Suppression of Laser-induced Choroidal Neovascularization Using Promiscuous Cytokine Antagonist

Abstract

Purpose: Monocytes/macrophages were suggested to exert a proangiogenic effect in the context of neovascular age-related macular degeneration (nvAMD). Several cytokines in addition to vascular endothelial growth factor may potentially mediate such an effect. We aim to explore simultaneous perturbation of several cytokines as a potential therapeutic strategy for choroidal neovascularization (CNV).

Methods: Laser injury induced CNV was generated in Long-Evans rats (n=15). BKT130, a promiscuous antagonist of several cytokines including MCP1, MIP-3A, IP-10, Mig, I-TAC, TARK and RANTES, was delivered via intraperitoneal (IP) injection (4 mg) at the day of laser injury and five days later. Control rats received IP PBS. CNV was evaluated via fluorescein angiogram (FA) that was performed 10 days following the laser injury. Retina flatmounts immunostained for CD11b served to quantify subretinal macrophages, and retinal pigment epithelium-choroid flatmounts stained with isolectin were utilized to quantify CNV.

Results: Masked quantification of isolectin staining showed a mean suppression of CNV area of 26% (p=0.0058; Mann Whitney test). CD11b immunostaining showed a mean of 23% reduction of subretinal macrophages number following BKT130 therapy (p=0.0011; Mann Whitney test). Systemic or ocular side effects were not identified.

Conclusions: These data further supports the putative pathogenic role of macrophages and their cytokine products in CNV growth. It also suggests that targeting multiple cytokines simultaneously using a single compound (polypharmacology) may potentially serve as a therapeutic strategy for the disease.