Abstract
Purpose :
Rho-associated protein kinase (ROCK), Janus kinase (JAK), and platelet-derived growth factor receptor beta (PDGFR-b) have been implicated in the development of choroidal neovascularization (NV) and vascular leakage in wet age-related macular degeneration (AMD) and retinal NV in proliferative diabetic retinopathy (PDR). This study evaluates AR-13154, a selective ROCK/JAK/PDGFR-b kinase inhibitor for its ability to inhibit NV in relevant animal models, either as monotherapy or in combination with an anti-VEGF agent.
Methods :
184 compounds from a library of ROCK inhibitors were screened at 500nM for activity against a panel of 456 human kinases. Subsequently, AR-13154 was selected for further investigation in rat laser-induced choroidal neovascularization (CNV) and mouse oxygen-induced ischemic retinopathy (OIR) models. In the rat CNV model, after retinal laser treatment on Day 0, AR-13154 (6mcg/mL; estimated vitreous concentration) or vehicle was administered by intravitreal (IVT) injection on Days 1, 4, and 10. Aflibercept (800mcg/mL) was administered by IVT injection on Day 1 as a positive control. In the OIR model, mice were treated from postnatal day P12 to P17 with either: 1) 0.06% AR-13154(S) administered topically to both eyes t.i.d.; 2) aflibercept (1mg/kg) administered intraperitoneally q.d.; 3) co-administration of 0.06% AR-13154(S) and aflibercept (1mg/kg); or 4) vehicle control. Retinal flat-mounts were stained with isolectin and areas of NV in both models were quantified using imaging software.
Results :
AR-13154 (500nM) inhibited ROCK2, JAK2, JAK3, and PDGFR-b by >99%, 72%, 97%, and 89%, respectively. In the rat CNV model, mean CNV lesion size was reduced by 35% (p<0.001) and 23% (p<0.05) following IVT administration of AR-13154 (6mcg/mL) or aflibercept (800mcg/mL), respectively. In the mouse OIR model, topical 0.06% AR-13154(S) reduced NV by 37% and aflibercept (1mg/kg) reduced NV by 34% (both p<0.0001). The combination of 0.06% AR-13154(S) and aflibercept (1mg/kg) reduced NV by 57%, and was statistically superior to either monotherapy (p<0.005).
Conclusions :
AR-13154, a selective multi-kinase inhibitor of ROCK/JAK/PDGFR-b, significantly inhibited NV in rat CNV and mouse OIR models. AR-13154 has therapeutic potential as a treatment option for wet AMD and PDR, either as monotherapy or in combination with anti-VEGF agents.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.