Retinal and choroidal neovascularization are a major cause of significant visual impairment, worldwide. Understanding the various factors involved in the accompanying physiopathology is vital for development of novel treatments, and most important, for preserving patient vision. The intraocular use of anti-vascular endothelial growth factor therapeutics has improved management of the retinal and choroidal neovascularization but some patients do not respond, suggesting other vascular mediators may also contribute to ocular angiogenesis. Several recent studies examined possible new targets for future anti-angiogenic therapies. Potential targets of retinal and choroidal neovascularization therapy include members of the platelet-derived growth factor family, vascular endothelial growth factor sub-family, epidermal growth factor family, fibroblast growth factor family, transforming growth factor-β superfamily (TGF-β1, activins, follistatin and bone morphogenetic proteins), angiopoietin-like family, galectins family, integrin superfamily, as well as pigment epithelium derived factor, hepatocyte growth factor, angiopoietins, endothelins, hypoxia-inducible factors, insulin-like growth factors, cytokines, matrix metalloproteinases and their inhibitors and glycosylation proteins. This review highlights current antiangiogenic therapies under development, and discusses future retinal and choroidal pro- and anti-angiogenic targets as wells as the importance of developing of new drugs.Electronic supplementary materialThe online version of this article (doi:10.1186/s40942-017-0084-9) contains supplementary material, which is available to authorized users.
Purpose To evaluate the expression of 19 angiogenic biomarkers in the aqueous humor before and after intravitreal bevacizumab injection (IVB) in eyes with neovascular age-related macular degeneration (AMD). Design Prospective, noncomparative, interventional case series. Participants Twenty-three eyes of 23 treatment-naïve patients with choroidal neovascularization (CNV) secondary to neovascular AMD. Methods Eyes were diagnosed with CNV secondary to neovascular AMD and were treated with 3 monthly IVBs. Aqueous humor samples were obtained by anterior chamber paracentesis at baseline and immediately before each intravitreal bevacizumab injection. Main Outcome Measures Aqueous humor levels of 19 angiogenic biomarkers (angiopoietin 2, bone morphogenetic protein 9 [BMP-9], epidermal growth factor [EGF], endoglin, endothelin 1, fibroblast growth factor [FGF]-1 and FGF-2, follistatin, granulocyte colony-stimulating factor [GCSF], heparin-binding EGF-like growth factor [HB-EGF], hepatocyte growth factor [HGF], interleukin 8, leptin, placental growth factor [PLGF], vascular endothelial growth factor [VEGF]-A, VEGF-C, VEGF-D, and tissue inhibitor of metalloproteinases [TIMP]-1 and TIMP-2) were measured. Best-corrected visual acuity (BCVA), spectral-domain OCT parameters, and intraocular pressure also were evaluated. Results Baseline aqueous VEGF-A expression was elevated in all study eyes before treatment initiation. A statistically significant decrease of VEGF-A was observed at the 1- and 2-month follow-ups. A statistically significant increased concentration was observed in 7 biomarkers: VEGF-C, angiopoietin 2, endothelin 1, follistatin, HB-EGF, HGF, and interleukin 8. The other 11 study biomarker levels (VEGF-D, BMP-9, EGF, endoglin, FGF-1, FGF-2, GCSF, leptin, PLGF, TIMP-1, and TIMP-2) did not show any significant difference during follow-up. The BCVA statistically improved significantly at 2 months. Spectral-domain OCT parameters improved significantly at all follow-ups. Mean intraocular pressure values were not statistically different during the study period. Conclusions Despite a decrease in VEGF-A, the aqueous levels of VEGF-C, angiopoietin 2, endothelin 1, follistatin, HB-EGF, HGF, and interleukin 8 increased significantly after intravitreal injection of bevacizumab. These upregulated angiogenic biomarkers may represent new therapeutic targets in exudative AMD.
Purpose: To evaluate the concentration of vascular endothelial growth factor (VEGF) in aqueous humor after a single intravitreal injection of bevacizumab (IVB) in eyes with neovascular age-related macular degeneration (AMD). Methods:In this prospective interventional case series study, 24 eyes of 24 patients with types 1 and 2 choroidal neovascularization secondary to neovascular AMD were treated with a single intravitreal injection of bevacizumab. Aqueous humor samples were obtained before the intravitreal injection and at one week, one month, and three months follow-up periods. Best-corrected visual acuity (BCVA) and three spectral-domain optical coherence tomography parameters (central retinal thickness, macular volume and macular area) were also analyzed and correlated with VEGF expression at the baseline and each follow-up period.Results: All of the ninety-six aqueous humor study taps were well tolerated by the study patients without adverse events. Increased VEGF levels (mean ± SD = 179.7 ± 88.3 pg/mL) were observed in the aqueous humor of all study patients before the intravitreal injection of bevacizumab. At all follow-up periods, compared to baseline, levels of VEGF significantly reduced (P < 0.0001), and BCVA significantly improved (P < 0.005). The lowest VEGF expression was observed at 1 week, and the greatest BCVA improvement occurred 1 month after treatment. At 1 month, central retinal thickness (CRT), macular volume (MV), and macular area (MA) significantly reduced compared to baseline (P < 0.0001, P = 0.0005, P = 0.007, P = 0.009, respectively). At 1 week and 3 months, although without statistical significance (P > 0.005), CRT, MV and MA also reduced in comparison to baseline. Conclusions: Single intravitreal bevacizumab injection in eyes with neovascular AMD resulted in a substantial decrease of aqueous VEGF levels 1 week after treatment with the greatest improvement of clinical outcomes occurring at 1 month follow-up.
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