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M. d. Cano, E. D. Karagiannis, M. S. Soliman, B. H. Bakir, A. S. Popel, P. L. Gehlbach; Peptides Derived From Type 1 Thrombospondin Repeat-Containing Proteins Inhibit Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4595.
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Vascular endothelial growth factor (VEGF) stimulates development of choroidal neovascularization (CNV). Anti-VEGF therapy has improved clinical outcomes in exudative age-related macular degeneration (AMD). Novel compounds with differing mechanisms of action may have complementary, additive or synergistic effects to anti-VEGF treatment. Here we evaluate synthesized peptide sequences predicted to be antiangiogenic by bioinformatics methods. The peptides tested are derived from the Type 1 thrombospondin repeat-containing, collagen type 4 and the CXC chemokine families of protein. The peptides were selected based on in vitro assessment of effects on endothelial cell proliferation and migration. Here we use the murine model of laser induced CNV to assess in vivo effectiveness.
Immediately following laser rupture of Bruchs membrane at three sites in each eye, thirty mice received a 1 ul intravitreous injection of peptide (100ug/ml) in the right eye and vehicle in the left eye. One week following laser the mice were re-injected. Two weeks after laser treatment the mice were perfused with fluorescein-labeled dextran; choroidal flat mounts were prepared and the area of CNV in treated and control eyes was compared. A paired t-test assuming equal variance with alpha assigned a value of 0.05 was used.
Both peptides derived from Type 1 thrombospondin repeat containing proteins (Wispostatin-1 and Thrombostatin-containing 6) caused significant reduction of CNV area as compared to vehicle treatment, (7379.88 µm2 vs. 12758.03 µm2 p = 0.02 and 9581.20 µm2 vs. 12816.4 µm2 p = 0.01), respectively. We did not observe a significant inhibition with a peptide from collagen type 4 (32626.12 µm2 vs. 34000.61µm2 p = 0.83) or one derived from the CXC chemokine family (34480.00 µm2 vs. 38384.55 µm2 p = 0.55).
We report an inhibitory effect on CNV for two novel peptides derived from the type 1 thrombospondin repeat-containing proteins (Wispostatin-1 and Thrombostatin-containing 6). Although in vitro activity was present the area of CNV was not decreased by the selected peptides derived from collagen type 4 or the CXC chemokine families, in this model. Evaluation of additional peptides in all families will provide insight into the pathogenesis of CNV while in vivoevaluation of novel antiangiogenic compounds of differing mechanism in animal models of eye disease is essential for eventual translation to therapeutic application.
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