Scripps Research scientists crack mystery of protein's dual function

Researchers at The Scripps Research Institute have solved a 10-year-old mystery of how a single protein from an ancient family of enzymes can have two completely distinct roles in the body. In addition to providing guidance for understanding other molecules in the family, the research supplies a theoretical underpinning for the protein's possible use for combating diseases including cancer and macular degeneration.

The research was published in the December 13, 2009 advance, online issue of the high-impact journal Nature Structural and Molecular Biology.

The scientists, led by Scripps Research Associate Professor Xiang-Lei Yang, focused on a molecule called human tryptophanyl-tRNA synthetase (TrpRS), finding that it contains a "functional switch" that enables it to perform two different functions. In one of its forms, the molecule acts to facilitate protein synthesis. In the second form, the same molecule works to inhibit the formation of new blood vesselsan effect that, if successfully harnessed, could be medically useful.

"I'm very excited about these findings," said Yang. "This piece of work provides a very deep mechanistic understanding. It has really shown that the activity of this tRNA synthetase is of biological significance and that it's a good example of the many, many different functions that have been found with the tRNA synthetase family."

One Enzyme, Two Functions

For some time, scientists have known that the aminoacyl tRNA synthetase family is composed of 20 ancient enzymes that attach the correct amino acid to a tRNA as the first step in the synthesis of proteins.

The mystery of the protein family's dual functionality, however, was born about a decade ago, with the publication of a 1999 paper in the journal Science by Paul Schimmel, who is Ernest and Jean Hahn Professor of Molecular Biology and Chemistry and a member of The Skaggs Institute for Chemical Biology at Scripps Research, in collaboration with a member of his lab at that time, Keisuke Wakasugi.

In the 1999 paper, Wakasugi and Schimmel showed that a member of the human aminoacyl-tRNA synthetase family, tyrosyl-tRNA synthetase (TyrRS), did more than adding the amino acid tyrosine to a protein chain during protein synthesis. In addition, a fragment of the protein could function to attract immune cells and to stimulate the growth of blood vessels.

The findings were met with astonishment and some skepticism in the scientific community.

Soon afterward, however, the Schimmel lab showed that another member of the family, TrpRS, also had a dual function. In addition to its role adding the amino acid tryptophan to a protein chain during protein synthesis, a fragment of TrpRS could inhibit new blood vessel formation.

Since that time, there has been considerable therapeutic interest in TyrRS, TrpRS, and other members of the aminoacyl-tRNA synthetase family. As a pro-angiogenic factor, the TyrRS fragment could be useful in diseases where growth of blood vessels is desirable, such as in some forms of heart disease or peripheral artery disease. Likewise, the TrpRS fragment's anti-angiogenic effects could help patients reduce undesirable blood vessel growth in diseases such as cancer and a great many eye diseases that lead to catastrophic vision loss.

In fact, fragments of TrpRS were used as part of a study led by Scripps Research Professor Martin Friedlander that successfully halted the progression in animal models of highly vascular brain tumor and neovascular eye disease (PNAS 2007 104:967-972).

Despite the interest in tRNA synthetases, however, no one has been able to figure out exactly how they perform their different rolesuntil now.

Mystery Mechanism Revealed

In the current study, the research team used a combination of techniques including structural modeling analysis, mutagenesis, and cell-based functional studies to unravel the secrets of TrpRS.

The scientists identified the specific molecular changes that enabled TrpRS to perform one function or another.

In the study, the scientists show that, for its role in protein synthesis, TrpRS is typically in its full-length form. This form of the molecule contains a tryptophan-binding pocket that enables it to bind with the amino acid and shepherd it to where it is needed in protein synthesis.

In the second active form, however, the protein must first be broken into fragments by the body, creating a piece called T2-TrpRS. With the removal of the end of the full-length protein (the N-domain), new grooves in the T2-TrpRS protein fragment are revealed. Containing the now-exposed tryptophan-binding pocket, the grooves fit together with side chains of another molecule, VE-cadherinknown to be indispensable for proper vascular development.

Interestingly, the new study found that tryptophan acts to inhibit of the vasculature function of TrpRS, locking the protein into its protein-synthesis form.

Therapeutic Potential

Yang notes that the therapeutic potential of TrpRS and other tRNA synthetases are particularly good because they normally exist in abundant amounts in the body.

"Naturally, you'd imagine the body's tolerance for such a protein is pretty good," she said, "and we could use the activated form of the molecule."

In addition, Yang points out that TrpRS is intriguing because it does not effect existing blood vessel growth, only new blood vessel formation, reducing the odds of negative side effects from its use.

For more information go to www.maculardegenerationassociation.org

Save your eyesight – stop smoking!

By Martin Burns

AMD (age-related muscular degeneration) Alliance International is strongly urging smokers to participate in tomorrow`s Great American Smokeout to protect their vision from the effects of macular degeneration.

The leading cause of blindness among people over the age of 50, AMD is two to three times as frequent among tobacco smokers, according to research by JM Seddon last month.

Further research in October by WG Christen revealed that regular heavy smoking can increase the risk of AMD by 144-fold in people with certain genetic backgrounds.

David Herman, AMD Alliance International chairman, said: "We [can] add vision loss to the list of significant and debilitating health risks that are caused by smoking. If you quit today, you can immediately begin lowering your risk of losing your sight to macular degeneration."

Healthcare provider Simplyhealth recently suggested that a diet lacking in fresh fruit and vegetables is a contributing factor to various eyesight conditions.

For more information go to www.maculardegenerationassociation.org

Lutein can Protect Against Macular Degeneration and Promote Eye Health

As people live longer eye diseases such as macular degeneration and cataracts are on the rise which has a negative effect on eye health. This often robs people of their freedom and quality of life. Age related macular degeneration (AMD) is the leading cause of irreversible blindness in people over 65. AMD occurs when the cells in the central part of the eye, which is called the macular, begin to degrade. This causes loss of sight in the central part of the field of vision, but leaves peripheral vision intact.

It is estimated that as many as 16 million Americans show signs of the initial stages of AMD. To put that into perspective that is roughly twice the population of Los Angeles. While this seems like a very high number the fortunate thing is that 90% exhibit the dry form of AMD which occurs over time and can be corrected with nutrition and lifestyle changes. The dry form of this disease is not associated with blindness, but, if left untreated can progress to the wet form of AMD. This sudden form of the disease leads to blindness in about 10% of AMD patients.

There are a number of factors that are known to lead to the development of AMD. Some of these include age, eye color, gender, exposure to sunlight, smoking, alcohol consumption and heart disease to name a few.

Lutein is a carotenoid found in some vegetables and fruits. It acts as a powerful antioxidant that can protect the eyes from disease and is essential for good vision and eye health. It is not made by the body and can only be obtained by the foods that we eat and nutritional supplements. The problem is that large amounts of fruits and vegetables would need to be consumed to get the required amount of lutein. It is found in green leafy vegetables such as spinach and kale. It is also found in corn and egg yolks. Carotenoids have shown benefits in reducing the risk of cancer, heart disease and eye disease and enhancing the body’s immune system.

Lutein is found in the macular which is the central part of the retina. While it is not a vitamin lutein is an antioxidant that may help to protect the macular tissue from destructive oxidation reactions by eliminating free radicals. It can also filter high energy blue light that has been known to damage the macula and skin.

It was first discovered by a researcher at Harvard University in 1994 that lutein plays an important role in eye health. Since that time there has been significant research on its ability to protect the eyes and is recommended by many eye doctors for their patients.

According to a recent study done by Kemin Foods 91% of eye doctors believe that lutein plays an important role in promoting good eye health. In addition, 58% of those surveyed believe lutein is the best nutrient for promoting long term eye health. This survey consisted of 150 ophthalmologists and 150 optometrists in the United States about their perceptions of lutein.

When the color of one’s eyes starts to fade it is not a result of aging but a loss of lutein. It is used by the eye as a natural antioxidant to eliminate damaging free radicals. Lutein as acts to filter damaging light from the eye. You can think of it as a pair of natural sunglasses.

Assuming that we are getting enough lutein thru diet or nutritional supplementation the good news is that it has the ability to build reserves in the eye to assure long term eye heath. Even for people that are not experiencing any eye problems they can benefit from lutein in preserving the good eye health they already have. Think of lutein as doing the same thing for your eyes as sun block and moisturizer does for your skin. If you start using it when you are young you maintain the healthy appearance of your skin as you age. The same analogy can be applied to your eyesight. When you are 60 it would be nice to have the same vision as when you were 30.

We know that we can not change our age, genetics or gender but there are things in our lifestyle that we can change to protect our eyesight. A few of these are to quit smoking, protect your eyes with sunglasses, limit your intake of alcohol and supplement with lutein.

For more information go to www.maculardegenerationassociation.org

Cataract Surgery Does Not Worsen Age-Related Macular Degeneration

Fran Lowry

Cataract surgery does not appear to increase the progression of age-related macular degeneration (AMD). Instead, it might reveal pre-existing AMD that had been hidden by the cataract, suggests a new study published in the November issue of the Archives of Ophthalmology.

"There has been a longstanding controversy among clinicians as to whether cataract surgery is contraindicated in eyes with nonneovascular AMD," write Li Ming Dong, PhD, from Stony Brook University School of Medicine in New York, and associates from Johns Hopkins University School of Medicine in Baltimore, Maryland. "A major concern has been whether cataract surgery increases the risk of progression to neovascular AMD in eyes at risk of progression, such as those with intermediate AMD (extensive medium-sized drusen, large drusen, or nonfoveal geographic atrophy)."

The aim of this study was to evaluate the course of AMD during the year after cataract surgery in individuals with preconfirmed nonneovascular AMD.

The investigators analyzed 86 patients with nonneovascular AMD who underwent cataract surgery to note the incidence of neovascular AMD development in the 12 months after the operation. Only 1 eye from each patient was analyzed.

Fluorescein angiography was performed preoperatively, and at 1 week, 3 months, and 12 months postoperatively.

The median age of the patients was 76 years (range, 58 to 92 years); 48% were women, 97% were white, and nearly two thirds were current or former cigarette smokers. The median preoperative visual acuity (Snellen equivalent) was 20/50 (range, ≥20/40 to 20/400).

Photographic documentation of AMD status was done in 71 patients (83%) at the 12-month visit. Sixty-six patients (77%) also completed a clinical examination at this visit.

Neovascular AMD was observed in 9 eyes (12.7%; 95% confidence interval [CI], 6.0% - 22.7%) by 12 months, including 1 that was graded as probable neovascular AMD. Five eyes displayed signs of neovascular AMD at the 1-week follow-up, but the size and location of the lesions indicated that they might have been present before surgery but not visible because of the opacity caused by the cataract, the authors report.

One eye did not have a 1-week follow-up. After excluding this eye, as well as the 5 eyes that showed lesions at the first follow-up period, the rate of confirmed progression to neovascular AMD between week 1 and month 12 decreased to 3 (4.6%) of 65 eyes (95% CI, 1.0% - 12.9%), the investigators report.

The investigators also noted the progression to neovascular AMD in the study subjects' phakic contralateral eyes. They report that neovascular AMD developed in only 1 eye (3%) at 12 months.

Previous Reports Might Be Biased

"Our findings suggest that previous reports of the association or progression of nonneovascular AMD to advanced AMD after cataract surgery could be biased by the absence of immediate preoperative and postoperative fluorescein angiography to rule out pre-existing neovascular AMD or geographic atrophy," the study authors write, adding that a strength of their study — the first to their knowledge — was the use of color fundus photographs and fluorescein angiography in the immediate pre- and post-cataract surgery setting.

However, they point out, their study is limited by its small size and limited duration of follow-up to just 12 months. In addition 15 eyes (17%) at risk for neovascular AMD had to be excluded from the analysis because their postsurgery AMD status at 12 months could not be determined because of unavailable or ungradable images.

"Only a small percentage of study participants with AMD had definite progression to either neovascular AMD or geographic atrophy within 1 year of cataract surgery when eyes were carefully monitored with immediate preoperative and postoperative fundus photographs and fluorescein angiograms," the study authors conclude. "Our findings do not support the hypothesis that cataract surgery accelerates the progression of AMD."

In an accompanying editorial, Barbara E. K. Klein, MD, MPH, from the University of Wisconsin in Madison, writes that several reports have shown an association between cataract surgery and AMD since the late 1980s.

"Some report a cross-sectional association, some, incidence of AMD after surgery, and yet others report progression to more severe AMD. Still, there are some studies that do not find a significant association after controlling for relevant confounders. What might explain the disparate results? In my estimation, the diversity of findings in no small part begins with differences in study design," Dr. Klein noted."

Discussing these inconsistencies will help patients and their physicians make a more informed decision about the risks for progression to early AMD and development of late AMD after cataract surgery, she writes. "Until we have better information regarding the risk of developing AMD in those undergoing cataract surgery, it is the best we can do for our patients."

For more information go to www.maculardegenerationassociation.org

Obese Britain Blind to Risk of Sight Loss

ANDOVER, England,

As the UK's obesity crisis burgeons, millions of overweight Brits are blind to the fact that their unhealthy lifestyles mean they are twice as likely to lose their sight as someone with a normal BMI (Body Mass Index).

A shocking new report launched by the sight charity Eyecare Trust and healthcare provider Simplyhealth to mark National Eye Week (9-15 November 2009) reveals that just eight per cent of us associate obesity with sight loss(1), despite weight being a major risk factor in the onset and progression of many sight-threatening eye conditions.

With more than half of all adults across the UK tipping the scales above their recommended weight and a staggering 23 per cent now classed as obese (2), millions of Brits are needlessly putting themselves at risk of poor vision or even worse - total sight loss.

Iain Anderson, Chairman of the Eyecare Trust warns: "Carrying excess weight causes pulmonary problems which can lead to irrevocable damage to the delicate blood vessels in the eye. A Body Mass Index of 30 or more doubles your risk of age-related macular degeneration - the UK's leading cause of blindness - and significantly increases your chances of developing cataracts or glaucoma."

The survey also found that people's perceptions about weight - and in particular obesity - are seriously wide of the mark. For example, four fifths of those polled (82 per cent) believed a man of 6ft weighing 13st 3lb is healthy, when in fact he is overweight.

Iain continues: "While people are more likely to be aware of threat to eye health from factors such as smoking, excessive alcohol consumption or poor diet, they just don't make the connection with obesity, which can also put people at risk of diabetic retinopathy whether or not they suffer from diabetes." The strong links between obesity and eye disease have been affirmed by recent international research undertaken by eminent ophthalmologists in Israel and Singapore(3).

Regular sight tests are vital for the early diagnosis and treatment of these eye conditions, yet the National Eye Week 'See the Benefit' poll found that obese people were the group least likely to visit their optician. Worryingly, the survey reveals that those with a BMI in excess of 25 are most likely to believe their eyes are in a state of 'good' or 'very good' health(4).

Raman Sankaran of Simplyhealth says: "As well as lifestyle choices having an impact on eye health, the research also worryingly found that cost - or the issue of perceived cost - affects whether people attend regular sight tests. In fact 75 per cent of people admit to putting off having their eyes tested due to the price of the examination and the expense of glasses or contact lenses if needed.

"Attending a sight test needn't be expensive or act as a barrier to good eye health as there are many options available to help people budget for eyecare, such as a cash plan from Simplyhealth," Raman adds.

The Eyecare Trust recommends that everyone should have an eye examination every two years, unless advised otherwise by an optometrist. As well as providing a valuable insight into the health of your eyes a sight test also acts as an essential general health check uncovering a number of other underlying health problems such as high cholesterol, high blood pressure, diabetes and an increased risk of stroke.

For more information go to www.maculardegenerationassociation.org

Blue light-filtering increases macular pigment, may protect against age-related vision loss

Age-related macular degeneration, a major cause of vision loss, affects millions of older persons

Results of an important new study show that implantation of blue light-filtering intraocular lens (IOLs) at the time of cataract surgery increases a nutritional component of the eye, which may afford protection against the development and/or progression of age-related macular degeneration (AMD).

The study, conducted by leading ophthalmology and vision researchers from the Macular Pigment Research Group at the Waterford Institute of Technology, is published in the October 2009 issue of the high impact journal Investigative Ophthalmology & Visual Science (IOVS).1

AMD is a disease affecting the central part of the retina and is the leading cause of vision loss in the developed world.2 Implantation of lenses that do not filter blue light during cataract surgery has been shown to increase the risk for development and/or progression of AMD.3

"Blue light-filtering lenses filter and block damaging blue light from reaching the retina, which holds the potential of reducing vision loss and improving the quality of life for millions of older patients," said the study's chief investigator, John M. Nolan, Fulbright Scholar, BSc, PhD, deputy director, Macular Pigment Research Group, Waterford Institute of Technology, Waterford, Ireland. "These data represent an important first step in fully realizing the benefits of blue light-filtering in improving a nutritional component of the eye known as macular pigment. There is a strong scientific rationale supported by an ever-growing body of scientific evidence which suggests that macular pigment plays a role in reducing the onset and progression of AMD."

Dr. Nolan and fellow Macular Pigment Research Group researchers discovered an increase in macular pigment levels shortly after cataract surgery among the study patients who had blue light-filtering IOLs implanted.1

"Since prolonged exposure to blue light is harmful to the retina, increased levels of macular pigment are considered a strong surrogate marker for protection against the processes that cause age-related blindness, including AMD," says Dr. Nolan.

According to the study, the potential benefits associated with increased macular pigment resulting from the use of blue light-filtering lenses for prevention and/or decreased progression of AMD would be conferred at the time of cataract surgery and are expected to continue thereafter, over a patient's lifetime.1 This is especially meaningful in the modern era of cataract surgery, which is being performed annually in millions of older persons who live for many years after the procedure, as well as certain patient subgroups, who have had the surgery at an earlier age.2 The researchers note that further studies are needed to confirm the clinical benefit of their findings.1

About the Study

Dr. Nolan and colleagues conducted a prospective study in which 42 patients scheduled for cataract surgery were randomized to implantation with a blue light-filtering acrylic IOL or a standard acrylic IOL (control), with macular pigment optical density measured by a reliable method (heterochromatic flicker photometry), and serum concentrations of the macular carotenoids were quantified by a scientific procedure known as high performance liquid chromatography, prior to surgery and then at several post-procedural time points over a 1-year follow-up period.1

Cataract surgery in older persons, where the natural diseased lens (cataract) is replaced with a clear artificial IOL, has been associated with increased subsequent risk for macular disease,4 perhaps due to increased transmission of potentially injurious short-wavelength (blue) light to the retina.3

Therefore, lens manufacturers have incorporated a blue light-filter into IOLs to help reduce photo-oxidative retinal injury and thereby reduce the risk of new-onset AMD and/or its progression. Evidence suggests that photo-oxidative stress is important in the development of AMD.5 The likelihood of retinal damage is highest for short-wavelength light (blue light). Several parts of the eye, most importantly the lens, act as filters to block short-wavelength light from reaching the retina.4

Macular pigment is thought to protect against AMD because it absorbs short-wavelength (blue) light before it reaches photoreceptors in the retina and because of its antioxidant properties (decreases oxidative stress by quenching free radicals). Portions of the eye behind (posterior to) macular pigment are exposed to approximately six times the amount of blue light in persons having the lowest levels of macular pigment, as compared to those with the highest levels.5 Macular pigment is obtained entirely from the diet and transported to the retina via the blood. Therefore, ongoing research is being conducted to determine to what extent a person's diet may affect AMD. However, the data available to date is in support of such a notion.5

About Cataracts and AMD

As the aging population grows and becomes a larger percentage of the overall population, age-related diseases such as cataracts and AMD will become more prevalent.6

Surgical removal of cataracts – lens that have become clouded from buildup of protein – is the most frequently performed surgery in the U.S.7, with more than 6 million cataract surgeries currently performed each year in the U.S. and Europe combined.7,8 While vision is almost universally improved immediately following cataract removal, implantation of lens that does not filter harmful short wavelength (blue) light may hasten the progression of AMD,5 the leading cause of vision loss in people over the age of 60 in the U.S.9

AMD is a disease that affects part of the back of the eye called the macula, the central part of the retina. The central vision of affected individuals becomes blurry or wavy and can be eventually lost, which severely alters their quality of life.9,10 Approximately 25-30 million individuals are affected worldwide, with the number estimated to triple in the next 25 years.11

For more information go to www.maculardegenerationassociation.org

NeoVista®, Inc. Completes Enrollment in Pivotal CABERNET™ Study

Neovascular AMD affects hundreds of thousands of patients globally. It is our hope that upon one-year follow-up, the data will support FDA approval in a most timely manner so that retinal surgeons, patients, and heath care systems in the US and around the world will have a cost effective option available for treating this dreadful disease in the immediate future.

NeoVista, Inc. today announced the completion of enrollment in its global 450-patient randomized controlled study of their revolutionary epimacular brachytherapy procedure for the treatment of neovascular age-related macular degeneration (AMD). The Company will now begin the mandated one-year data follow-up before submitting the final clinical module of its Pre-Market Approval (PMA) submission to the FDA.

"It's exciting to reach this long anticipated milestone in the CABERNET Study," said John N. Hendrick, President and CEO of NeoVista. "Neovascular AMD affects hundreds of thousands of patients globally. It is our hope that upon one-year follow-up, the data will support FDA approval in a most timely manner so that retinal surgeons, patients, and heath care systems in the US and around the world will have a cost effective option available for treating this dreadful disease in the immediate future."

The largest study of its kind to date, the multi-center CABERNET (CNV Secondary AMD Treated with BEta RadiatioN Epiretinal Therapy) Study assigned patients into one of two arms: a control arm where patients were administered regular Lucentis® (Genentech, South San Francisco, CA) injections and a one time surgical arm, where patients were administered a dose of strontium-90 beta radiation via a short surgical procedure, followed by concomitant injections of Lucentis when needed. The primary efficacy endpoint for the CABERNET Study is based on one-year follow-up of the surgical arm cohort when compared to the control group.

"The CABERNET Study has brought together multi-disciplinary clinical teams aligned around the mission of addressing the serious problem of neovascular AMD," said Pravin U Dugel, Managing Partner, Retinal Consultants of Arizona, Phoenix, Arizona and principal investigator for the CABERNET Study. "I look forward to the final results of this ambitious clinical trial. More than any other recent trial, this clinical trial has the potential of improving the quality of life and the overall treatment of patients with neovascular AMD. It could potentially have a significant impact on the practice patterns and economics of retinal physicians as well as global health care systems."

For more information go to www.maculardegenerationassociation.org

Signs Of Macular Degeneration May Predict Heart Disease

A large study found strong evidence that older people who have age-related macular degeneration (AMD) are at increased risk for coronary heart disease (CHD), although not for stroke. This result adds to mounting evidence that AMD and cardiovascular disease may share some risk factors--smoking, high blood pressure, inflammatory indicators such as C-reactive protein, genetic variants such as complement factor H--and disease mechanisms.

For more information go to www.maculardegenerationassociation.org

Patent-pending process improves eye disease detection

Memphis Business Journal - by Michael Sheffield

A collaboration between two professors at the University of Memphis and Southern College of Optometry could result in earlier detection of retinal diseases through a patent-pending testing process.

The Pseudo 2D Fractal Analysis was developed through a collaboration between Khan Iftekharuddin, associate professor in the Department of Electrical and Computer Engineering at the University of Memphis, and Pinakin Gunvant, assistant professor at Southern College of Optometry.

The process uses light beamed through the back of the retina to measure the thickness of retinal tissue at certain points. If the tissue is thick at the “12 and six o’clock” points, it is an indicator of glaucoma. The reflection of the light provides an indicator of the tissue’s thickness.

Gunvant says previous testing methods were accurate 85% of the time, but the 2D method has proven to be 98% accurate.

“That’s very clinically significant,” Gunvant says. “But you’re not inventing new devices. You’re just analyzing the data better.”

Gunvant and Iftekharuddin were doing separate research, with Gunvant focusing on retinal research at the Southern College and Iftekharuddin doing imaging work at the U of M. Gunvant said neither of the two had any idea the other existed until he looked Iftekharuddin up online. Ironically, the U of M professor was out of the country when Gunvant first contacted him.

“I found him through my good friend, Google, and he was right down the road,” Gunvant says. “If it wasn’t for technology, we might have never met.”

Iftekharuddin had used imaging to detect brain tumors through work with St. Jude Children’s Research Hospital, but hadn’t done any research with glaucoma. He says fractal imaging is able to pick up any irregularities in shapes or signals.

“We just took that and applied it to glaucoma and the results turned out to be excellent,” Iftekharuddin says. “Like any other disease, if you diagnose early you can treat it better.”

Once the two professors ensured the technique worked, the University of Memphis began the patent process, which can take up to three years. But it could also yield a viable product for the school to market and license, says Kevin Boggs, director of technology transfer and research development at the University of Memphis.

Boggs says the length of the patent process won’t prevent the two schools from marketing the product to companies that have a history of licensing patent applications.

“Once they’re familiar with the product, they’ll invest in it knowing the odds of getting a patent,” Boggs says. “There are a couple of options. We could either go with an exclusive or non-exclusive license, but we’d have to look at what would bring the product to the broadest possible market to help the most people.”

Gunvant says the technique could also detect other causes of blindness, like diabetes or macular degeneration. The immediate focus, however, is glaucoma, which is the second-leading cause of blindness in the world and the leading cause of blindness among African-Americans.

Gunvant says the new focus of the research will be trying to reach 100% accuracy.

“I doubt we’ll ever hit 100%, but most scientists get proven wrong in 15 years,” Gunvant says. “Glaucoma is very variable and affects different individuals in different ways. We’d have to do a very large scale study to get better than where we are at the moment.”

Gunvant says the technique probably would not have been perfected without the team effort.

“It’s hard to be an expert in every field, so multi-disciplined collaboration is required,” he says. “When you look at a problem from one angle, your brain gets fried, so you have to have someone else to come in and help you solve it.”

For more information go to www.maculardegenerationassociation.org

Retinal implant could help the blind see

By Emma Woollacott

MIT researchers are working on a retinal implant that could help blind people regain a useful level of vision.

It's designed for sufferers of retinitis pigmentosa and age-related macular degeneration, two of the leading causes of blindness. It won't restore normal vision, but could help blind people get around more easily.

Patients would wear a pair of glasses with a camera that sends images to a microchip attached to the eyeball. The glasses contain a coil that wirelessly transmits power to receiving coils surrounding the eyeball.

When the microchip receives visual information, it activates electrodes that stimulate nerve cells in the areas of the retina corresponding to the features of the visual scene. The electrodes directly activate optical nerves that carry signals to the brain, bypassing the damaged layers of retina.

In previous implants, the electrodes were attached directly to the retina from inside the eye, which carries more risk of damage. In the latest version, the implant is attached to the outside of the eye, and the electrodes are implanted behind the retina.

The team has been working on the implant for 20 years, and hopes to start testing it in blind patients within the next three years. The goal is to produce a chip that can be implanted for at least 10 years.

They've tried it out in Yucatan miniature pigs, which have roughly the same sized eyeballs as humans, purely to determine whether the implants remain functional and safe. So far, the prototypes have been successfully implanted in pigs for up to 10 months.

The researchers hope that once human trials begin and blind patients can offer feedback on what they're seeing, they will learn much more about how to configure the algorithm implemented by the chip to produce useful vision.

Patients have said that what they would like most is the ability to recognize faces. "If they can recognize faces of people in a room, that brings them into the social environment as opposed to sitting there waiting for someone to talk to them," says Shawn Kelly, a researcher in MIT's Research Laboratory for Electronics.

For more information go to www.maculardegenerationassociation.org

High-tech glasses help the nearly blind see

CBC News

An Ottawa company is developing computerized glasses that help people with severe visual impairments see — as well as zoom in on and replay what they saw with the press of a button.

The company, eSight Corp., received a $500,000 grant from the Ontario government this week to develop its evSpex product as part of a special $4.5 million fund to help 10 start-up companies bring products to market.

The device, which resembles a pair of large sunglasses, has a high-resolution camera on the outside and tiny LCD screens on the inside that project images to the wearer's eyes.

Before the image is projected, it's custom-processed by a tiny computer, said company president Rob Hilkes.

"So that when it's presented to a person who has diseased eyes … it's presented to the pieces of their vision that are most functional," he added.

Réjean Munger, a senior scientist at the Ottawa Hospital Research Institute who helped develop the glasses, said that can help people with a variety of diseases.

"We can take advantage of every bit of vision they have," he said.

The company hopes to start commercial production next year.

Sister of company chairman inspiration for glasses
Anne Lewis, who is legally blind as a result of Stargardt's disease, has been testing the prototype and is very excited about it.

"I see this product as a gift; I truly do," she said at the news conference announcing the funding.

Lewis is the sister of Conrad Lewis, eSight's chairman and one of the company's founders, and her disability was the inspiration for the glasses.

Stardgardt's disease is a form of macular degeneration that has destroyed Anne Lewis's sight except for her peripheral vision.

"It's like looking at a bubble and the inside of the bubble is black, the outside is clear," she said.

Lewis said using the glasses will allow her to read body language in meetings at work, stand on her deck and see flowers blooming, navigate shopping malls and flag down the right bus.

Unlike other products she has tried, it works even while she is moving.

The product is expected to be able to help people with age-related macular degeneration, diabetic retinopathy, glaucoma and retinitis pigmentosa.

Users can record, zoom
Because the device is essentially recording a loop of video at all times, it will include special functions that people with normal vision don't have. For example, the user can save the last 10 seconds of what they saw at the press of a button so they can have another look at something that went by too quickly. The video can also be viewed later on a DVD player or computer. In addition, they could zoom in on certain things in their field of view.

Hilkes said the features are available because the "inherent guts" of the device are a computer.

"Once you pack a lot of electronics into a system like this, then creative people start to think of all kinds of ways that you could use it," he said.

In the future, the company hopes to market the technology to people with normal vision as wearable binoculars, night vision goggles or video gaming devices.

For more information go to www.maculardegenerationassociation.org

Increase Your Omega-3s

Within the polyunsaturated fat category, there are two important subclasses of fatty acids: omega-3s and omega-6s. Vegetable oils are rich in omega-6 fatty acids, and most Americans unknowingly get plenty of them in the diet. On the other hand, omega-3 fatty acids, which are found in fish and shellfish, tofu, flax, nuts and canola and soybean oils, are generally lacking in our diets.

Omega-3s appear to have a positive effect on heart rhythm and according to one recent study, may even reduce the incidence of the most common type of stroke. In fact, on the basis of the current research, the U.S. Food and Drug Administration approved the use of a qualified health claim for dietary supplements of omega-3 fatty acids relating them to a reduced risk of heart disease.

Another intriguing area of research on omega-3 fatty acids pertains to their role in brain and visual function, as some research suggests they may have a role in preventing macular degeneration, a common form of blindness.

Continuing research involves the role of omega-3 fatty acids and the immune system, and suggests a positive influence on rheumatoid arthritis, asthma, lupus, kidney disease and cancer, as well as promising research at the National Institutes of Health on depression.

For more information go to: www.maculardegenerationassociation.org

Palladium-103 plaque radiation therapy for macular degeneration: results of a 7 year study

Aim: To report 7 year results of ophthalmic plaque radiotherapy for exudative macular degeneration.

Methods: In a phase I clinical trial, 30 patients (31 eyes) were treated with ophthalmic plaque irradiation for subfoveal exudative macular degeneration. Radiation was delivered to a mean 2 mm from the inner sclera (range 1.2–2.4) prescription point calculated along the central axis of the plaque. The mean prescription dose was 17.62 Gy (range 12.5–24) delivered over 34 hours (range 18–65). Early Treatment Diabetic Retinopathy Study (ETDRS) type standardised visual acuity determinations, ophthalmic examinations, and angiography were performed before and after treatment. Clinical evaluations were performed in a non-randomised and unmasked fashion.

Results: At 33.3 months (range 3–4), 17 of 31 (55%) eyes had lost 3 or more lines of vision on the ETDRS chart, five (16%) had improved 3 or more lines, and the remaining nine (29%) were within 2 lines of their pretreatment visual acuity measurement. Overall, 45% of patients were within or improved more than 2 lines of their initial visual acuity. Five eyes developed macular scars, eight developed subsequent neovascularisation or haemorrhage, and three progressed through therapy. Two patients were lost to follow up. The most common finding of patients followed for 6 or more months (n = 18 of 29 (62%)) was regression or stabilisation of the exudative process. No radiation retinopathy, optic neuropathy, or cataracts could be attributed to irradiation.

Conclusion: Ophthalmic plaque radiation can be used to treat exudative macular degeneration. At the dose and dose rates employed, most patients experienced decreased exudation or stabilisation of their maculas. No sight limiting radiation complications were noted during 7 year follow up. Owing to the variable natural course of this disease, a prospective randomised clinical trial should be performed to evaluate the efficacy of plaque radiation therapy for exudative macular degeneration.

Researchers Grow Eye Cells From Skin Cells

Researchers have succeeded in growing light-sensing eye cells from human skin cells, opening the possibility of restoring sight to patients blinded by certain diseases.

Researchers at the University of Wisconsin have grown retinal cells from skin cells, a development that could be used to treat degenerative eye diseases.

A number of genetic disorders involve the degeneration of the retina, the light-sensitive cells at the back of the eye. The disorders cause the cells to die, and vision is gradually lost, resulting in blindness.

The researchers manipulated human skin cells to act like embryonic stem cells, which can be coaxed to grow into any tissue in the body. The development suggests that doctors may someday be able to repair damage to the retina with new cells generated from the patient's own skin.

Lead researcher David Gamm, a professor of ophthalmology and visual sciences at the University of Wisconsin, says his research could benefit people with macular degeneration and retinitis pigmentosa. In both diseases, the visual field gradually narrows, eventually leading to blindness.

"In particular these diseases are quite devastating to the patients who are affected by them," he said. "They rob them of their vision either when they are younger in the case of retinitis pigmentosa or when they are older in the case when they are older in the case of macular degeneration. And there are no cures and very few if any treatments for them. So it is a big need, especially from the macular degeneration standpoint, as the population ages."

An estimated one million people worldwide are affected by macular degeneration alone.

Gamm says the laboratory process of creating human retinal cells helps researchers better understand how eyes develop, so diseases that lead to vision loss may someday be treated or even cured with retinal stem cells.

The development could also further research on genetic eye conditions. For example, using skin cells from a patient with retinitis pigmintosa researchers could create retinal cells with the defective gene and subject them to various potential drugs for treating or curing the condition.

Gamm says the same technique could help scientists find treatments for other genetic diseases, not just eye disorders.

"Now we could take theoretically any human disease, especially those that have specific gene defects underlying them, and produce cell types of interest in those diseases and test them directly for the efficacy of various drugs or how in fact those cells die in disease," he added.

The study on the development of eye cells is published this week in the journal Proceedings of the National Academy of Sciences.

By Jessica Berman
Washington

An Overview of Macular Degeneration Research

Doctors and scientists are currently conducting macular degeneration research. Macular degeneration research studies are designed to answer important questions and to find out whether new approaches are safe and effective. This research already has led to many advances, and researchers continue to search for more effective methods for dealing with macular degeneration.

Current Areas of Focus in Macular Degeneration Research
A number of macular degeneration research studies are being conducted to learn what causes macular degeneration and how it can be better treated.

One macular degeneration research study is also evaluating the effects of certain vitamins and minerals in preventing or slowing the progress of the disease.

At the same time, scientists studying macular degeneration are trying to learn more about how the cells in the retina work. This knowledge will allow them one day to pinpoint the causes of macular degeneration and come up with ways to prevent it.

Other areas of current research include:


* Studying the possibility of transplanting healthy cells into a diseased retina
* Evaluating families with a history of macular degeneration to understand genetic and hereditary factors that may cause the disease
* Looking at certain anti-inflammatory treatments for the wet form of macular degeneration.


This macular degeneration research should provide better ways to detect, treat, and prevent vision loss in people with the disease.

for more information www.maculardegenerationassociation.org

Novel Biomarker for Age-Related Macular Degeneration

A team of researchers at the University of Kentucky has discovered a biological marker for neovascular age-related macular degeneration (AMD), the leading cause of blindness in older adults. The scientists say the biomarker shows strong potential as a means for both the early detection of the disease and for preventive treatment.

The Aging Eye: Researchers Aim To Stop the Clock

By JANE E. BRODY

AGING Americans expect more from their eyes these days than ever before. People in their 70's and 80's want to be able to drive, play cards, recognize people on the street, travel with their grandchildren, take advantage of senior discounts in the movies and read the books they missed while working full time.

But eyes have a way of aging that can render such expectations unrealistic. Far worse than the loss of visual acuity that prompts most middle-aged people to resort to magnifying lenses are sight-robbing diseases like glaucoma, cataracts, age-related macular degeneration, diabetic retinopathy and other retinal disorders that afflict tens of millions of Americans, usually after age 50.

The incidence of such potentially blinding disorders is increasing rapidly as the number of older people grows. Experts predict, for example, that by the year 2030, 6.3 million older Americans will develop macular degeneration, up from 1.7 million in 1995. It is a still-irreversible disorder that robs people of the central vision needed to drive, read, watch television, recognize faces, play cards or do any fine work. If Grandma Moses had had macular degeneration, her artistic talents would never have been noticed.

Fortunately, research is progressing on a number of promising new treatments, including low doses of radiation, and a combination of lasers and light-activated chemicals, both of which are used for some particularly hard-to-treat forms of macular degeneration. Other research is concentrating on how to stop toxins that damage the eye in glaucoma, and the genetics of several different eye diseases.

''Older Americans today expect to enjoy their retirement with the same visual capacity that they had in their younger years,'' said Dr. Harold Spalter, professor of ophthalmology at Columbia-Presbyterian Medical Center in New York. But, alas, as was apparent at a four-day seminar that Dr. Spalter chaired here last month, researchers are still a long way from knowing how to reverse most blinding eye disorders.

Still, major progress in understanding and treating these conditions -- and perhaps detecting them early enough to blunt their effects -- was evident at the seminar, organized by Research to Prevent Blindness, a New York-based voluntary organization. Unfortunately, though, many elderly Americans cannot afford the early detection procedures described at the seminar because Medicare and many other insurance programs do not cover such preventive measures.

For example, while insurance companies would routinely cover a visual field examination for a patient who already has glaucoma, most would not pay for this test for a person who has not yet experienced vision loss, when the disease process might be stopped without lasting vision damage.

Furthermore, an ongoing study of 2,520 men and women aged 65 to 84 in Salisbury, Md., has revealed that the usual eye chart test for visual acuity is inadequate to assess vision losses that interfere with the ability of elderly people to get around on their own, perform tasks of daily living and avoid accidents that can result in serious or fatal injuries. Rather, Dr. Sheila West, professor of ophthalmology at Johns Hopkins Medical Institutions, reported that tests for contrast sensitivity -- the ability to distinguish, say, a step from the one below it -- are more revealing of functional disability in older people.

''We have found that loss of contrast sensitivity is as important as arthritis and heart failure in determining loss of mobility in the aged,'' Dr. West said. She traced this loss to ''nonspecific retinal changes'' and the beginnings of cataracts, a gradual clouding of the lens of the eye that eventually obscures vision. However, early-stage cataracts are rarely recognized by those who have them and are often dismissed as inconsequential by eye doctors.

Sunlight, Dr. West said, is a major factor in the formation of cataracts, and the damage is cumulative. By assessing the exposure of study participants to sunlight, Dr. West and colleagues determined that for every 1 percent increase in exposure to ultraviolet-B light, the risk of developing cataracts rose by 10 percent.

''There is no threshold for sun-related damage, the dosage is cumulative and no group is immune to it,'' Dr. West said the study showed. She recommended that when out of doors, everyone -- starting in childhood -- should wear lenses that block ultraviolet light and a cap with a brim that shades the eyes.

Dr. M. Cristina Leske, head of preventive medicine at University Medical Center in Stony Brook, N.Y., and associates, identified other risk factors for cataracts. Through a five-year study of 764 patients, they found that Caucasians are three times as likely as blacks to develop cataracts. Those who take the gout medicine allopurinol face more than a two-fold increase in risk, and smokers have a 60 percent increase.

On the other hand, certain nutrients appear protective. The risk was 30 percent lower among those who took multivitamin-mineral supplements and nearly 60 percent lower among those who took a vitamin E supplement, a finding that is now being tested in a clinical trial sponsored by the National Eye Institute. Still another study of 247 women aged 56 to 71 conducted at Tufts University in Boston found that taking vitamin C supplements for more than 10 years reduced the risk of early cataracts by 77 percent and the risk of moderately advanced cataracts by 83 percent.

But while cataracts can usually be treated very successfully by surgically removing the damaged lens and replacing it with a synthetic lens implant, age-related macular degeneration, the leading cause of legal blindness in the elderly, has yet to yield to an effective treatment. Macular degeneration involves progressive damage to the cells in the center of the retina that are responsible for straight-ahead vision.

Early cases are often treated with lasers, which have the unfortunate side effect of destroying normal retinal cells as well as the damaged areas beneath them. Furthermore, after laser treatment, the vision-damaging tissue often grows back.

Dr. Dennis M. Marcus, an ophthalmologist at the Medical College of Georgia in Augusta, said that laser therapy usually cannot be used for the most severe form of the disease -- so-called wet macular degeneration, which involves the growth of leaky blood vessels beneath the central retina. Instead, he and his colleagues are testing low-dose radiation to destroy the blood vessels but spare the normal retinal cells. Thus far, 100 patients have been treated in a clinical trial that will eventually involve 500 people with wet macular degeneration. While it is too soon to evaluate the effectiveness of the treatment, Dr. Marcus said that he has seen no radiation-induced complications.

Another clinical study is testing a technique called photodynamic therapy. It starts with the intravenous administration of a photosensitive dye that collects in the damaging blood vessels that are growing beneath the retina. The eye is then exposed to laser light that activates the dye, destroying those vessels only. Dr. Joan W. Miller, an ophthalmologist at the Massachusetts Eye and Ear Infirmary, said that preliminary studies showed that the technique effectively closes off the leaky vessels in the majority of patients. And while these vessels reopen and leak in some patients, the treatment can be repeated, if needed, without harm to the eye.

Some seminar participants said the best hope for conquering blinding eye diseases was unraveling the sometimes complex genetics underlying many if not all of these conditions. Just last month, for example, a team of scientists announced the discovery of the first genetic link to age-related macular degeneration, which strikes 25 percent of Americans over the age of 65 and is the major cause of vision loss in the elderly. The researchers hope that by studying mutations in this gene they will gain an understanding of how the disease damages the eye, a means of identifying those at risk and methods of prevention and treatment.

Glaucoma, for example, usually involves elevated pressure inside the eye, leading eventually to the death of ganglion cells, the nerve cells that transmit information from the eye to the brain. This disease afflicts perhaps eight million Americans and causes blindness in 5,500 each year. Currently the only available treatment involves continual use of eye drops that reduce intraocular pressure. This only works if treatment is begun early.

Dr. Robert W. Nickells, an eye researcher at the University of Wisconsin in Madison, said, however, that ''new advances suggest that glaucoma could be treated during the second or even the third stage of the disease.'' The second stage involves the release of high concentrations of ''excitotoxins,'' amino acids that are toxic to nerve cells. Dr. Nickells said that several compounds that intervene in the formation of excitotoxins have been developed to treat other neurodegenerative disorders and may also prove useful in treating glaucoma.

As for the third stage, he and his colleagues have found in monkeys and rodents that ganglion cells succumb to a form of programmed cell death that appears to be controlled by three genes that act as a molecular switch. One of the genes, called bcl-x, prevents the fatal blow and might be harnessed therapeutically to override the cell death mechanism, Dr. Nickells said.

But discoveries about the genetics of eye disorders can sometimes raise more questions than they answer. For example, Dr. Fulton Wong of Duke University Medical Center reported that as many as 50 genes are believed to be involved in the progressive disease retinitis pigmentosa, which begins as night blindness and loss of peripheral vision and eventually destroys central vision, leaving people blind. Thus far, four genes have been identified, each with multiple mutations that may result in different aberrations of the condition. One of the genes that codes for the production of the visual pigment rhodopsin can exist in 92 different mutated forms, Dr. Wong reported.

This year alone, three genes for various forms of glaucoma have been identified. But Dr. Janey Wiggs, an ophthalmologist and geneticist at Tufts University School of Medicine in Boston, said: ''This is a very complicated disease, with maybe 20 or 30 genes involved. And finding genes is only the first step. Where and when is the gene required and how does it produce disease? Does it result in too much or not enough of a gene product or make a toxic product?''

Still, she and others expressed guarded enthusiasm for the prospects of gene therapy to treat various devastating eye diseases. ''The eye is accessible,'' she said. ''It can be given selective treatment, using the other untreated eye as a control to see how well the treatment is working.''

Dr. J. Timothy Stout, head of the division of ophthalmology at Children's Hospital in Los Angeles, said, ''The potential use of gene therapy is nearly limitless for the ophthalmologist.'' He and his colleagues are exploring in animals the potential of a so-called suicide gene to treat eye diseases that involve excessive cell division, such as intraocular proliferative disease, macular degeneration and diabetic retinopathy. Normally, most cells in an adult eye are not dividing. Using as a gene carrier a virus that infects only actively dividing cells, he introduces into the eye a gene that by itself is not toxic but that results in cell death when combined with the drug ganciclovir, which also does not harm normal cells. Thus, the treatment is specific for the proliferating cells involved in the eye disease.

New uses for existing drugs

REPRINTED FROM THE NEW YORK TIMES

Housed in a row of white freezers in a nondescript laboratory at the Johns Hopkins University School of Medicine in Baltimore are more than 3,000 of the estimated 10,000 drugs known to medicine. There is no sign on the door to indicate that this is perhaps the largest public drug library available to researchers interested in finding new uses for old and often forgotten drugs.

Already, researchers have used the library to discover that itraconazole, a drug used for decades to treat toenail fungus, may also inhibit the growth of some kinds of tumors and may forestall macular degeneration. Another drug, clofazimine, used more than a century ago to treat leprosy, may be effective against autoimmune disorders like multiple sclerosis and psoriasis.

“It takes 15 years and costs close to a billion dollars to develop a new drug,” said Jun O. Liu, professor of pharmacology and director of the Johns Hopkins Drug Library. “Why not start with compounds that already have proven safety and efficacy?”

He and his colleagues have been building the collection since 2002 and hope to have it complete by 2011. They acquire the drugs through donations, purchases and sometimes lab synthesis. And they will send researchers a complete set — minuscule amounts of every drug in the library — for $5,000, which covers the cost of shipping and replenishment.

Since the toenail and leprosy drugs are approved for use in the United States and are no longer under patent protection, clinical trials to test their new uses are either under way or close to regulatory approval, Dr. Liu said.

Drugs still under patent protection are more complicated; patent holders seldom allow independent research on alternative uses. “The drug companies haven’t been too keen on helping us,” Dr. Liu said.

There are other drug libraries, both commercial and noncommercial. Commercial suppliers offer considerably fewer drugs than Johns Hopkins (though they may have medicines it does not), and they charge much more. Noncommercial drug libraries include those at the National Institutes of Health; the University of California, San Francisco; and McMaster University in Hamilton, Ontario. But they will usually not send drugs to unaffiliated researchers. And like the commercial libraries, their holdings are smaller and composed largely of compounds from Hopkins.

Regardless of the source, researchers typically order copies of entire collections rather than individual drugs they think may work in their experiments.

“We’ve found drugs that are active in ways no one would have ever hypothesized,” said Marc G. Caron, a professor of cell biology at Duke who is using the Johns Hopkins library to find drugs that might quell the cravings of substance abusers.

Testing of these compounds has become much easier in recent years as a result of an automated technology called H.T.S., for high-throughput screening. The drugs are dissolved in a solution and stored in rectangular, compartmented plates reminiscent of ice trays; they can then be delivered to researchers for testing of their efficacy against various diseases, or disease mechanisms like inflammation.

Computerized droppers, plate agitators and microscope image readers can now accomplish in days what it once took bench scientists years to do.

Although H.T.S. has been around for at least a decade, it is just within the last five years that the technology has been widely available. Previously, only big pharmaceutical companies could afford to screen thousands of compounds; now more public and academic institutions are doing so, and their emphasis tends to be on rediscovering or tweaking the chemical structure of old drugs rather than developing new ones.

“The instrumentation to do sophisticated, large-scale screening of drugs has gotten significantly better and cheaper,” said Michelle Arkin, associate director of the Small Molecule Discovery Center at U.C. San Francisco.

Some institutions, like McMaster in Ontario and Rockefeller University in New York City, allow outside researchers to use their H.T.S. facilities for $10,000 to $20,000, depending on the complexity of the project.

Access to such facilities has increased demand for compounds, particularly already approved and off-patent drugs, to analyze. Johns Hopkins and commercial suppliers report a surge in orders over the last two years — because there are more H.T.S. laboratories, they said, and because of efforts to find cheaper therapies against third world scourges like malaria and tuberculosis.

“Old drugs are the low hanging fruit in terms of finding safe and inexpensive treatments for these diseases,” said Carl Nathan, chairman of microbiology at Weill Cornell Medical College in New York. Dr. Nathan receives plates of drugs from Johns Hopkins as well as commercial suppliers and does high-throughput screening at Rockefeller, which has a partnership with Weill.

“I’m addicted to it,” he said.

Researchers aim for rare treatment of macular degeneration

Friday, May 1, 2009
Researchers aim for rare treatment of macular degeneration
By Marc Songini

One of the most prevalent eye diseases is age-related macular degeneration, affecting millions in the United States, and there are few if any cures, or even approved treatments, say experts. That makes the work of a group of local researchers developing an implanted treatment particularly vital.

The AMD ailment takes two forms: One is “wet” and involves blood vessels and has limited treatments, including Lucentis, a drug from San Francisco-based Genentech Inc. (now part of Swiss firm Roche). The other is “dry” and occurs when light-sensitive cells malfunction. An estimated 15 million Americans have AMD.

For the 10 percent to 20 percent of AMD patients that have the wet form, the treatments are “reasonably effective,” said Paul Ashton, president and CEO of Watertown-based pSivida Corp., which develops eye treatments. “We have nothing for the 80 percent to 90 percent who have the dry form.” In part, this is because big pharma didn’t realize the huge market for eye treatments until about a decade ago, he said. Additionally, “Getting drugs into the eye without getting very high levels of drug everywhere else is very hard,” noted Ashton.

For dry AMD, in particular, there’s “a huge unmet need and a huge market,” said Emmett Cunningham, a partner with Cambridge-based Clarus Ventures LLC, a life sciences investment company. In part, said Cunningham, a doctor and eye expert based in Clarus’ South San Francisco office, this is because dry AMD is “complex,” and there is no one easily discerned cause. Also, there are no reliable animal models for testing.

“You’d have to take a big bet to get human proof of concept data,” he said. A venture capital firm would be prone to waiting till a dry AMD startup was in the Phase 2 or Phase 3 stage before investing the $20 million to move toward full approval.

However, one research team based at Boston College and the University of Massachusetts Medical School in Worcester is trying to solve the problems of AMD and other eye diseases by creating nano-structured retinal implants. These are tiny devices placed in the eye to take the place of the malfunctioning rods and cones in the retina, explained Michael Naughton, a professor of physics at BC, whose team is working on the nanotechnology of the implant.

“The implant is designed to reconnect to the surviving cell circuitry and provide the electronic stimulus formerly provided by the rods and cones,” said Naughton. Ideally, these implants could have a form factor similar to contact lenses. They would be widely available, although requiring retinal surgery. “Until such a time as genetic engineering can cure or regenerate rods and cones, these artificial retinas could provide a viable path to restoring vision.” Potentially, the market is worth hundreds of millions of dollars annually, he estimated.

Currently, he estimates that he needs $42 million to pay for the prototype and the animal and human studies over the next 18 months. He said there are no implants on the market for consumer use at this time, though a number are in development.

Cunningham noted that for an investor, implants are an interesting area, but the key is getting compelling data that the technical risks associated with the device have been met, because it requires surgical implantation. Also, a startup must demonstrate the size of the market is big enough related to the cost of the device, he said.

Other firms working to treat AMD and other eye ailments include Lincoln, R.I.-based Neurotech Pharmaceuticals Inc., whose lead candidate NT-501 is an intraocular implant made of genetically modified human cells. In March, it released Phase 2 exploratory study data that indicated positive results in AMD treatment, with no “serious adverse events,” said Ted Danse, president and CEO of Neurotech.

Also, pSivida’s drug Iluvien is in Phase 2 trials for both forms of AMD, said Ashton. And New Haven, Conn.-based Optherion Inc. is developing a diagnostic service and drug platform for AMD. By year’s end, Optherion plans to file an independent new drug application (IND) submission to the U.S. Food and Drug Administration for its drug, said Colin Foster, CEO and president.

For the past several years, Bedford-based Resolvyx Pharmaceuticals Inc. has been evaluating its Resolvin inflammation control drug’s effectiveness against AMD, as well.

Functional annotation of the human retinal pigment epithelium transcriptome

Functional annotation of the human retinal pigment epithelium transcriptome


To determine level, variability and functional annotation of gene expression of the human retinal pigment epithelium (RPE), the key tissue involved in retinal diseases like age-related macular degeneration and retinitis pigmentosa. Macular RPE cells from six selected healthy human donor eyes (aged 63-78 years) were laser dissected and used for 22K microarray studies (Agilent technologies).

Data were analyzed with Rosetta Resolver, the web tool DAVID and Ingenuity software.

Results: In total, we identified 19,746 array entries with significant expression in the RPE. Gene expression was analyzed according to expression levels, interindividual variability and functionality.

A group of highly (n=2,194) expressed RPE genes showed an overrepresentation of genes of the oxidative phosphorylation, ATP synthesis and ribosome pathways. In the group of moderately expressed genes (n=8,776) genes of the phosphatidylinositol signaling system and aminosugars metabolism were overrepresented.

As expected, the top 10 percent (n=2,194) of genes with the highest interindividual differences in expression showed functional overrepresentation of the complement cascade, essential in inflammation in age-related macular degeneration, and other signaling pathways. Surprisingly, this same category also includes the genes involved in Bruch's membrane (BM) composition.

Among the top 10 percent of genes with low interindividual differences, there was an overrepresentation of genes involved in local glycosaminoglycan turnover.

Conclusions: Our study expands current knowledge of the RPE transcriptome by assigning new genes, and adding data about expression level and interindividual variation.

Functional annotation suggests that the RPE has high levels of protein synthesis, strong energy demands, and is exposed to high levels of oxidative stress and a variable degree of inflammation. Our data sheds new light on the molecular composition of BM, adjacent to the RPE, and is useful for candidate retinal disease gene identification or gene dose-dependent therapeutic studies.

Author: Judith C Booij, Simone van Soest, Sigrid MA Swagemakers, Anke HW Essing, Annemieke JMH Verkerk, Peter J van der Spek, Theo GMF Gorgels and Arthur AB Bergen
Credits/Source: BMC Genomics 2009, 10:164

National study is looking for Dry Macular Degeneration (AMD)patients for Landfall Eye Associates clinical trial

National study is looking for Dry Macular Degeneration (AMD)patients for Landfall Eye Associates clinical trial

April 16th, 2009

AMD patients who are interested to volunteer the Landfall Eye Associates study, will be reimbursed to cover study related transportation costs. Approximately four visits will be required of all participants.

It's a clinical study to determine if repetitive stimulation of the preferred retinal locus, the area near the central blind spot used to focus on words, letter, and object, will help in their ability to read.

The patients will be divided into two groups. One group of patients will use a medical device that looks like a computer screen and will display bright objects to stimulate the preferred retinal locus.

Participants must be able to perform the therapy twice daily for about 40 to 50 minutes each day, six times per week. The therapy will be performed in the participant’s home for approximately three months.

The other group is the control group, will not use the medical device or perform therapy. Participants will be randomly assigned to a group.

If the trial study shows the treatment with the medical device is effective, the participants who did not perform the therapy will be offered the opportunity to do so at a later date at no charge.

Source: WebWire

Landfall Eye Associates is participating in this multicenter national study sponsored by NovaVison, Inc., headquartered in Boca Raton, Fla.

Othera reports positive interim results from Phase II dry AMD trial

Othera reports positive interim results from Phase II dry AMD trial

Published:13-April-2009

By Datamonitor staff writer

137 patients enrolled at 20 leading retinal disease treatment centers across the US

Othera Pharmaceuticals, a specialty pharmaceutical company, has reported positive interim data from its Phase II trial of OT-551 in treating geographic atrophy, an advanced form of dry age-related macular degeneration for which there is no FDA-approved treatment.

According to Othera, the 12-month findings from the two-year Omega trial suggest an emerging trend for reducing moderate vision loss in patients with geographic atrophy (GA) who were treated with OT-551 compared with placebo. This numeric trend was more pronounced in subgroups based on GA characteristics or level of visual acuity at baseline.

The Omega study is a randomized, double-masked, dose-ranging, multi-center, Phase II study of topical OT-551 in patients with GA associated with age-related macular degeneration (AMD). Approximately 137 patients were enrolled at 20 leading retinal disease treatment centers across the US in this two-year study.

OT-551 has demonstrated a dose-dependent protective effect on photoreceptor activity in an animal model of AMD, and has been shown to reach the back of the eye after topical dosing in multiple species. This profile supports the rationale for studying the drug in patients with degenerative retinal conditions, such as GA, the company said.

Al Reaves, senior vice president of clinical development at Othera, said: "Based on these preliminary results, OT-551 continues to exhibit the excellent safety profile seen in prior studies. Given OT-551's safety profile and the positive trend on visual acuity, continued follow-up of this elderly population with GA should allow us to profile the drug's effect on visual acuity and better understand its long term safety."

*

Feds Give Life to New Research
UCSB To Take Advantage of New Stem Cell Policy

By Sara-Fay Katz / Staff Writer

Published Wednesday, April 8, 2009

Issue 100 / Volume 89

After eight years in the cold, stem cell research is poised to benefit from the open support of the Obama administration.

Under the Bush presidency, federal funding was distributed only to researchers experimenting on 21 existing stem cell lines, thus limiting developments in the field. When President Barack Obama lifted the ban on March 9, he made federal funding available for the study of new embryonic stem lines, and UCSB researchers stand to gain from his decision.

Dennis Clegg, chair of the Dept. of Molecular, Cellular and Developmental Biology, said the Bush-era ban had significantly hindered the progress of biological research for almost a decade.

“Back in 2001, President Bush said you could only use federal funding when using existing [stem cell] lines,” Clegg said. “So, it really slowed down the progress of stem cell research in the country. Now with the lifting of the ban, it will lessen the red tape associated with this kind of study and provide new funding for stem cell research.”

Clegg said new research into regenerative medicines such as stem cells has the potential to render many fatal diseases harmless, or at least make them readily treatable.

“We are in a very exciting time for stem cell research right now,” Clegg said. “Stem cell research has great potential for treating a variety of human diseases like macular degeneration, diabetes, Parkinson’s and Alzheimer’s.”

A co-director of strategy, planning and operations at the UCSB Center for Stem Cell Biology and Engineering, Clegg said UCSB has the power to make major advancements in the growing field.

“We have quite a bit of exciting work going on in basic molecular biology and bioengineering, and we’re partnering with other universities and institutions to bring our findings to clinical applications,” Clegg said. “I think UCSB has unique strengths that will allow us to make a significant contribution in the field of stem cell research.”

Lincoln Johnson, associate director of the Center for the Study of Macular Degeneration, said the removal of the ban now ensures more options for the treatment of human diseases using natural mechanisms.

“Not all embryonic stem cell lines are the same,” Johnson said. “So for instance, with cardiac muscle for the treatment heart disease, one stem cell line might be better than another, so it’s important to have a variety. For regenerative medicine such as constructing organs, having a wider variety of stem cells to choose from will help better match the donor organ to the recipient.”

Despite the avenues of stem cell research opened by the Obama administration, Johnson said the field is still in its infancy.

“There’s a lot of research to be done, but having more cell lines and more funding will speed up the process,” Johnson said. “The better the research and the more people involved, the greater influence UCSB might have on policy formation.”

In addition to getting the go-ahead for more stem cell research, professor of chemical engineering Frank Doyle said UCSB has plans to open a new bioengineering building that will be suited for new developments in national research.

“We are in the planning stages of trying to set up a bioengineering building and we’re probably about four years away from realizing this dream,” Doyle said. “It would be a home to a rich range of engineers, chemists, biologists and physicists. I think what were hoping this building will be home to a big thrust of research on the campus, particularly an interface between medicine and engineering.”

For those interested in learning more about stem cell research, UCSB offers a class this quarter in Life Sciences Building 1001 - MCDB 146: Stem Cell Biology in Health and Disease taught by Professor Clegg. Students can also consult the UCSB Center for Stem Cell Biology and Engineering’s Web site, www.stemcell.ucsb.edu.

Brain Adapts to Age-Related Eye Disease

Brain Adapts to Age-Related Eye Disease
Neurons seek input from undamaged areas to compensate, study finds

(HealthDay News) -- When macular degeneration causes one to start losing his or her sight, the affected neurons simply start seeking visual input from other, non-affected parts of the eye, Massachusetts Institute of Technology researchers report.

"This study shows us one way that the brain changes when its inputs change. Neurons seem to want to receive input: When their usual input disappears, they start responding to the next best thing," senior author Nancy Kanwisher, of MIT's McGovern Institute for Brain Research, said in an university news release.

The researchers found when the cells in the fovea, the part of the retina responsible for the central field of vision, were damaged by macular degeneration (MD) -- the neuron attached to them begin responding to stimuli in an undamaged section -- a type of internal reorganization of the eye's visual map as opposed to the cortex's work being shifting to other neurons.

"Our study shows that the changes we see in neural response in people with MD are probably driven by the lack of input to a population of neurons, not by a change in visual information-processing strategy," Kanwisher said.

The findings are published in the March 4 issue of the Journal of Neuroscience.

Macular degeneration, the most common form of adult blindness, affects almost 2 million people in the United States. Patients often compensate for lack of central vision by rolling their eyes upward so they can utilize the preferred retinal locus (PRL), an undamaged area under and adjacent to the affected part of the retina.

"Macular degeneration is a great opportunity to learn more about plasticity in the adult cortex," Kanwisher said.

MD Linked with Range of Illnesses

TUESDAY, Mar. 10 (HealthDay News) -- Elderly patients with age-related macular degeneration are more likely than their counterparts without the eye disease to experience a wide range of illnesses, including depression, hip fracture and blindness, according to a report published in the March issue of the Archives of Ophthalmology.

Ashley Wysong, of Duke University School of Medicine in Durham N.C., and colleagues studied Medicare claims data on 32,702 adults aged 68 years and older who were newly diagnosed with age-related macular degeneration in 1994 and 32,702 matched controls, who were all followed up in 2004 to ascertain the prevalence of a range of health conditions.

Rates of blindness, vision loss, depression, hip fracture and nursing home residence were higher among the patients with age-related macular degeneration versus those without, and they had a higher prevalence of 11 other general health conditions such as congestive heart failure, dementia and liver disease, the investigators found.

"This nationally longitudinal study documents increased rates of visual and functional health complications that occurred within 10 years of an age-related macular degeneration diagnosis," the authors write. "These findings demonstrate that the health issues of the age-related macular degeneration population are multifaceted, especially when viewed in a 10-year period, highlighting the importance of a multidisciplinary, integrated approach to the care of elderly persons with an age-related macular degeneration diagnosis."

New Technique May Spot Evidence of Macular Degeneration Years Earlier

New Technique May Spot Evidence of Macular Degeneration Years Earlier

February 26, 2009

Adapted from Rochester University

A layer of "dark cells" in the retina that is responsible for maintaining the health of the light-sensing cells in our eyes has been imaged in a living retina for the first time.

The ability to see this nearly invisible layer could help doctors identify the onset of many diseases of the eye long before a patient notices symptoms. The findings are reported in the February, 2009 issue of Investigative Ophthalmology and Visual Science.

"Our goal is to figure out why macular degeneration, one of the most prevalent eye diseases, actually happens," says David Williams, director of the Center for Visual Science and professor in the Institute of Optics at the University of Rochester. "Macular degeneration affects one in 10 people over the age of 65, and as the average age of the U.S. population continues to increase, it is only going to get more and more common. We know these dark retinal cells are compromised by macular degeneration, and now that we can image them in the living eye, we might be able to detect the disease at a much earlier stage."

In 1997, Williams' team was the first to image individual photoreceptor cells in the living eye, using a technique called adaptive optics, which was borrowed from astronomers trying to get clearer images of stars. To image the dark cells behind the photoreceptors, however, Williams employed adaptive optics with a new method to make the dark cells glow brightly enough to be detected.

The cells, called retinal pigment epithelial, or RPE cells, are nearly black, and form a layer that recharges the photoreceptor cells of the eye after they are exposed to light, Williams explains. The photoreceptors contain molecules called photopigments. When light strikes these molecules, they absorb the light and change shape, sending a signal to the brain indicating they've "seen" light.

Once a photopigment molecule absorbs light, says Williams, it needs to get recharged, so it is shuttled out of the photoreceptor and down to the RPE cells. The RPE cells recharge the photopigment molecules and send them back to the photoreceptors to start the process again. In addition, the RPE layer keeps the photoreceptors healthy by collecting and storing toxic waste products that are produced during the process of regenerating the photopigment. In macular degeneration, for reasons that are not yet completely clear, the RPE cells are unable to provide this support for the photoreceptors and both kinds of cells eventually die.

Given their critical role supporting the photoreceptors, Williams says that scientists will benefit from being able to image RPE cells in patients to see what is malfunctioning in individual cells.

Williams and his team now hope to learn exactly how RPE cells are related to macular degeneration. At the moment, scientists aren't sure how the disease starts, but being able to monitor the health of individual RPE cells may help doctors begin to piece together a picture of what mechanisms are malfunctioning in the retina. Williams also says that since the technique may eventually be able to spot illness in the RPE long before the patient experiences symptoms, doctors could start patients on therapies early enough to possibly slow or stop the onset of macular degeneration. Currently, when a patient begins treatment, a great deal of irreparable damage has been done.

What Drives Brain Changes in Macular Degeneration

ScienceDaily (Mar. 13, 2009) — In macular degeneration, the most common form of adult blindness, patients progressively lose vision in the center of their visual field, thereby depriving the corresponding part of the visual cortex of input. Previously, researchers discovered that the deprived neurons begin responding to visual input from another spot on the retina — evidence of plasticity in the adult cortex.

Just how such plasticity occurred was unknown, but a new MIT study sheds light on the underlying neural mechanism.
"This study shows us one way that the brain changes when its inputs change. Neurons seem to 'want' to receive input: when their usual input disappears, they start responding to the next best thing," said Nancy Kanwisher of the McGovern Institute for Brain Research at MIT and senior author of the study appearing in the March 4 issue of the Journal of Neuroscience.
"Our study shows that the changes we see in neural response in people with MD are probably driven by the lack of input to a population of neurons, not by a change in visual information processing strategy," said Kanwisher, the Ellen Swallow Richards Professor of Cognitive Neuroscience in MIT's Department of Brain and Cognitive Sciences.
Macular degeneration affects 1.75 million people in the United States alone. Loss of vision begins in the fovea of the retina — the central area providing high acuity vision that we use for reading and other visually demanding tasks. Patients typically compensate by using an adjacent patch of undamaged retina. This "preferred retinal locus" (PRL) is often below the blind region in the visual field, leading patients to roll their eyes upward to look at someone's face, for example.
The visual cortex has a map of the visual field on the retina, and in macular degeneration the neurons mapping to the fovea no longer receive input. But several labs, including Kanwisher's, previously found that the neurons in the visual cortex that once responded only to input from central vision begin responding to stimuli at the PRL. In other words, the visual map has reorganized.
"We wanted to know if the chronic, prior use of the PRL causes the cortical change that we had observed in the past, according to what we call the use-dependent hypothesis," said first author Daniel D. Dilks, a postdoctoral fellow in the Kanwisher lab. "Or, do the deprived neurons respond to stimulation at any peripheral location, regardless of prior visual behavior, according to the use-independent hypothesis?"
The previous studies could not answer this question because they had only tested patients' PRL. This new study tests both the PRL and another peripheral location, using functional magnetic resonance imaging (fMRI) to scan two macular degeneration patients who had no central vision, and consequently had a deprived central visual cortex.
Because patients habitually use the PRL like a new fovea, it could be that the deprived cortex might respond preferentially to this location.
But that is not what the researchers found. Instead, the deprived region responded equally to stimuli at both the preferred and nonpreferred locations.
This finding suggests that the long-term change in visual behavior is not driving the brain's remapping. Instead, the brain changes appear to be a relatively passive response to visual deprivation.
"Macular degeneration is a great opportunity to learn more about plasticity in the adult cortex." Kanwisher said. If scientists could one day develop technologies to replace the lost light-sensitive cells in the fovea, patients might be able to recover central vision since the neurons there are still alive and well.
Chris Baker of the Laboratory of Brain and Cognition (NIMH) and Eli Peli of the Schepens Eye Research Institute also contributed to this study, which was supported by the NIH, Kirschstein-NRSA, and Dr. and Mrs. Joseph Byrne.
Adapted from materials provided by Massachusetts Institute of Technology.

MIT study sheds light on brain changes in macular degeneration

MIT study sheds light on brain changes in macular degeneration
Wednesday, March 4, 2009
CBC News
The brain adapts to find new visual information when a person gets eye disease causing blindness, according to a study from the Massachusetts Institute of Technology.

Researchers found that when people lose their sight because of macular degeneration, the affected neurons simply start seeking visual input from other, non-affected parts of the eye.

Their findings were published Wednesday in the Journal of Neuroscience.

"This study shows us one way that the brain changes when its inputs change. Neurons seem to 'want' to receive input: when their usual input disappears, they start responding to the next best thing," wrote lead researcher Nancy Kanwisher of the McGovern Institute for Brain Research at MIT.

It appears the long-term change in visual behaviour is not driving the brain's remapping; rather, it's the brain's relatively passive response to visual deprivation.

Macular degeneration is the most common form of adult blindness. It affects 800,000 people in Canada. Those suffering from it progressively lose vision in the central visual field of their retina, or their fovea. That means the corresponding part of the visual cortex in the brain also loses input.

"Macular degeneration is a great opportunity to learn more about plasticity in the adult cortex," Kanwisher said in a news release. "If scientists could one day develop technologies to replace the lost light-sensitive cells in the fovea, patients might be able to recover central vision since the neurons there are still alive and well."

Previously, researchers found deprived neurons would begin responding to visual input from another spot on the retina, essentially building a new visual map on the cortex. That information provided evidence of plasticity in the adult cortex. However, there were still questions as to how that happened.

MIT's study sheds light on the underlying neural mechanism.

"Our study shows that the changes we see in neural response in people with MD are probably driven by the lack of input to a population of neurons, not by a change in visual information processing strategy," said Kanwisher.

Typically, people suffering from MD will compensate by using an adjacent patch of undamaged retina. They'll roll their eyes upward to look at someone's face instead of focusing straight on, for instance. That undamaged patch becomes their new "preferred retinal locus," or PRL.

The researchers wanted to find out if the cortical change was caused by chronic prior use of the PRL, said another study author, Daniel D. Dilks, a postdoctoral fellow in the Kanwisher lab.

"Or, do the deprived neurons respond to stimulation at any peripheral location, regardless of prior visual behaviour," he wrote.

The previous studies could not answer this question because they had only tested patients' PRL. This new study tests both the PRL and another peripheral location, using functional magnetic resonance imaging to scan two macular degeneration patients who had no central vision, and consequently had a deprived central visual cortex.

Because patients habitually use the PRL like a new fovea, it could be that the deprived cortex might respond preferentially to this location.

But that is not what the researchers found. Instead, the deprived region responded equally to stimuli at both the preferred and nonpreferred locations.

Wet and Dry Age-Related Macular Degeneration (AMD)

The present Competitive Intelligence Report about Wet and Dry Age-Related Macular Degeneration (AMD) provides a competitor evaluation in the field of R&D projects for treatment of AMD as of February 2009.

Macular degeneration in the elderly (“age-related macular degeneration”, AMD) is a major cause of blindness. Its prevalence increases to 30% in patients 75 to 85 years of age. AMD occurs in two forms: dry and wet AMD. Central geographic atrophy, the “dry” form of advanced AMD, results from atrophy to the retinal pigment epithelial layer below the retina, which causes vision loss through loss of photoreceptors (rods and cones) in the central part of the eye. While no treatment is available for this condition, vitamin supplements appear to slow the progression of dry macular degeneration and, in some patients, improve visual acuity. Neovascular or exudative AMD, the “wet” form of advanced AMD, causes vision loss due to abnormal blood vessel growth in the choriocapillaries, ultimately leading to blood and protein leakage below the macula. Bleeding, leaking, and scarring from these blood vessels eventually cause irreversible damage to the photoreceptors and rapid vision loss if left untreated.

It is only recently that new drugs have been approved for wet AMD which halt progression of the visual loss or even lead to improvement. The humanized antibody fragment ranibizumab (Lucentis) directed against vascular endothelial growth factor (VEGF) was developed by Genentech and Novartis has been approved in more than 70 countries worldwide since 2006 and posted record sales of US$ 1.76 bln in 2008.

The proven effectiveness and commercial success of the anti-VEGF treatment of wet AMD has encouraged many companies to develop new treatments of wet AMD based on the proven target VEGF as well as on other experimental approaches (anti-angiogenic, anti-proliferative, anti-inflammatory). More than 20 different approaches are in clinical development and more than 20 preclinical stage projecs are under evaluation for wet AMD. Among the projects are many biologics (antibodies, peptides, proteins, antisense, DNA, cells) facilitated by the topical (intravitreal administration). Small molecule approaches may confer the convenience of oral administration but efficacy still has to be demonstrated. Fewer projects are in clinical development for dry AMD, but the most prominent ones have reached advanced clinical testing, but definitive results are still lacking.

Time course of morphologic effects on different retinal compartments after ranibizumab therapy in age-related macular degeneration.

Ophthalmology. 2008 Aug;115(8):e39-46.


Ahlers C, Golbaz I, Stock G, Fous A, Kolar S, Pruente C, Schmidt-Erfurth U.

Medical University of Vienna, Vienna, Austria.

PURPOSE: To analyze the effect of ranibizumab therapy on retinal and subretinal compartments in age-related macular degeneration and to compare the time course of compartment specific effects to visual function.

DESIGN: Prospective noncomparative case series.

PARTICIPANTS: Fourteen patients with changes in 3 major compartments owing to neovascular age-related macular degeneration.

METHODS: Standard treatment with 3 monthly doses of intravitreal ranibizumab was performed. Eyes were examined at baseline and weeks 1, 4, and 12 using a standardized protocol. Manual segmentation was applied to all 128 B-scans contained in a macular raster scan (MRS).

MAIN OUTCOME MEASURES: Morphology and time course of different retinal and subretinal compartments.

RESULTS: High-definition optical coherence tomography and manual segmentation allowed for precise identification of volumes within individual compartments. All morphologic parameters responded positively to therapy, but demonstrated a specific time course. Subretinal fluid was identified as the most relevant factor for visual function, whereas changes in retinal and subpigment epithelial volumes did not correlate with the time course of functional rehabilitation.

CONCLUSION: Analysis of MRS identified a characteristic impact of therapy on retinal and subretinal morphology.

PMID: 18675694 [PubMed - indexed for MEDLINE]

Serum Cystatin C Level, Kidney Disease Markers, and Incidence of Age-Related Macular Degeneration

The Beaver Dam Eye Study

Ronald Klein, MD, MPH; Michael D. Knudtson, MS; Kristine E. Lee, MS; Barbara E. K. Klein, MD, MPH

Arch Ophthalmol. 2009;127(2):193-199.

Objective
To examine the associations of the serum cystatin C level and chronic kidney disease with the incidence of age-related macular degeneration (AMD) over 15 years.

Methods
In this population-based cohort study of 4926 individuals aged 43 to 86 years at baseline, 3779 participated in 1 or more follow-up examinations. Age-related macular degeneration was determined by grading photographs of the macula. Individuals were defined as having mild or moderate to severe chronic kidney disease based on a value of more than 45 mL/min/1.73 m2 to 60 mL/min/1.73 m2 or less and 45 mL/min/1.73 m2 or less, respectively, according to the Modification of Diet in Renal Disease Study equation.

Results
While controlling for age and other risk factors, the level of serum cystatin C at baseline was associated with the incidence of early AMD (odds ratio per log standard deviation [95% confidence interval], 1.16 [1.01-1.35]) and exudative AMD (1.42 [1.03-1.96]) but not geographic atrophy (0.89 [0.56-1.41]) or progression of AMD (1.02 [0.88-1.18]). Mild chronic kidney disease was associated with the 15-year cumulative incidence of early AMD (odds ratio per log standard deviation, 1.36 [95% confidence interval, 1.00-1.86]) but not the incidence of other AMD end points.

Conclusion
There is a relationship between the level of serum cystatin C and chronic kidney disease with the incidence of AMD. The underlying biological processes remain to be determined.

Author Affiliations: Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison.