OPHTHALMOLOGY

Growth Factor’s Protection of Eye Shows Dark Side of Anti-angiogenesis Drugs

Results in Healthy Mice Suggest Patients Receiving Anti-VEGF Therapy Should Be Monitored for Possible Retinal Damage

A molecule better known for pathologic promotion of leaky new blood vessels in tumors and eye diseases may also protect vision, according to a study of vascular endothelial growth factor (VEGF) in healthy adult mice. The data suggest a possible new risk of anti-VEGF therapy, if the findings hold true in people.

Graham Ramsay

According to a study by (from left) Magali Saint-Geniez, Patricia D’Amore, Tony Walshe, Arindel Maharaj (not pictured), and their co-authors, the effective anti-VEGF drugs used for age-related macular degeneration should be administered with caution until researchers learn if the risk to vision in mice that they discovered holds true in people.

The study expands the known roles of VEGF, named for the feature of interest to scientists who aim to halt cancer by blocking vessels that feed tumors. As that research has advanced into the clinic, newer studies show VEGF more broadly supports the health of adult tissues, such as by protecting both normal adult neuronal cells and vasculature.

Clinical Precaution
Injection of anti-VEGF drugs into diseased eyes has revolutionized treatment for age-related wet macular degeneration. It is the first big therapeutic success story in angiogenesis research. The therapy is being tested in clinical trials for diabetic retinopathy, another devastating eye disease involving leaky new blood vessels. In both cases, the leaked fluid and blood cause the blinding eye damage.

In response to the new animal data, which show abnormal thinning of the retina, clinicians and researchers need to start monitoring the eyes of treated patients to learn if VEGF inhibition prompts similar cell death of photoreceptors, the major vision processing cells, said senior author Patricia D’Amore, HMS professor of ophthalmology (pathology) at Schepens Eye Research Institute.

“In and of itself, this important paper probably won’t change clinical practice, but it should prompt a deep investigation into whether or not these changes are happening in people,” agreed Jayakrishna Ambati, professor and vice chair of ophthalmology and visual sciences at the University of Kentucky, Lexington, who was not involved in the study.

Unpublished data from his lab seems to corroborate signs of ongoing VEGF function in the retina of human donor eyes, Ambati said. Other researchers have reported retinal ganglion cell apoptosis from long-term VEGF blockade in rat eyes. Medical practices and ongoing clinical trials of the therapies should use noninvasive imaging, such as optical coherence tomography, to measure any changes in the thickness of the retinal photoreceptor layer, he said.

In the case of advanced age-related macular degeneration, the potential vision risk may be offset compared to the vision saved or even gained, especially if the deleterious effects take time to develop. The disease is usually diagnosed at about age 75, and patients live an average of 12 more years. The risk–benefit calculus may change for middle-aged or younger populations or for disease with other good treatment options.

“A body of evidence has been building to support concerns about both systemic and ocular risks” of anti-VEGF therapy, said Delia Sang, HMS clinical instructor in ophthalmology at Schepens, who was not involved in the study. It may be nearly impossible to distinguish potential anti-VEGF complications from the natural history of disease in an elderly population, including potential worsening of dry macular degeneration (a precursor to wet), stroke damage, and thromboembolic events, she said. “Being unable to identify the true incidence of complications does not mean we ignore the necessity for precautions,” Sang said. She and her colleagues recommended combining anti-VEGF therapy with other treatments (to decrease the total number of anti-VEGF injections) earlier this month in their course at the American Academy of Ophthalmology in Atlanta.

The News and the Nuances
When the anti-VEGF therapies were first approved two years ago, the ­eyesight-saving benefits of ranibizumab (Lucentis) were heralded as “miraculous” in an editorial in The New England Journal of Medicine that accompanied the publication of the phase III clinical trials that led to approval by the Food and Drug Administration. Clinicians also inject bevacizumab (Avastin), the related anti-VEGF drug approved for colorectal cancer, in off-label, low-dose use with anecdotally similar improvement at much less cost (about $50 per injection, compared to $2,200); the National Eye Institute has initiated a head-to-head trial of the two drugs to compare efficacy and safety.

“I don’t want to sound like a naysayer for anti-VEGF drugs,” D’Amore said. “If I or someone in my family had wet macular degeneration, I would absolutely accept treatment.”

This study started partly in response to the interest of VEGF as a clinical target. “People did not know the function of VEGF in the normal eye,” said Magali Saint-Geniez, postdoctoral fellow and first author. “So we asked a very basic and crucial question.”

Courtesy PLoS One and Patricia D'Amore

Vision loss. Mice treated with a VEGF inhibitor (right) for four weeks showed substantial thinning of the retina, compared to untreated mice (left). Other tests showed increased apoptosis of photoreceptors and decreased visual function in treated mice.

Because knocking out a VEGF gene is lethal to embryos, researchers need to use a different strategy to learn how VEGF works. In this case, Saint-Geniez and her co-authors used an adenovirus in adult mice to make soluble receptors (sFlt1) that sop up VEGF.

In examining their mouse eyes four weeks later, the researchers were puzzled by the lack of effect of VEGF’s absence on the retinal vasculature. Encouragingly for anti-VEGF eye injections, the study showed that the normal vessels in the eye seemed to be resistant to a vascular breakdown side effect reported in the kidney and other organs with systemic anti-VEGF therapy, at least in the short time frame of their study.

Then they looked at the neural layers at the back of the retina. The photoreceptor layers of mice were noticeably thinner. Electroretinogram recordings showed retinal dysfunction. To isolate the effect of VEGF from the photoreceptors, they cultivated purified photoreceptors in dishes using two different techniques. Bathing the photoreceptors in VEGF reduced the cell death, or apoptosis, rate by 80 percent at three days, losing only 8 percent of cells compared to 38 percent of photoreceptors that died without VEGF.

The VEGF that photoreceptors need likely comes from the microglial support cells known as Müller cells, which also supply themselves with the factor. In the study, VEGF-starved Müller cells died after upregulating the pro-apoptotic gene Bax.

“VEGF seems to be a survival factor for a lot of different cell types,” Saint-Geniez said. “If it proves to be a strong neurotrophic factor, it may be transformed from a target into a new therapeutic agent.” The paper was published online Nov. 3 in PLoS One.

—Carol Cruzan Morton, with reporting by Kelly Dakin

For Students: Contact Patricia D’Amore at patricia.damore@gmail.com for more information on this and other lab projects.

Conflict Disclosure: PA—Novartis; JA—Allergan, Genentech, Novartis, Pfizer, Quark; DS—Novartis, Eyetech.

Funding Sources: The National Institutes of Health and the Department of Defense   

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