Efficacy of Aflibercept Treatment and Its Effect on the Retinal Perfusion in the Oxygen-Induced Retinopathy Mouse Model of Retinopathy of Prematurity

Abstract

Introduction: Bevacizumab and ranibizumab, which are anti-vascular endothelial growth factor (VEGF) medications, are used frequently in the treatment for retinopathy of prematurity (ROP) in infants. Aflibercept, or VEGF Trap, has been used anecdotally, but translation and clinical studies are lacking. Objective: This study investigates the efficacy of aflibercept at reducing areas of non-perfused retina and studies its effect on normal angiogenesis in the oxygen-induced retinopathy mouse model of ROP. Methods: C57BL/6 J mice were assigned to room air control (n = 21 eyes) or hyperoxia with 75% oxygen (n = 84 eyes). The hyperoxic mice were assigned to 1 of 3 groups: 0 ng (n = 14 eyes), 100 ng (n = 35 eyes), or 1,000 ng (n = 35 eyes) of intravitreal aflibercept administered on postnatal day 14. Eyes were enucleated at PN17 and PN25 postinjection. Retinas were stained with anti-collagen IV antibody and photographed with microscopy. Areas of perfused and non-perfused retina were quantified using ImageJ software. Statistical comparisons were made using ANOVA with Tukey post hoc comparisons. Results: At PN17, there was no significant difference in the area of non-perfused retina between the hyperoxic control and the 100 and 1,000 ng aflibercept groups. At PN25, the 100 ng (p < 0.05) and 1,000 ng (p = 0.008) treatment groups displayed less non-perfusion compared to hyperoxic controls. At the 1,000 ng dose, there was increased non-perfusion compared to the 100 ng dose (p = 0.02). There was reduced non-perfusion by PN25 compared to PN17 for the 100 ng group (p < 0.05), with no difference in the 1,000 ng group. Conclusions: The study shows that the area of non-perfused retina decreases effectively with aflibercept at PN25 with 100 ng dosage. With the 1,000 ng dosage, there is an inhibition of the physiologic angiogenesis with a higher area of non-perfused retina.

Low-Dose Recombinant Adeno-Associated Virus-Mediated Inhibition of Vascular Endothelial Growth Factor Can Treat Neovascular Pathologies Without Inducing Retinal Vasculitis

“…1A ). Because expression of KH902 before P12 further dampens the development of the vasculature, and each vector serotype may exhibit different expression dynamics, we opted to quantify abnormal vascular growth by counting the number of aneurysms that form during the catch-up growth phase, rather than quantifying the area of normal vascularization, as has been done in other studies 45 , 46 , 48 ( Fig. 1B–D ).…”

“…The OIR of prematurity model is a well-established system for inducing abnormal vascular proliferation, which is characterized by a vascular catchup growth phase that is induced by a preceding hyperoxic phase during the development of the retinal vasculature 44 . Previous reports have shown that inhibition of VEGF during the catchup phase by conbercept 29 , or other anti-VEGF [45][46][47] drugs, reduces neovascular areas in the OIR mouse model. We thus compared the efficacy of rAAV2-and rAAV2.7m8-KH902 vectors in reducing neovascular pathologies in the OIR mouse model after intravitreal delivery.…”

Cytokine Profiles and the Effect of Intravitreal Aflibercept Treatment on Experimental Choroidal Neovascularization

“…For example, Torimura et al [10] showed that aflibercept can act on VEGFR-1 and -2 in mice. Amin et al [11] and Sergeys et al [12] reported that after intravitreal injection of aflibercept in mice, the leakage of CNV and inflammation were significantly improved [13]. Although the laser-induced CNV mouse model cannot completely simulate the pathophysiological process of CNV in humans, it is a model of acute wound-healing tempo for laser-induced damage.…”

Assessment of Mouse VEGF Neutralization by Ranibizumab and Aflibercept

“…10,11 Currently, bevacizumab, ranibizumab, and a ibercept are the major anti-VEGF drugs in ophthalmic practice. 12 Accordingly, bevacizumab, [13][14][15][16] ranibizumab, [17][18][19][20][21][22][23] and a ibercept [24][25][26][27][28] are frequently used in experiments with mouse models of retinal vascular diseases. Notably, Ferrara N et al reported that bevacizumab's ability to neutralize VEGF was species speci c and lacking in mice.…”