21 Feb 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.
Wednesday, February 25, 2009
Tuesday, February 17, 2009
Protect Your Eyes with Sunglasses
Protect your eyes with sunglasses that offer ultraviolet protection. The second strategy is to wear 'blue blocking' glasses.
The color that blocks blue is yellow, so blue blockers must contain a yellow tint. There are ready-made "NOIR" sunglasses that block blue and UV light with a variety of tints, including:
light yellow,
dark yellow, amber, and
plum.
NOIR glasses are available as clip-ons, and as large plastic frames that fit over your regular glasses.
The color that blocks blue is yellow, so blue blockers must contain a yellow tint. There are ready-made "NOIR" sunglasses that block blue and UV light with a variety of tints, including:
light yellow,
dark yellow, amber, and
plum.
NOIR glasses are available as clip-ons, and as large plastic frames that fit over your regular glasses.
Thursday, February 12, 2009
Avastin is inexpensive for Macular Degeneration therapy
Implications:
Ophthalmologists around the country use Avastin intravitreally for wet macular degeneration in doses far smaller than those used for systemic cancer. Although it is an "off-label" use of the drug, the cost for using Avastin is 1/6oth of Lucentis, a very similar drug, also made by Genentech, that IS FDA approved for macular degeneration. Yet, Avastin works just as well as Lucentis for far less cost. I am able to get the Avastin for $50 per dose, whereas Lucentis is $3,000 per dose. So, where Avastin is expensive for a small benefit in cancer therapy, it is quite inexpensive and highly effective in the treatment of macular dengeneration.
Analysis:
Avastin, while an expensive drug, has other uses that are currently "off-label" according to the FDA. Yet the doses are small and the cost is much less than the comparable FDA approved drug. The cost issue of Avastin is an artificial one, caused by the FDA's regulatory methods. It's efficacy in both metastatic colon cancer and macular degeneration has been well shown, and the FDA is responsible for the cost differential (see "Key Implications" above). The New York Times article does not adequately address the real reasons behind the high cost of Avastin for systemic use. The FDA regulatory process is also responsible for the high cost of any medicine that carries the FDA stamp of approval. The FDA process is flawed, not the prescribers of the drug, makers of the drug, or the recipients who get substantial benefits.
Ophthalmologists around the country use Avastin intravitreally for wet macular degeneration in doses far smaller than those used for systemic cancer. Although it is an "off-label" use of the drug, the cost for using Avastin is 1/6oth of Lucentis, a very similar drug, also made by Genentech, that IS FDA approved for macular degeneration. Yet, Avastin works just as well as Lucentis for far less cost. I am able to get the Avastin for $50 per dose, whereas Lucentis is $3,000 per dose. So, where Avastin is expensive for a small benefit in cancer therapy, it is quite inexpensive and highly effective in the treatment of macular dengeneration.
Analysis:
Avastin, while an expensive drug, has other uses that are currently "off-label" according to the FDA. Yet the doses are small and the cost is much less than the comparable FDA approved drug. The cost issue of Avastin is an artificial one, caused by the FDA's regulatory methods. It's efficacy in both metastatic colon cancer and macular degeneration has been well shown, and the FDA is responsible for the cost differential (see "Key Implications" above). The New York Times article does not adequately address the real reasons behind the high cost of Avastin for systemic use. The FDA regulatory process is also responsible for the high cost of any medicine that carries the FDA stamp of approval. The FDA process is flawed, not the prescribers of the drug, makers of the drug, or the recipients who get substantial benefits.
Thursday, February 5, 2009
EXPERIMENTAL THERAPY MAY LEAD TO MACULAR DEGENERATION, RESEARCHERS CAUTION
Johns Hopkins Medicine
Media Relations and Public Affairs
Media Contacts: Maryalice Yakutchik; 443-287-2251; myakutc1@jhmi.edu
Audrey Huang; 410-614-5105; audrey@jhmi.edu
August 27, 2008
Having discovered a genetic trigger for age-related macular degeneration, the leading cause of vision loss in people over 50, researchers report that an experimental state-of-the-art therapy for treating eye disease could adversely affect the vision of some patients with the "wrong" genetic makeup.
In the August 28 online issue of the New England Journal of Medicine, a multi-institutional team, including an interdisciplinary contingent from Johns Hopkins, reports that a mutation in toll-like receptor 3 (TLR3), a protein known to help cells fight some types of infection, is associated with protection from geographic atrophy. Geographic atrophy, also known as the "dry" form of macular degeneration, is the progressive shriveling of retinal cells in the central part of the tissue called the macula where cell loss equates to irreversible vision loss.
The new study implies that there could, in fact, be adverse consequences in some individuals who undergo a new treatment using a method called RNA interference to silence genes in the wet form of age-related macular degeneration (AMD), where growth of abnormal blood vessels causes vision loss.
RNA interference (RNAi) can be used in some cases to turn off disease-causing genes. Human trials using RNAi therapy already are under way for a host of diseases, including AMD. In theory, turning off a disease gene is a good idea, but it may not be good for everyone because everyone differs in their genetic makeup, cautions Nicholas Katsanis Ph.D., an associate professor of ophthalmology, molecular biology and genetics and member of the Institute of Genetic Medicine at the Johns Hopkins School of Medicine.
"The problem is that if you happen to be an individual who has the 'wrong' genetic code in TLR3, you might inadvertently trigger a detrimental effect in your retina," he explains. "You might cure the individual of one thing and increase their risk in something else." In this case, it's possible to cure the wet form of AMD but at the same time increase risk for the other form.
"This discovery has significant implications for diagnosing the dry form of (AMD), which is the most prevalent form, affecting more than 8 million Americans," says Kang Zhang, M.D., Ph.D., a professor of ophthalmology and human genetics and member of the Shiley Eye Center at the University of California San Diego. "It also allows us to develop new drugs to treat the dry form of AMD, for which there currently is no treatment."
In the current report, the team describes experiments on mouse and human genes showing that the activity of your TLR3 can determine whether or not you're afforded a degree of protection from geographic atrophy. TLR3 is activated in response to viral infection; it causes infected cells to die. Based on one's genetic code, some people have more active TLR3 while others, less active.
"What TLR3 does in the case of infection is sacrifice an infected cell to protect the neighborhood," Zhang explains.
Biologically well-intentioned though the sacrifice may be, it can lead to blindness.
Based on previous reports hinting to TLR3 involvement in macular degeneration, Katsanis, Zhang and colleagues first set out to determine whether that link was real.
By analyzing the DNA of patients in a case-control study, the researchers not only verified previously published reports indicating an association between TLR3 and macular degeneration, but also went on to show a specific association between one "fairly common" variant of TLR3 and geographic atrophy. They found that people with specific chemical difference in the TLR3 protein were less likely to have geographic atrophy.
To test the assumption that the chemical difference rendered TLR3 less active, the researchers next used cells from human eyes containing either a "normal" or variant version of TLR3. To activate TLR3, they infected these cells with fake RNA mimicking genetic material common to many viruses, and measured how many cells died. Fifty percent fewer cells with the variant version of TLR3 died compared to cells containing the normal version, leading the researchers to conclude that the variant version of TLR3 must be less active and therefore kills fewer cells.
Finally, to be sure that differences in TLR3 activity cause similar differences in cell death in whole eyes (and not just isolated eye cells), they teamed up with the team of Jayakrishna Ambati, M.D., a professor of physiology, ophthalmology and visual sciences at University of Kentucky and injected RNA into mice, one set of which was genetically engineered to have no TLR3. Two weeks later, researchers examined their eyes and found that those mice with TLR3 exhibited 61 percent more dead eye cells than mice without TLR3, further indicating that TLR3 activity triggers cells to die, which in turn can lead to geographic atrophy.
"You and me, we have a good 20 to 30 percent chance of getting macular degeneration," Katsanis says. "So when the time comes for us to start thinking about intervention, we might want to get genotyped first, and then decide what kind of therapeutic paradigm might be most appropriate for us."
The researchers envision a day when vaccines might protect us from the viruses that trigger the pathways that are inappropriately activated or repressed in models of macular degeneration: "If we can figure out which viruses might be acting as triggers, we might be able to find a way to combat them. This would be a far more effective therapy, in my view, than trying to design a gene therapy approach," says Zhang.
The TLR3 discovery bolsters a growing body of research that illustrates how genetic information stratifies individuals for responses to particular therapies; it is the first involving the retina.
"Clearly, the statement that we're not all the same is not exactly novel, and yet, I'm still struck by how homogenized people become when it comes to clinical trials," Katsanis says. "It baffles me, frankly."
The research was funded by the National Institutes of Health, the Foundation Fighting Blindness and the Macula Vision Research Foundation, Veterans Affairs Merit Award, the Ruth and Milton Steinbach Fund, Research to Prevent Blindness, Burroughs Wellcome Fund, Clinical Scientist Award in Translational Research, and the American Health Assistance Foundation.
Other participating researchers are from Johns Hopkins University, University of California San Diego, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China, University of Utah School of Medicine, Oregon Health & Science University, University of Kentucky, Greater Baltimore Medical Center, Keck School of Medicine of the University of Southern California, and Rockefeller University.
On the Web:
http://www.hopkinsmedicine.org/geneticmedicine/
http://content.nejm.org/
Media Relations and Public Affairs
Media Contacts: Maryalice Yakutchik; 443-287-2251; myakutc1@jhmi.edu
Audrey Huang; 410-614-5105; audrey@jhmi.edu
August 27, 2008
Having discovered a genetic trigger for age-related macular degeneration, the leading cause of vision loss in people over 50, researchers report that an experimental state-of-the-art therapy for treating eye disease could adversely affect the vision of some patients with the "wrong" genetic makeup.
In the August 28 online issue of the New England Journal of Medicine, a multi-institutional team, including an interdisciplinary contingent from Johns Hopkins, reports that a mutation in toll-like receptor 3 (TLR3), a protein known to help cells fight some types of infection, is associated with protection from geographic atrophy. Geographic atrophy, also known as the "dry" form of macular degeneration, is the progressive shriveling of retinal cells in the central part of the tissue called the macula where cell loss equates to irreversible vision loss.
The new study implies that there could, in fact, be adverse consequences in some individuals who undergo a new treatment using a method called RNA interference to silence genes in the wet form of age-related macular degeneration (AMD), where growth of abnormal blood vessels causes vision loss.
RNA interference (RNAi) can be used in some cases to turn off disease-causing genes. Human trials using RNAi therapy already are under way for a host of diseases, including AMD. In theory, turning off a disease gene is a good idea, but it may not be good for everyone because everyone differs in their genetic makeup, cautions Nicholas Katsanis Ph.D., an associate professor of ophthalmology, molecular biology and genetics and member of the Institute of Genetic Medicine at the Johns Hopkins School of Medicine.
"The problem is that if you happen to be an individual who has the 'wrong' genetic code in TLR3, you might inadvertently trigger a detrimental effect in your retina," he explains. "You might cure the individual of one thing and increase their risk in something else." In this case, it's possible to cure the wet form of AMD but at the same time increase risk for the other form.
"This discovery has significant implications for diagnosing the dry form of (AMD), which is the most prevalent form, affecting more than 8 million Americans," says Kang Zhang, M.D., Ph.D., a professor of ophthalmology and human genetics and member of the Shiley Eye Center at the University of California San Diego. "It also allows us to develop new drugs to treat the dry form of AMD, for which there currently is no treatment."
In the current report, the team describes experiments on mouse and human genes showing that the activity of your TLR3 can determine whether or not you're afforded a degree of protection from geographic atrophy. TLR3 is activated in response to viral infection; it causes infected cells to die. Based on one's genetic code, some people have more active TLR3 while others, less active.
"What TLR3 does in the case of infection is sacrifice an infected cell to protect the neighborhood," Zhang explains.
Biologically well-intentioned though the sacrifice may be, it can lead to blindness.
Based on previous reports hinting to TLR3 involvement in macular degeneration, Katsanis, Zhang and colleagues first set out to determine whether that link was real.
By analyzing the DNA of patients in a case-control study, the researchers not only verified previously published reports indicating an association between TLR3 and macular degeneration, but also went on to show a specific association between one "fairly common" variant of TLR3 and geographic atrophy. They found that people with specific chemical difference in the TLR3 protein were less likely to have geographic atrophy.
To test the assumption that the chemical difference rendered TLR3 less active, the researchers next used cells from human eyes containing either a "normal" or variant version of TLR3. To activate TLR3, they infected these cells with fake RNA mimicking genetic material common to many viruses, and measured how many cells died. Fifty percent fewer cells with the variant version of TLR3 died compared to cells containing the normal version, leading the researchers to conclude that the variant version of TLR3 must be less active and therefore kills fewer cells.
Finally, to be sure that differences in TLR3 activity cause similar differences in cell death in whole eyes (and not just isolated eye cells), they teamed up with the team of Jayakrishna Ambati, M.D., a professor of physiology, ophthalmology and visual sciences at University of Kentucky and injected RNA into mice, one set of which was genetically engineered to have no TLR3. Two weeks later, researchers examined their eyes and found that those mice with TLR3 exhibited 61 percent more dead eye cells than mice without TLR3, further indicating that TLR3 activity triggers cells to die, which in turn can lead to geographic atrophy.
"You and me, we have a good 20 to 30 percent chance of getting macular degeneration," Katsanis says. "So when the time comes for us to start thinking about intervention, we might want to get genotyped first, and then decide what kind of therapeutic paradigm might be most appropriate for us."
The researchers envision a day when vaccines might protect us from the viruses that trigger the pathways that are inappropriately activated or repressed in models of macular degeneration: "If we can figure out which viruses might be acting as triggers, we might be able to find a way to combat them. This would be a far more effective therapy, in my view, than trying to design a gene therapy approach," says Zhang.
The TLR3 discovery bolsters a growing body of research that illustrates how genetic information stratifies individuals for responses to particular therapies; it is the first involving the retina.
"Clearly, the statement that we're not all the same is not exactly novel, and yet, I'm still struck by how homogenized people become when it comes to clinical trials," Katsanis says. "It baffles me, frankly."
The research was funded by the National Institutes of Health, the Foundation Fighting Blindness and the Macula Vision Research Foundation, Veterans Affairs Merit Award, the Ruth and Milton Steinbach Fund, Research to Prevent Blindness, Burroughs Wellcome Fund, Clinical Scientist Award in Translational Research, and the American Health Assistance Foundation.
Other participating researchers are from Johns Hopkins University, University of California San Diego, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China, University of Utah School of Medicine, Oregon Health & Science University, University of Kentucky, Greater Baltimore Medical Center, Keck School of Medicine of the University of Southern California, and Rockefeller University.
On the Web:
http://www.hopkinsmedicine.org/geneticmedicine/
http://content.nejm.org/
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