A small biomimetic collagen IV derived peptide reduces leakage and suppresses ocular neovascularization in mouse models

CAMPOCHIARO PA; KIM J; LORENC VE; GREEN JJ; SHEN J; LIMA E SILVA R; POPEL AS; PANDEY NB

Hawaii

Congreso; ARVO (Association for Research in Vision and Opthalmology) 2018 Annual Meeting; 2018

Purpose: To evaluate the short-term efficacy of a small collagen IV derived peptide, AXT120, following intravitreous (IVT) injection in different mouse model of choroidal neovascularization (CNV), retinal NV (RNV), subretinal leakage and retinal detachment (RD).Methods: C57BL/6J mice had laser photocoagulation-induced rupture of Bruch?s membrane and then received IVT injection of 1l containing 0.1 or 1g of AXT120, 40g of aflibercept or 1g of control peptide. Another group of mice were treated with a combination of 1g of AXT120 and 40g of aflibercept at the same day as the laser photocoagulation. Fourteen days after laser, the total CNV area was measured. For regression of CNV, mice received treatment 7 days post laser induction and the area of CNV was measured 1 week after the IVT injections. At postnatal day (P) 12, mice with ischemic-induced retinopathy (OIR) were treated with 1g of AXT120 or control peptide. At P17 the retinas were stained with GSA-Lectin and the area of RNV was measured. At P20 rho/VEGF transgenic mice were given an IVT injection of 1g of AXT120 or control peptide. At P21, mice were euthanized and retinal flat mounts were immunofluorescently double-stained with GSA-Lectin and anti-mouse serum albumin antibody for assessment of subretinal leakage and the area of subretinal NV was measured. At Day 0, Tet/Opsin/VEGF transgenic mice were divided in two groups and given a single IVT injection of 1g of AXT120 or control in one eye and no injection in the fellow eye. On Day 6 after doxycycline was initiated, mice were anesthetized, pupils were dilated, and ocular fundus pictures were taken using a Micron camera. OCT scan was performed on AXT120-treated eyes and control-treated eyes and it was noted whether there was no retinal detachment, partial detachment or total retinal detachment. Results: A significant decrease in the area of CNV was found in eyes treated with the combination of the drugs (0.0021±0.0008), AXT120 (0.0026±0.0004) or aflibercept (0.0014±0.0002) compared to the control (0.009±0.003). A significant decrease in the area of CNV was found in the eyes treated with the combination of the drugs (0.0021±0.0008) compared to the treatment with either AXT120 (0.0026±0.0004) or aflibercept alone (0.0014±0.0002). The group treated with 1g of AXT120 (0.013±0.002) showed significantly smaller area of CNV compared to the control group (0.031±0.005) and to the baseline group (0.023±0.004). Retinas from OIR mice stained with GSA-Lectin showed higher number of tufts of retinal NV on its surface when treated with control (0.018±0.002) compared to eyes treated with 1g of AXT120 (0.010±0.001). Rho/VEGF transgenic mice that received IVT injections of 1g of AXT120 (0.005±0.002) prior to the immunostaining showed significantly less leakage in the retina compared to control (0.026±0.004). High power magnification of retinal flat mounts from rho/VEGF transgenic mice from 1g of AXT120-treated eyes at P21 showed significantly decrease in subretinal NV (0.008±0.002) compared to eyes treated with control (0.018±0.001). Tet/Opsin/VEGF transgenic mice treated with AXT120 showed significant protective effect on preventing retinal detachment that was better than their respective fellow eye and control-treated eyes. Conclusions: Intravitreal injection of AXT120 suppresses choroidal and retinal NV, reduces retinal leakage, prevents retinal detachment in murine model and may provide a new treatment for neovascular AMD.