BOSTON, Nov. 3 Scientists at Schepens Eye ResearchInstitute have found that reducing the levels of vascular endothelial growthfactor (VEGF), which is best known as a stimulator of new blood vessel growth,in adult mice causes the death of photoreceptors and Muller glia -- cells ofthe retina that are essential to visual function. This finding, published inthe November 3, 2008 PLoS ONE, holds implications for the chronic use ofpromising new anti-VEGF drugs such as Lucentis, which eliminate abnormal anddamaging blood vessel growth and leakage in the retina by neutralizing VEGF.
"The take home message of this study is that physicians should be vigilantin monitoring patients undergoing anti-VEGF treatments for any possible signsof these side effects," says Principal Investigator Patricia D'Amore, SeniorScientist at Schepens Eye Research Institute. "Drugs such as Lucentis are verygood at reducing the edema (fluids) and eliminating the abnormal blood vesselsthat characterize wet macular degeneration, but our results suggest that therecould be unanticipated side effects."
Scientists have long known that VEGF is essential for normal developmentof the vascular system and for wound healing. It triggers the formation of newblood vessels that nourish the growing body and heal organs and tissues. VEGFalso stimulates -- in an apparent misguided attempt to heal perceived damagein the retina -- the growth of abnormal blood vessels that leak and damagedelicate retinal tissue.
However, a growing body of evidence also indicates that beyond its impacton blood vessel growth, VEGF may play other vital roles in the adult body andeye, so that eliminating the growth factor might lead to unexpectedconsequences.
Given the popularity and promise of the new anti-VEGF drugs for thetreatment of macular degeneration, D'Amore and her team believed thatinvestigating the broader role of this growth factor in the normal adultretina was critical. She and her laboratory mimicked the action of theanti-VEGF drugs by introducing into adult mice a soluble VEGF receptor, knownas sFlt1, which binds and neutralizes the VEGF -- in much the same way thatLucentis does in the eye.
After two weeks, the team found no effect on blood vessels of the innerretina, but did find a significant increase in the number of dying cells ofthe inner and outer nuclear layers which include amacrine cells thatparticipate in transmitting the visual signal; Muller cells that alsoparticipate in the visual signal and support the photoreceptors; and,photoreceptors, which are responsible for color and night vision. The teamthen used electroretinograms to measure visual function and found asignificant loss in visual function. Consistent with these observations, theydiscovered that both photoreceptors and Muller cells express VEGFR2, the majorVEGF signaling receptor and they found that neighboring Muller cells expressVEGF.
Parallel studies in tissue culture demonstrated that suppressing VEGF inMuller cells led to Muller cell death, indicating an autocrine role for VEGFin Muller cells (i.e. Muller cells both make VEGF and use it for survival).Further, they used cultures of freshly isolated photoreceptors to show thatVEGF can act as a protectant for these cells.
"Insight into the complex role of VEGF in the eye and in other parts ofthe body indicates that increased care should be taken in the long-term use ofthese drugs and that this new information should be considered in the designof future clinical studies to ensure that these possible side effects aretaken into account," says D'Amore.
"Mice eyes differ from human eyes in many ways, so we cannot directlyextrapolate these results to humans, but this study is an important heads-upthat clinical application of anti-VEGF therapy in the eye needs to proceedwith caution," she adds.
From a clinical perspective, Dr. Delia Sang of Ophthalmic Consultants ofBoston points out that the use of anti-VEGF therapy in the treatment ofpatients with wet macular degeneration has revolutionized outcomes in thisdisease. However, in light of the work of Dr. D'Amore and others, inelucidating possible systemic and ocular side effects of these drugs, "cautionmust be exercised in identifying patients at increased risk of problems withlong-term VEGF blockade, and potential side effects must be detected early inthe assessment of patients who will require repeated dosages of anti-VEGFagents."
The study is also relevant to the drug Avastin, which was initiallyapproved for intravenous use as an anti-angiogenic agent in the treatment ofcancer, but is also widely used intravitreally for the treatment of wet AMDbecause of its similar mode of action and much lower cost.
The next steps in D'Amore's research will include investigating thespecific functions of VEGF in the eye.
Authors of the study include: Magali Saint-Geniez (1,2), Arindel S. R.Maharaj (1), Tony E. Walshe (1,2), Budd A. Tucker (1,2), Eiichi Sekiyama(1,2), Tomoki Kurihara (1), Diane C. Darland (4), Michael J. Young (1,2),Patricia A. D'Amore (1,2,3)
Schepens Eye Research Institute is an affiliate of Harvard Medical Schooland is the largest independent eye research institute in the nation.(1) Schepens Eye Research Institute (2) Department of Ophthalmology, Harvard Medical School (3) Department of Pathology, Harvard Medical School (4) University of North Dakota, Grand Forks, North Dakota
SOURCE Schepens Eye Research Institute