1464-P: Targeted Delivery of shRNA-Lipids to Activated Monocytes and Inhibition of Neovascularization in Proliferative Retinopathy

Introduction & Objective: Proliferative retinopathy is a vision threatening condition in diabetic patients. We observed, using single cell RNA sequencing data analysis, activation of bone marrow-derived cells in peripheral blood from patients with Type-1 diabetes, and also in animal models of proliferative retinopathy. These activated monocytes and progenitor cells migrate into the retina in response to inflammation and neovascularization. However, contribution of these cells to neovascularization is largely unknown. We describe here the synthesis of a new hybrid nanoparticle for targeted delivery and gene silencing in activated monocytes that are associated with pathological neovascularization.

Methods: Single cell RNA sequencing data analysis were performed to characterize mRNA expression in peripheral blood from patients with Type-1 diabetes, and in oxygen-induced retinopathy (OIR) model. Targeted AS-shRNA-lipids were synthesized by conjugating diacyl-lipids to anti-sense short hairpin RNA with an anti-sense sequence complimentary to endoglin mRNA.

Results: Endoglin mRNA expression was associated with CD14^high and IL1B positive activated monocytes in peripheral blood from Type-1 diabetic patients, and in OIR model. In addition, endoglin mRNA expression was inhibited by AS-shRNA-lipid. In addition, significant reduction of neovascularization was achieved in OIR after intraperitoneal injection of AS-shRNA-lipids.

Conclusions: Diabetes may contribute to monocyte activation and inhibition of endoglin mRNA could regulate the activation. We have developed a novel method for targeted delivery and inhibition of mRNA targets in activated monocytes in the living tissues using AS-shRNA-lipids. These studies may provide a framework for a novel strategy to inhibit retinal neovascularization.