Verifying VEGF

LA JOLLA, Calif.—Vascular endothelial growth factor (VEGF)has been a favored target for therapies for years, in indications from cancerto macular degeneration. The protein stimulates angiogenesis, the growth of newblood vessels, and in cases of "wet" macular degeneration in particular, VEGFis a primary target, as low oxygen levels in the eyes of elderly individuals ordiabetic patients can trigger overproduction of the protein, leading to anabundance of abnormal, leaky blood vessels in the eyes. Traditional treatmentfor macular degeneration consists of anti-VEGF drugs, but a recent study fromThe Scripps Research Institute has shown that extreme suppression of VEGFactivity may be just as harmful as over-expression.

A group of Scripps researchers began by deleting the genefor VEGF in the retina cells of adult mice, and as a result, a large subset oflight-sensing cells in the retinas shut down in reaction to losing their mainblood, leading to severe vision loss.

"It's becoming clear that VEGF has a critical function inmaintaining the health of the retina, and we need to preserve that criticalfunction when we treat VEGF-related conditions," Dr. Martin Friedlander ofScripps, senior author of the new study, said in a press release.

The study found a way around a difficult issue indetermining the effects of anti-VEGF drugs on the protein: generating adultanimals that lack the VEGF gene, since removing the gene from mouse embryoscauses the mice to die before birth. In the Scripps approach, Friedlanderlaboratory postdoctoral fellows Dr. Toshihide Kurihara and Dr. Peter D. Westenskowpioneered a way to delete the gene in adults, and confined the deletion to theretinal pigment epithelial (RPE) cells, which serve to nourish and repair theretina and serve as a major retinal source of VEGF.

"Only three days after we knocked down the gene, we observedthe complete deterioration of the choriocapillaris, a layer of capillaries thatis a major supplier of nutrients to the outer retina, the location of the rodand cone photoreceptors," said Kurihara in a press release.

Light-sensing cone cells also saw rapid losses of functionthat led to significant vision losses. Retinal damage and vision loss wereevident even seven months after the VEGF gene knockdown, with Westenskow notingin a press release that "the deterioration seems irreversible if VEGF is notpresent."

Another approach studied by the Scripps team was thedeletion of genes that code for HIFs, low-oxygen signaling proteins, since theoverproduction of these proteins is also involved with VEGF-related tumors andeye conditions. The researchers discovered that deletion of the HIF genes inretinal cells largely inhibited overgrowth of blood vessels in mouse models,without affecting the normal-level production retinal VEGF or leading to eyedamage.

The obvious question, whether these kinds of side effectsare occurring with existing anti-VEGF treatments, is still unanswered, butsomething Friedlander considers necessary to determine.

Friedlander notes that most drugs, including the anti-VEGFdrugs used today, act on a bell-shaped curve—too little is not effective, toomuch results in adverse events. Current anti-VEGF drugs, he says, obviouslydemonstrate therapeutic benefits, but adverse events are also seen, even ifthey aren't significant. His and his colleagues' concern, he says, is theupcoming generation of VEGF antagonists.

"Our concern certainly is the current drugs that are outthere, but more so the new drugs that are coming along, which are much morepotent and have the potential to do far more harm than good," explainsFriedlander. "Having said that, there are increasing numbers of studies whichshow that patients who are being chronically treated with VEGF antagonists haveclear indications of progression of what we call geographic atrophy, or failureof photoreceptors in RPE cells … And whether that's because of the disease orbecause it's accelerated by VEGF antagonism hasn't yet been determined."

Moving forward, Friedlander and his colleagues will beconducting additional studies in this field, examining patients with maculardegeneration 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 followthe patients once the anti-VEGF treatment starts, examining retinal thickness,cone function, the state of the choriocapillaris and blood tests as well on aregular basis. Their study is "gearing up now," he adds, noting that they arein the process of drawing up protocols and awaiting approval, with hopes ofstarting within the next several months and "certainly within the next year."

The study, "Targeted deletion of Vegfa in adult mice induces vision loss," appeared in the November2012 issue of the Journal of ClinicalInvestigation.