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
Friday, August 28, 2009
Tuesday, August 4, 2009
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
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
Sunday, July 12, 2009
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.
Saturday, June 6, 2009
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.
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.
Saturday, May 30, 2009
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.
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.
Sunday, May 10, 2009
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.
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.
Sunday, May 3, 2009
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
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
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