Login Register Cart 0
Generic placeholder image

Current Neurovascular Research

Editor-in-Chief

ISSN (Print): 1567-2026
ISSN (Online): 1875-5739

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Anti-vascular Endothelial Growth Factor Antibody Limits the Vascular Leakage and Decreases Subretinal Fibrosis in a Cynomolgus Monkey Choroidal Neovascularization Model

Author(s): Satoshi Inagaki, Masamitsu Shimazawa*, Koji Hamaguchi, Wataru Otsu, Tomoaki Araki, Yuji Sasaki, Yosuke Numata, Hideshi Tsusaki and Hideaki Hara

Volume 17, Issue 4, 2020

Page: [420 - 428] Pages: 9

DOI: 10.2174/1567202617666200523163636

Price: $65

Abstract

Objective: This study was conducted to evaluate the effects of anti-vascular endothelial growth factor (VEGF) antibody (bevacizumab) on vascular leakage and fibrosis in a monkey choroidal neovascularization (CNV) model. The relationship between fibrotic tissue and subretinal hyper-reflective material (SHRM), in optical coherence tomography (OCT) images, was also investigated.

Methods: Experimental CNV was induced in male cynomolgus monkeys by laser photocoagulation. Intravitreal injection of bevacizumab at 0.5 mg/eye/dosing was initiated 2 weeks before or after laser irradiation and thereafter, conducted intermittently at 2- or 3-week intervals. Fluorescein fundus angiography (FA) and OCT imaging were conducted weekly from 2 to 7 weeks after laser irradiation. CNV leakage was evaluated by an established grading method using FA images. To assess the fibrosis and scarring, Masson’s trichrome specimens of each CNV lesion were prepared, and morphometric analysis was conducted using an image analysis software.

Results: The effects of bevacizumab on vascular leakage were shown using an established evaluation method. Morphometric analysis of Masson’s trichrome-stained (MT) specimens revealed that collagen fiber synthesis was suppressed by bevacizumab pre-treatment (-29.2%) or post-treatment (-19.2%). SHRM was detected in OCT images in a monkey CNV model, and a significant correlation between the SHRM area in the OCT images and the collagen fiber area in the MT specimens was noted.

Conclusion: In the established cynomolgus monkey CNV model, bevacizumab prevented blood leakage but could not completely suppress fibrosis. SHRM in the OCT images reflected retinal fibrous tissue in a laser-induced CNV monkey model. This model might be useful for elucidating the pathology and development therapy for neovascularization or fibrosis.

Keywords: Anti-VEGF therapy, choroidal neovascularization, cynomolgus monkey, fibrosis, Age-related macular degeneration, fibrotic scarring.

« Previous Next »
[1]
Lim LS, Mitchell P, Seddon JM, Holz FG, Wong TY. Age-related macular degeneration. Lancet (London, England) 2012; 379(9827): 1728-38.
[2]
Friedlander M. Fibrosis and diseases of the eye. J Clin Invest 2007; 117(3): 576-86.
[3]
Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004; 351(27): 2805-16.
[4]
Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006; 355(14): 1419-31.
[5]
Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011; 364(20): 1897-908.
[6]
Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 2012; 119(12): 2537-48.
[7]
Hachana S, Fontaine O, Sapieha P, Lesk M, Couture R, Vaucher E. The effects of anti-VEGF and kinin B(1) receptor blockade on retinal inflammation in laser-induced choroidal neovascularization. Br J Pharmacol 2020; 177(9): 1949-66.
[8]
Daniel E, Toth CA, Grunwald JE, et al. Risk of scar in the comparison of age-related macular degeneration treatments trials. Ophthalmology 2014; 121(3): 656-66.
[9]
Ishikawa K, Kannan R, Hinton DR. Molecular mechanisms of subretinal fibrosis in age-related macular degeneration. Exp Eye Res 2016; 142: 19-25.
[10]
Krzystolik MG, Afshari MA, Adamis AP, et al. Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment Arch Ophthalmol (Chicago, Ill : 1960) 2002; 120(3): 338-46.
[11]
Nork TM, Dubielzig RR, Christian BJ, et al. Prevention of experimental choroidal neovascularization and resolution of active lesions by VEGF trap in nonhuman primates Arch Ophthalmol (Chicago, Ill : 1960) 2011; 129(8): 1042-52.
[12]
Lichtlen P, Lam TT, Nork TM, Streit T, Urech DM. Relative contribution of VEGF and TNF-alpha in the cynomolgus laser-induced CNV model: comparing the efficacy of bevacizumab, adalimumab, and ESBA105. Invest Ophthalmol Vis Sci 2010; 51(9): 4738-45.
[13]
Balser C, Wolf A, Herb M, Langmann T. Co-inhibition of PGF and VEGF blocks their expression in mononuclear phagocytes and limits neovascularization and leakage in the murine retina. J Neuroinflam 2019; 16(1): 26.
[14]
Caballero S, Swaney J, Moreno K, et al. Anti-sphingosine-1-phosphate monoclonal antibodies inhibit angiogenesis and sub-retinal fibrosis in a murine model of laser-induced choroidal neovascularization. Exp Eye Res 2009; 88(3): 367-77.
[15]
Jo N, Mailhos C, Ju M, et al. Inhibition of platelet-derived growth factor B signaling enhances the efficacy of anti-vascular endothelial growth factor therapy in multiple models of ocular neovascularization. Am J Pathol 2006; 168(6): 2036-53.
[16]
Jaffe GJ, Ying GS, Toth CA, et al. macular morphology and visual acuity in year five of the comparison of age-related macular degeneration treatments trials. Ophthalmology 2019; 126(2): 252-60.
[17]
Jaffe GJ, Ciulla TA, Ciardella AP, et al. Dual antagonism of PDGF and VEGF in neovascular age-related macular degeneration: A phase IIb, multicenter, randomized controlled trial. Ophthalmology 2017; 124(2): 224-34.
[18]
Rosenfeld PJ. Optical coherence tomography and the development of antiangiogenic therapies in neovascular age-related macular de-generation. Invest Ophthalmol Vis Sci 2016; 57(9): 14-26.
[19]
Michalewski J, Nawrocki J, Izdebski B, Michalewska Z. Morphological changes in spectral domain optical coherence tomography guided bevacizumab injections in wet age-related macular degeneration, 12-months results. Indian J Ophthalmol 2014; 62(5): 554-60.
[20]
Grossniklaus HE, Kang SJ, Berglin L. Animal models of choroidal and retinal neovascularization. Prog Retin Eye Res 2010; 29(6): 500-19.
[21]
Cohen SY, Oubraham H, Uzzan J, Dubois L, Tadayoni R. Causes of unsuccessful ranibizumab treatment in exudative age-related macular degeneration in clinical settings. Retina (Philadelphia, PA) 2012; 32(8): 1480-5.
[22]
Regatieri CV, Branchini L, Duker JS. The role of spectral-domain OCT in the diagnosis and management of neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 2011; 42: S56-66.
[23]
Unver YB, Yavuz GA, Bekiroglu N, Presti P, Li W, Sinclair SH. Relationships between clinical measures of visual function and anatomic changes associated with bevacizumab treatment for choroidal neovascularization in age-related macular degeneration. Eye (Lond England) 2009; 23(2): 453-60.
[24]
Little K, Ma JH, Yang N, Chen M, Xu H. Myofibroblasts in macular fibrosis secondary to neovascular age-related macular degeneration - the potential sources and molecular cues for their recruitment and activation. EBioMedicine 2018; 38: 283-91.
[25]
Wynn TA. Common and unique mechanisms regulate fibrosis in various fibro proliferative diseases. J Clin Invest 2007; 117(3): 524-9.
[26]
Kent D, Sheridan C. Choroidal neovascularization: A wound healing perspective. Mol Vis 2003; 9: 747-55.
[27]
Ahn SJ, Park KH, Woo SJ. Subretinal fibrosis after anti-vascular endothelial growth factor therapy in eyes with myopic choroidal neovascularization. Retina (Philadelphia, PA) 2016; 36(11): 2140-9.
[28]
Xiao H, Zhao X, Li S, et al. Risk factors for subretinal fibrosis after anti-VEGF treatment of myopic choroidal neovascularisation. Brit Ophthalmol 2020. [Epub ahead of print]
[29]
Bogdanovich S, Kim Y, Mizutani T, et al. Human IgG1 antibodies suppress angiogenesis in a target-independent manner. Signal Transduct Target Ther 2016; 1: 15001.

Rights & Permissions Print Cite
Article Metrics
65
© 2024 Bentham Science Publishers | Privacy Policy