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Kevin Carbajal, Meredith Weksler, Lori Moore, Jindong Ding, Casey Kopczynski, Cheng-Wen Lin; AR-13503 Enhances the Efficacy of Aflibercept in a Mouse Model of Proliferative Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2018;59(9):200.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetic retinopathy (DR) and its complications can lead to irreversible vision loss. New therapies with novel mechanisms of action are needed as anti-vascular endothelial growth factor (VEGF) and steroid treatments have significant limitations. Rho kinase (ROCK) has been implicated in the development of retinal neovascularization (NV) and vascular leakage in neovascular age-related macular degeneration (nAMD) and proliferative diabetic retinopathy (PDR). AR-13503 is a potent ROCK and protein kinase C (PKC) inhibitor. We have separately shown that AR-13503 inhibited angiogenesis and enhanced retinal pigmented epithelium barrier function in in vitro and ex vivo assays. Here, we investigated the effect of AR-13503 on the formation of aberrant neovascularization (NV) in an animal model of PDR.
In the oxygen-induced retinopathy (OIR) animal model, 7-day old neonatal C57BL/6 mice were housed with foster mothers at 75% oxygen from postnatal day (P)7 to P12. Upon return to normoxia on P12, mice were treated by once daily intraperitoneal injections with vehicle control, aflibercept, or AR-13503 in combination with aflibercept. Tissues were harvested following 5 days of treatment and stained for isolectin-IB4 for visualization and analysis of NV. Retinas were also harvested for pharmacokinetic analysis.
AR-13503 was detectable in mouse retinas following systemic treatment with 1.25 mg/kg/day. Mice treated with aflibercept alone had a reduction in NV of ~55% relative to vehicle control. The combination of AR-13503 and aflibercept had a greater (~75%) reduction in NV than aflibercept alone. There were no significant differences in the size of avascular areas among groups.
The data presented in this study suggest that AR-13503 is a promising new molecule for the treatment of DR. Inhibition of ROCK and PKC may address some of the limitations of anti-VEGF and steroid therapies.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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