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LA JOLLA, Calif.—Vascular endothelial growth factor (VEGF) has been a favored target for therapies for years, in indications from cancer to macular degeneration. The protein stimulates angiogenesis, the growth of new blood vessels, and in cases of "wet" macular degeneration in particular, VEGF is a primary target, as low oxygen levels in the eyes of elderly individuals or diabetic patients can trigger overproduction of the protein, leading to an abundance of abnormal, leaky blood vessels in the eyes. Traditional treatment for macular degeneration consists of anti-VEGF drugs, but a recent study from The Scripps Research Institute has shown that extreme suppression of VEGF activity may be just as harmful as over-expression.
A group of Scripps researchers began by deleting the gene for VEGF in the retina cells of adult mice, and as a result, a large subset of light-sensing cells in the retinas shut down in reaction to losing their main blood, leading to 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," Dr. Martin Friedlander of Scripps, senior author of the new study, said in a press release.
The study found a way around a difficult issue in determining the effects of anti-VEGF drugs on the protein: generating adult animals that lack the VEGF gene, since removing the gene from mouse embryos causes the mice to die before birth. In the Scripps approach, Friedlander laboratory postdoctoral fellows Dr. Toshihide Kurihara and Dr. Peter D. Westenskow pioneered a way to delete the gene in adults, and confined the deletion to the retinal pigment epithelial (RPE) cells, which serve to nourish and repair the retina and serve as a major retinal source of VEGF.
"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 in a press release.
Light- sensing cone cells also saw rapid losses of function that led to significant vision losses. Retinal damage and vision loss were evident even seven months after the VEGF gene knockdown, with Westenskow noting in a press release that "the deterioration seems irreversible if VEGF is not present. "
Another approach studied by the Scripps team was the deletion of genes that code for HIFs, low-oxygen signaling proteins, since the overproduction of these proteins is also involved with VEGF-related tumors and eye conditions. The researchers discovered that deletion of the HIF genes in retinal cells largely inhibited overgrowth of blood vessels in mouse models, without affecting the normal-level production retinal VEGF or leading to eye damage.
The obvious question, whether these kinds of side effects are occurring with existing anti-VEGF treatments, is still unanswered, but something Friedlander considers necessary to determine.
Friedlander notes that most drugs, including the anti-VEGF drugs used today, act on a bell-shaped curve—too little is not effective, too much results in adverse events. Current anti-VEGF drugs, he says, obviously demonstrate therapeutic benefits, but adverse events are also seen, even if they aren't significant. His and his colleagues' concern, he says, is the upcoming generation of VEGF antagonists.
"Our concern certainly is the current drugs that are out there, but more so the new drugs that are coming along, which are much more potent and have the potential to do far more harm than good," explains Friedlander. "Having said that, there are increasing numbers of studies which show that patients who are being chronically treated with VEGF antagonists have clear indications of progression of what we call geographic atrophy, or failure of photoreceptors in RPE cells … And whether that's because of the disease or because it's accelerated by VEGF antagonism hasn't yet been determined."
Moving forward, Friedlander and his colleagues will be conducting additional studies in this field, examining patients with macular degeneration who are about to be treated with an anti-VEGF. Ideally, he says, they will conduct a battery of tests to determine a baseline and then follow the patients once the anti-VEGF treatment starts, examining retinal thickness, cone function, the state of the choriocapillaris and blood tests as well on a regular basis. Their study is "gearing up now," he adds, noting that they are in the process of drawing up protocols and awaiting approval, with hopes of starting within the next several months and "certainly within the next year."