Macular Degeneration drugs may do More harm than good ( anti-VEGF drugs )

Scripps Research Institute Study Suggests Caution and Further Studies on Drugs Used to Treat Macular Degeneration

LA JOLLA, CA – October 24, 2012 – Millions of people with “wet” macular degeneration are prescribed a class of medication known as anti-VEGF drugs. But now scientists at The Scripps Research Institute (TSRI) have found that a drastic reduction of VEGF activity may do more harm than good.

In the new study, the researchers deleted the gene for the blood-vessel growth factor VEGF, which has been implicated in stimulating abnormal blood vessel growth in a range of cancers and eye diseases, from cells in the retinas of adult mice. The results showed that without VEGF a large subset of light-sensing cells lost their main blood supply and shut down, causing severe vision loss.

“It’s becoming clear that VEGF has a critical function in maintaining the health of the retina, and we need to preserve that critical function when we treat VEGF-related conditions,” said TSRI Professor Martin Friedlander, MD, PhD, senior author of the new study, which appears in the November 2012 issue of the Journal of Clinical Investigation.

Major Target for Drug Developers

VEGF (vascular endothelial growth factor) has long been a major target for drug developers. Tumors often overproduce VEGF to stimulate local blood vessel growth and thus keep their fast-dividing cells well supplied with oxygen and nutrients. Low-oxygen conditions in the eyes of elderly or diabetic individuals also can trigger the overproduction of VEGF, resulting in a vision-destroying bloom of abnormal, leaky retinal blood vessels.

Several anti-VEGF drugs (such as Lucentis® (ranibizumab), Macugen (pegaptanib), Eylea® (aflibercept) and Avastin® (bevacizumab)) are already in use, and dozens more are in clinical trials against cancers and common eye disorders such as wet macular degeneration.

However, to date there have not been extensive studies on the effects of such drugs on the normal role of VEGF, in part because it is hard to generate adult animals that lack the VEGF gene. When the gene is removed from the embryos of mice, in a standard“knockout” experiment, the mice fail to develop normally and die before birth.

New Insights

In the new study, Friedlander laboratory postdoctoral fellows Toshihide Kurihara, MD, PhD, and Peter D. Westenskow, PhD, found a way to delete the major VEGF gene from mice after the animals had grown to adulthood. To determine VEGF’s role in the retina, they confined the gene deletion to the animals’ retinal pigment epithelial cells, which nourish and repair the retina and are a major retinal source of VEGF. The result suggests that VEGF does have a crucial function in the adult retina.

“Only three days after we knocked down the gene, we observed the complete deterioration of the choriocapillaris, a layer of capillaries that is a major supplier of nutrients to the outer retina, the location of the rod and cone photoreceptors,”said Kurihara.

Nearby light-sensing cone cells, which are specialized for detecting color and fine detail in visual images, also rapidly lost their function, causing pronounced vision loss in the mice. Seven months after the knockdown of the VEGF gene, the retinal damage and vision loss were still evident. “The deterioration seems irreversible if VEGF is not present,” said Westenskow.

Rod cells, which support low-light and peripheral vision, were not affected by the VEGF-gene deletion. The researchers note that cone cells may be more vulnerable because they are unusually active metabolically and may be unable to withstand a significant decrease in blood supply. Cone cells also bear receptors for VEGF molecules and thus may require direct VEGF stimulation to remain healthy. In any case, even if only cone cells died and rod cells were spared, a patient would experience severe vision loss. “You’d be defeating your purpose if you dried up the abnormal blood vessel growth but at the same time killed off the cone cells,” said Friedlander.

Paths for Future Research

Whether such side effects are happening with existing anti-VEGF treatments is unclear. While these assessments are possible, but they have been considered prohibitively expensive and invasive.

Friedlander, however, now believes such studies are necessary and plans to conduct such assessments in eye-disorder patients—who typically receive direct injections of anti-VEGF drugs to their eyes—to determine whether the drugs are causing these adverse side effects. He notes that the evaluations may be particularly necessary for a new class of anti-VEGF drugs recently approved for use in the treatment of age-related macular degeneration—drugs that are much more potent and persistent than previous anti-VEGF agents.

Fortunately, anti-VEGF drugs are not the only possible strategy for treating pathological blood vessel growth, as the new study makes clear. VEGF-related tumors and eye conditions also involve the overproduction of low-oxygen signaling proteins known as HIFs. The team found that deleting the genes for these HIFs in retinal cells largely prevents blood vessel overgrowth in a standard mouse model—without affecting the normal-level production of retinal VEGF or causing eye damage.

“In light of the present findings, other strategies for treating these eye conditions could be a possibility,” Friedlander said. “Conceivably, an anti-HIF treatment could also be combined with an anti-VEGF treatment, allowing the dose of the latter to be lowered significantly.”

The Friedlander lab, in collaboration with the laboratories of David Cheresh, PhD, and Michael Sailor, PhD, of the University of California, San Diego, has also been exploring the potential utility of inhibiting microRNAs that regulate angiogenic genes further upstream to VEGF. This work is being supported by a $10 million grant from the National Eye Institute and could lead to the development of antagonists that avoid the off-target effects of VEGF inhibitors.

In addition to Friedlander, Kurihara and Westenskow, other contributors to the study, “Targeted deletion of Vegfa in adult mice induces vision loss,” were Stephen Bravo and Edith Aguilar, both of TSRI. For more information on the paper, see http://www.jci.org/articles/view/65157.

The study was supported in part by grants from the National Eye Institute of the National Institutes of Health (EY-11254, EY-021416), the Lowy Medical Research Institute, the Manpei Suzuki Diabetes Foundation and The Japan Society for the Promotion of Science.

About The Scripps Research Institute

The Scripps Research Institute is one of the world’s largest independent, not-for-profit organizations focusing on research in the biomedical sciences. Over the past decades, Scripps Research has developed a lengthy track record of major contributions to science and health, including laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. The institute employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including three Nobel laureates—work toward their next discoveries. The institute’s graduate program, which awards Ph.D. degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.

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http://www.scripps.edu/news/press/2012/20121024friedlander.html

A high omega-3 fatty acid diet reduces retinal lesions in a murine model of macular degeneration

2009 study posted for filing

Contact: Angela Colmone
acolmone@asip.org
301-634-7953
American Journal of Pathology

The ‘see food’ diet

Bethesda, MD — Current research suggests that a diet high in omega-3 fatty acids may help prevent one of the leading causes of legal blindness among the elderly. The related report by Tuo et al, “A high omega-3 fatty acid diet reduces retinal lesions in a murine model of macular degeneration,” appears in the August 2009 issue of the American Journal of Pathology.

Age-related macular degeneration (AMD), loss of vision in the center of the visual field (macula) due to retinal damage, is one of the leading causes of legal blindness among the elderly. Approximately 10% of people from 66 to 74 years of age will develop some level of macular degeneration, making it difficult for them to read or even recognize faces.

A diet high in omega-3 fatty acids has been found to protect against a variety of diseases including atherosclerosis and Alzheimer’s disease. Retrospective studies have suggested that diets high in fish oil or omega-3 fatty acids may also contribute to protection against AMD. A group led by Dr. Chi-Chao Chan at the National Eye Institute in Bethesda, MD examined the direct effect of omega-3 fatty acids on a mouse model of AMD. A diet with high levels of omega-3 fatty acids resulted in slower lesion progression, with improvement in some lesions. These mice had lower levels of inflammatory molecules and higher levels of anti-inflammatory molecules, which may explain this protective effect.

Tuo et al suggest that “a diet enriched in EPA and DHA can ameliorate the progression of retinal lesions in their mouse model of AMD” and that “the results in these mice are in line with the epidemiological studies of AMD risk reduction by long chain n-3 fatty acids.” The results “further provide the scientific basis for the application of omega-3 fatty acids and their biologically active derivatives in the prevention and treatment of AMD.” In future studies, Dr. Chan and colleagues plan to use this murine model “to evaluate [other] therapies that might delay the development of AMD.” Their ongoing projects include the “testing of systematic delivered pharmacochaperones and antioxidative molecules, as well as intraocularly delivered gene therapies.”

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This work was supported by grants from The Intramural Research Program of the National Eye Institute, the National Institutes of Health, and the American Health Assistance Foundation.

Tuo J, Ross RJ, Herzlich AA, Shen D, Ding X, Zhou M, Coon SL, Hussein N, Salem Jr N, Chan C-C: A high omega-3 fatty acid diet reduces retinal lesions in a murine model of macular degeneration. Am J Pathol 2009 175: 799-807

For press copies of the articles, please contact Dr. Angela Colmone at 301-634-7953 or acolmone@asip.org.

For more information on Dr. Chi-Chao Chan, please contact:

Office of Communication
(301) 496-5248
neinews@nei.nih.gov
National Eye Institute, NIH
Building 31, Room 6A32
31 Center Drive, MSC 2510
Bethesda, MD 20892-2510.

The American Journal of Pathology, official journal of the American Society for Investigative Pathology, seeks to publish high-quality, original papers on the cellular and molecular biology of disease. The editors accept manuscripts that advance basic and translational knowledge of the pathogenesis, classification, diagnosis, and mechanisms of disease, without preference for a specific analytic method. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, animal, biological, chemical, and immunological approaches in conjunction with morphology.