Characterization of a novel caveolin modulator that reduces vascular permeability and ocular inflammation

Abstract

Purpose: Caveolin (Cav) regulates various aspect of endothelial cell signaling and cellpermeable peptides (CPPs) fused to domains of Cav can reduce retinal damage and inflammation in vivo. Thus, the goal of the present study was to identify a novel CPP that improves delivery of a truncated Cav modulator in vitro and in vivo. Methods: Phage display technology was used to identify a small peptide (RRPPR) that was internalized into endothelial cells. Fusions of Cav with the peptide were compared to existing molecules in three distinct assays, vascular endothelial growth factor-A (VEGF) induced nitric oxide (NO) release, VEGF induced vascular leakage, and in a model of immune mediated uveitis. Results: RRPPR was internalized efficiently and was potent in blocking NO release. Fusing RRPPR with a minimal Cav inhibitory domain (CVX51401) dose-dependently blocked NO release, VEGF induced permeability, and retinal damage in a model of uveitis. Conclusions: CVX51401 is a novel Cav modulator that reduces VEGF and immune mediated inflammation. Translational Relevance: CVX51401 is an optimized Cav modulator that reduces vascular permeability and ocular inflammation that is poised for clinical development.