increasing, and the search for new ways to prevent and treat diseases such as age-related macular degeneration (AMD) has become a high priority in the eye care community., recognizing faces and driving become difficult, if not impossible. The disease not only takes a physical toll on its patients, but also can have a devastating emotional impact on them, their families and caregivers.

"Even a little vision loss to a fully sighted adult can compromise function more globally than any other impairment, increasing the risk of falls and injuries, medication mix-ups, poor nutrition, social isolation and clinical depression," said presenter Lylas G. Mogk, M.D., founding director of the Visual Rehabilitation and Research Center at the Henry Ford Health System Eye Care Services. "For most people, losing both legs would actually impact our lives less than losing our central vision. So it's not a surprise that sighted Americans fear vision loss second only to loss of mental capacity."

Living with vision loss does not have to be such a lonely and isolating experience. Today, vision rehabilitation services are available to maximize independence and preserve quality of life for the hundreds of thousands of Americans living with age-related macular degeneration. Between six and ten percent of patients with AMD progress to the wet form of the disease, characterized by the growth of abnormal blood vessels. Currently only 25 percent of patients with wet AMD have a treatment option approved by the U.S. Food and Drug Administration (FDA). In addition to vision rehabilitation, innovations in biotechnology have the potential to fill the large unmet medical need by offering new treatments to wet AMD patients.

Hope on the Horizon: Anti-VEGF, Anti-Angiogenic and Angiostatic Treatments

Dr. Carmen A. Puliafito, Chairman of the Bascom Palmer Eye Institute at the University of Miami, said that a new treatment paradigm for wet macular degeneration is emerging. This new treatment paradigm is based on the use of drugs which block VEGF (vascular endothelial growth factor), the molecule which promotes the growth of abnormal blood vessels in wet macular degeneration. These drugs can be delivered directly into the eye by injection and attack abnormal VEGF in the retina and adjoining tissues in eyes with wet macular degeneration.

"There are several reasons why anti-VEGF treatment for macular degeneration is so exciting. For the first time, we will have a treatment option for all new cases of wet age-related macular degeneration; right now we only treat a limited number of angiographically defined subtypes," said Dr. Puliafito. "These agents also offer a unique strategy for restoring retinal function and structure in eyes with wet AMD."

Evaluating Emerging Wet AMD Therapies: Is a Bright Future Ahead?

Data presented at this year's American Academy of Ophthalmology meeting show that significant progress is being made to bring new therapies to wet AMD patients at the earliest possible time.

Two anti-VEGF treatments currently in development include pegaptanib sodium (to be marketed as MacugenTM by Eyetech Pharmaceuticals and Pfizer Inc), an anti-VEGF aptamer that binds to one particular form of VEGF in the eye, thereby neutralizing its activity, and ranibizumab (to be marketed as LucentisTM by Genentech Inc and Novartis Ophthalmics), an antibody fragment that also binds to VEGF and inhibits its activity. New clinical trial data on pegaptanib presented during the Retina Subspecialty symposium showed that wet AMD patients benefit from two years of treatment with pegaptanib, which demonstrates that longer-term use may be beneficial for patients suffering from this chronic disease. Pegaptanib is currently under priority review by the FDA and the agency expects to make its decision on the drug by mid-December. Genentech's ranibizumab is currently in phase III clinical trials.

Data from another investigational treatment known as anecortave acetate, an angiostatic cortisene that inhibits the abnormal growth of blood vessels, was also presented at the AAO meeting. Initial analysis of the one-year data from a comparative study of anecortave acetate versus photodynamic therapy in the treatment of wet AMD showed there was no statistical difference between the two therapies. Additional analyses of treatment interval and drug reflux, two controllable factors that some say negatively affected the results, were presented during the meeting. The company is continuing to analyze the data and plans to submit its New Drug Application to the FDA by the end of the year.

Donald D'Amico, M.D., professor of ophthalmology at Harvard University and associate chief of ophthalmology for clinical affairs at the Massachusetts Eye and Ear Infirmary, is optimistic about the future of treatment. "The future looks brighter for people with wet AMD," said D'Amico. "Investigational therapies have the potential to usher in a new era in treatment for wet AMD and offer hope to patients where once there was little or none. Patients have been waiting for new treatment options and the data presented at this meeting show that we are getting closer to making these important new therapies available to wet AMD patients and the physicians who treat them."

Gene defects found in age-related macular degeneration

Tue, 27 Jul 2004 02:32:00 PST

( from http://www.rxpgnews.com ) Howard Hughes Medical Institute (HHMI) researchers have identified subtle defects in a single gene that underlie a hereditary form of age-related macular degeneration, the leading cause of irreversible vision loss in the developed world.

Although the genetic mutations discovered by the researchers affect only about two percent of patients with the disorder, the findings offer important insights for researchers who seek to understand age-related macular degeneration (AMD).

"The clinical entity that we call AMD is actually as many as fifty diseases," said the study's lead author, HHMI investigator Edwin M. Stone, who is at the University of Iowa Carver College of Medicine. "They simply look so similar that clinicians call them the same thing. Because of such complexity, we don't understand the molecular mechanisms of the disease very well, and this has limited our ability to develop preventive therapy for it.

"Looking for genetic causes of AMD is potentially very meaningful because it will help us identify the mechanisms of the disease," he said. "Knowing the genetic bases of AMD would also enable us to create an animal model that could be used to test therapies. And, if we understood several of the mechanisms, we could potentially divide the patient population into clinically relevant subgroups, so that we could direct specific treatments to those most likely to benefit from them."

Stone and HHMI investigator Val C. Sheffield led the research team that published its findings in the July 22, 2004, issue of the New England Journal of Medicine (NEJM). Stone and Sheffield collaborated on the study with colleagues at the University of Iowa and the University of Southampton.

AMD is a worldwide problem, affecting some seven million people in the United States alone. Vision loss occurs when deposits of protein and fat accumulate beneath the center of the retina, compromising and ultimately destroying its function.

For the study published in NEJM, the researchers recruited 402 people with AMD and 429 healthy subjects. They obtained blood samples from the study subjects, which they used to extract DNA that was then examined for variations in genes that code for proteins called fibulins. The researchers chose the fibulin genes because previous studies by Stone, Sheffield and their colleagues identified a mutation in one of the genes, FBLN3, in a disease resembling AMD.

In their study, the researchers screened the genes FBLN1, FBLN2, FBLN4, FBLN5, and FBLN6 for variations that could affect the function of the resulting fibulin proteins. To determine whether disease-causing mutations existed, they compared the patients' genes with those of control individuals who did not have AMD.

The researchers found variations in FBLN1, FBLN2, FBLN4, and FBLN6 that could have contributed to AMD, but these changes were not statistically significant in terms of their comparative occurrence in AMD patients and healthy controls.

However, the researchers found that seven of the 402 AMD patients each had a different change in the FBLN5 gene that was not found in the healthy control group. Six of these seven changes altered an amino acid in the fibulin 5 protein that has been highly conserved during evolution.

Stone believes the finding offers an important lesson about searching for genetic causes for AMD. "Fifteen years ago, we and others believed that there would be a single gene that would be responsible for a substantial percentage of AMD," he said. "This experiment suggests that in reality a significant genetic cause of AMD may affect only two percent of the total. And so, fifteen years ago if we had done an experiment with 100 people and had seen a change in one only person, it wouldn't have fit our concept of the disease, and we would have probably ignored it completely."

Stone emphasized that future searches for causative mutations of AMD must be painstaking in their precision and involve large numbers of patients. "It may well be that some of the variations we found in the other fibulin genes also cause AMD, but with our current analytical limitations, they are not detectable."

The researchers' next steps will include producing cell cultures and animal models that harbor the mutations identified in the NEJM study. These steps will help researchers determine whether the fibulin proteins do have an altered function that would produce AMD.

The discovery of the AMD-related mutations in the fibulin genes will open the way to exploring whether other components of the cellular machinery involving fibulins might be disrupted by mutations that cause AMD, said Stone.

"The most immediate clinical implication of these findings is that if we can use fibulin gene mutations to distinguish a particular group of AMD patients, we could imagine exploring whether they do better with a certain type of treatment than other AMD patients," he said. "Such distinctions are important, because pharmaceutical companies might already have a treatment that works for perhaps five percent of AMD patients. But if they treated a hundred patients with such a compound, they would conclude that it didn't work, because it wouldn't work for ninety-five percent of those patients."

Racial variations in nursing home resident vision loss

Wed, 14 Jul 2004 02:35:00 PST

( from http://www.rxpgnews.com ) Cataract was the primary cause of low vision in 54 percent of African American nursing home residents compared to 37 percent of white residents, according to an article in the July issue of Archives of Ophthalmology, one of the JAMA/Archives journals.

According to background information in the article, blindness and visual impairment rates increase with age, and are also higher among nursing home residents.

David S. Friedman, M.D., M.P.H., of the Wilmer Eye Institute, The Johns Hopkins University, Baltimore, and colleagues measured the vision of 1,307 nursing home residents (304 African Americans, 997 white residents) in 28 nursing homes in Maryland and Delaware. Residents with visual acuity worse than 20/40 in their better-seeing eye (N = 412) were also examined by an ophthalmologist to determine the main cause for reduced vision.

Cataract was the leading cause of low vision in both African American and white residents (54 percent and 37 percent, respectively), and was a more common cause of vision loss among African American patients (24.2 percent) than white patients (11.8 percent). Macular degeneration caused low vision in 29 percent of white residents and 7 percent in African American patients. In four percent of white residents and ten percent of African American residents, glaucoma caused low vision.

"The higher prevalence of cataract among African American persons can be attributed to any of several factors. Previous researchindicates that African American persons are less likely to visit an ophthalmologist, and they obtain cataract surgery at lower rates than white persons," the authors write.

"In summary, low vision and blindness are highly prevalent among residents of nursing homes, with more than one third affected. African American subjects have a greater burden of unoperated cataract and glaucoma, while white subjects have much higher prevalence rates of AMD [age-related macular degeneration]. Cataract remains the most common cause of low vision for both racial groups, pointing to a potential benefit of intervention programs aimed at providing surgical services to this population."