A new class of RNA interference therapeutic agent against (pro)renin receptor suppresses choroidal neovascularization

Abstract

Purpose : To investigate the effect of a novel single-stranded RNA interference (RNAi) agent targeting (pro)renin receptor [(P)RR]/ATP6AP2, (P)RR-PshRNA, on attenuation of choroidal neovascularization (CNV).

Methods : Laser photocoagulation was performed to induce CNV in C57BL/6J mice, followed by intravitreal injection of (P)RR- or control-PshRNA. Seven days after laser injury, choroidal flat mounts were prepared and the size of the CNV lesions was quantified. The retinal pigment epithelium (RPE)-choroid complex was harvested 3 days after laser injury and the levels of (P)RR/Atp6ap2 and inflammation-associated molecules (e.g., tumor necrosis factor-α, adhesion G protein-coupled receptor E1 (also known as F4/80), interleukin-6, monocyte chemotactic protein-1, intercellular adhesion molecule-1) were analyzed using real-time qPCR.

Results : Real-time qPCR showed that the levels of (P)RR/ATP6AP2 mRNA significantly decreased following exposure to human RPE and mouse endothelial cells with (P)RR-PshRNA as well as a conventional double-stranded (P)RR-siRNA. Compared to the mice treated with control-PshRNA or PBS, the mice treated with intravitreal injection of (P)RR-PshRNA showed a significant attenuation of CNV size in a dose-dependent manner (p < 0.05), and a notable decrease in the mRNA levels of (P)RR/Atp6ap2 and inflammation-associated molecules in the RPE-choroid complex (p < 0.05).

Conclusions : (P)RR-PshRNA, a novel single-stranded RNAi agent targeting human and mouse (P)RR/ATP6AP2, can reduce expression of inflammation-associated molecules and suppress CNV formation. Our data suggest the possibility that (P)RR-PshRNA can be used for neovascular age-related macular degeneration as a novel therapeutic agent.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.