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EW RETINA 156 by Maxine Lipner EyeWorld Senior Contributing Writer lander said, adding that this kept the mice from producing VEGF, which they found then led to their inabil- ity to produce CFH in the RPE as well as in podocytes in the kidney. Complement factor H protects cells from damage, he stressed. "If you have CFH around you can protect cells from activation of the com- plement pathway," he said. As it is, patients who have macular degen- eration have a breakdown in some of the garbage removal machinery in the back of your eye, Dr. Fried- lander explained, adding that every morning, the average RPE cell "eats around 20,000 shed photoreceptor outer segments for breakfast." If you damage those cells, you're going to accumulate debris and damage in the back of your eye that can lead to damaging inflammatory changes, he continued. "One problem that patients with macular degeneration have is the accumulation of subretinal deposits of debris, which have not been removed properly by RPE cells," Dr. Friedlander said. "As it turns out, we observed that VEGF stimulates RPE cells to make CFH in the back of the eye. This is a good thing because you can imagine you would want to have CFH coating the RPE so they don't accidently accumulate activated complement deposits that could damage cells in the posterior retina." Thus, if you know that VEGF stimulates CFH protection in the RPE, it is also logical to assume that if you shut down VEGF, you're going to have less CFH, Dr. Friedlander explained. "That's exactly what we observed—that if you exposed cultured human RPE cells to VEGF antagonists, they shut down the production of CFH," he said. He added that parallel experiments were done in the kidney with a group in England that collaborated on the paper since VEGF antagonists, given for cancer, were known to cause side effects in some patients. Without the VEGF, some kidney cells likewise weren't producing CFH, he noted. Investigators then checked to see if introducing a CFH variant observed in patients with macular degeneration would make them more susceptible to damage. "We found that we got far more damage down podocyte-specific VEGF pro- duction in the kidney, you observed significant effects on the vasculature and health of the renal glomerulus, the fundamental unit of the kidney. "For a number of years, we talked about the analogies between retinal pigmented epithelial [RPE] cells in the eye and podocytes in the kidney, and we thought it might be worth looking at the effects of VEGF in maintaining neurons in the back of the eye," Dr. Friedlander said. Years before, others had shown that VEGF not only promotes vascular permeability but is also a very potent trophic factor, critical for normal maintenance of blood vessels and neurons in the back of the eye, he noted. "It just seemed to us that if you shut down VEGF com- pletely with these drugs, you may want to think about potential side effects," Dr. Friedlander said. For the study, investigators used inducible targeted deletion in RPE cells in mice to replicate the effects of the anti-VEGF drugs. "We weren't quite sure what to expect," Dr. Fried- lems," Dr. Friedlander said, adding that previous work indicated that if you shut down VEGF production in interneurons in the eye, you could have a significant effect on the cho- riocapillaris. This is the same blood supply that becomes abnormal in macular degeneration, he explained. In addition, if you decrease that blood supply by damaging the cells, you can get secondary degenera- tion of the photoreceptors leading to decreased visual functioning, he continued. Role of CFH A post-doctoral fellow in his lab- oratory, Lindsey Keir, MD, PhD, became interested in this work and brought with her a background in nephrology. "She had done her PhD work with collaborators in Bristol and had shown that there were potential off target effects by shutting down VEGF in the kidney," Dr. Friedlander said. He also pointed out that Susan E. Quaggin, MD, had likewise previously published a paper showing that if you shut Considering how side effects may occur W hile anti-vascular en- dothelial growth fac- tor (VEGF) agents are valuable for treating wet age-related mac- ular degeneration and some cancer, they may also lead to issues in some patients, new research suggests, according to Martin Friedlander, MD, PhD, professor, Department of Molecular Medicine, The Scripps Re- search Institute, La Jolla, California. As results published in the January 2017 issue of the Journal of Clinical Investigation indicated, use of such agents curtail the body's ability to produce the protective complement factor H (CFH), which can lead to issues in the eyes and kidneys. 1 The idea for the study was the outgrowth of earlier work. "We have published other papers showing that if you shut down VEGF production in animal models of eye disease, you observed complications or prob- April 2017 Investigating anti-VEGF agents Research highlight

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