The broad, long-term objectives of the application are to develop antisense inhibitors of retinopathy and document their mechanism(s) of action. Retinopathy is a significant cause of eye disease and has a major impact on development, learning, communicating, working, health, and quality of life for affected individuals. This application focuses on the inhibition of retinal neovascularization using antisense oligomers directed against endothelial cell alphav integrins, using a mouse model of retinopathy of prematurity. Alphav integrins are highly up-regulated during angiogenesis, and pharmacologic inhibitors of alphav integrins prevent angiogenesis in vivo. Whereas small organic molecules, synthetic peptides, and monoclonal antibodies have been used in the past to inhibit av integrin function, this application proposes to use antisense oligomer inhibition of alphav integrin expression. Preliminary studies show that antisense oligomers directed against integrin alphav inhibit retinal neovascularization in mice in a sequence-specific manner. Furthermore, the specificity of antisense oligomers holds the promise of minimal side-effects compared to previous pharmacologic inhibitors.
The specific aims are: I - To identify an alphav antisense oligomer sequence that effectively inhibits translation of human and mouse av integrin. II - To identify an optimal dose and route of administration of the alphav antisense PMO identified in Aim I that effectively inhibits neovascularization in the retina of ROP mice. This will be achieved by screening a series of antisense phosphorodiamidate morpholino oligomers using in vitro alphav translation assays and an in vivo mouse model of retinopathy of prematurity. The primary goal of this grant is to identify the optimal antisense alphav PMO, dose and schedule that maximally decreases alpha V expression and inhibits retinopathy of prematurity.
