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Yiwen Li, Weng Tao, Vincent Ling, Arne Nystuen, Susan Elliott, Paul Stabila, Rong Wen; Inhibition of choroidal neovascularization by neutralizing PDGF with a recombinant fusion protein of PDGFR β domain. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4625. doi: https://doi.org/.
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The exudative or wet age-related macular degeneration (AMD), characterized by the existence of choroidal neovascularization (CNV), could result in rapid and severe loss of vision. In the present work, we evaluate the contribution of PDGF to the development of CNV in a subretinal matrigel CNV model by using a recombinant Fc-fusion protein of a PDGFR β extracellular domain that neutralizes PDGF (Neurotech 974), and a recombinant Fc-fusion protein of VEGFR1 / R2 chimera (Neurotech 910).
Sprague Dawley rats, female, 2 months of age were divided into 4 groups: Control, 910 only, 974 only, and 910+974. Matrigel was diluted 3:1 with PBS (Matrigel:PBS), or PBS containing recombinant proteins. Final concentration: 910, 0.24 µg/µl; 974, 0.3 µg/µl; 910+974, 0.24 and 0.3 µg/µl, respectively. CNV was induced in by subretinal injection of 1.2 µl of Matrigel. CNV was allowed to develop for 12 days. At the endpoint, animals were killed and perfused with DiI solution to visualize blood vessels. Eyes were embedded in 5% agarose. Serial sections were cut on a vibratome to cover the entire Matrigel area and examined by confocol microscopy. CNV area was calculated and analyzed.
Extensive CNV was found in control eyes injected with Matrigel only, with an average CNV area of 9.9±2.4 (x105 µm2, n=3). In the eyes treated with the PDGF neutralizing protein 974, the CNV was significantly smaller with an average CNV area of 2.6±1.7 (x105 µm2, n=3, P<0.001, ANOVA). Significantly smaller CNV was also found in eyes treated with VEGF neutralizing protein 910, with an average CNV area of 3.8±1.6 (x105 µm2, n=3, P<0.01). In the 4 eyes treated with the combination of 910 and 974, CNV was absent in 3 and was very small in only one eye. The average of CNV area is 0.2±0.4 (x105 µm2, n=4, P<0.001). In fact, the CNV area in the eyes treated with 910+974 is significantly smaller than in the eyes treated with 910 alone (P<0.05).
Our results confirm the contribution of PDGF signaling in the development of CNV independent of VEGF signaling, and identify PDGF as a therapeutic target for CNV. The combination therapy neutralizing both VEGF and PDGF synergistically inhibits the development of CNV.
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