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Tine Van Bergen, Tjing-Tjing Hu, Isabelle Etienne, Geert Reyns, Lieve K M Moons, Jean Feyen; Neutralization of placental growth factor as a novel treatment option in diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4247.
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© ARVO (1962-2015); The Authors (2016-present)
Anti-vascular endothelial growth factor (VEGF) therapy has shown a significant improvement in visual acuity in patients with diabetic retinopathy (DR), however treatment response can be variable and might be associated with potential side effects. In this study, inhibition of placental growth factor (PlGF) was explored as a possible alternative therapy for DR by investigating its effect on different hallmarks of DR in various experimental murine models.
The in vivo efficacy of the anti-PlGF antibody (5D11D4; 0.77 – 5.4 µg/eye) was tested in diabetic streptozotocin (STZ; n=15-30/group) and Akimba mouse models (n=20-27/group) and in the laser-induced mouse model of choroidal neovascularization (CNV; n=10-20/group). Intravitreal (IVT) administration of the anti-PlGF antibody was compared to anti-VEGFR-2 antibody (DC101; 3.1 - 6.2µg/eye), VEGF-Trap (aflibercept; 2.4 -20 µg/eye), triamcinolone acetonide (TAAC; 40 µg/eye) and PBS as negative control. Vascular leakage was investigated by FITC-labelled bovine serum albumin perfusion or by fluorescein angiography. Immunohistological stainings were performed to check for neurodegeneration (Brn3a), inflammation (CD45, F4/80) and fibrosis (collagen type 1a and Sirius Red).
In the diabetic STZ and Akimba models, repeated IVT administration of 5D11D4 reduced vascular leakage with 34±14% and 22±13% (P<0.05), respectively. This effect was equally efficacious as DC101 treatment in STZ mice (P=0.43). 5D11D4 treatment did not alter retinal ganglion cell (RGC) density, whereas DC101 significantly reduced RGC density with 20±6% (P=0.04). In the CNV model, 5D11D4 injection dose-dependently reduced inflammation and fibrosis, as compared to PBS treatment (P<0.05). Equimolar administration of 5D11D4, aflibercept and TAAC decreased leukocyte and macrophage infiltration with 45±5% (P<0.001), whereas DC101 had no effect on the inflammatory response (P=0.96). Administration of 5D11D4 and TAAC similarly reduced collagen I and total collagen deposition with 40±5% and 35±8% (P<0.001), while no effect was observed after equimolar DC101 (P=0.82) nor aflibercept administration (P=0.66).
The neutralization of PlGF showed equal efficacy compared to VEGF inhibition on the process of vascular leakage, but differentiates itself by also reducing inflammation and fibrosis, without triggering a neurodegenerative response.Financial disclosure: ThromboGenics NV.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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