Subretinal neovascularization (SRN) is a catastrophic development in many degenerative retinal diseases, including age-related macular degeneration--the most common cause of loss of reading vision among the elderly. Our past studies have been directed to the development and study of animal models of SRN and to perfection of an intraocular cannula system for the prolonged delivery of drugs to the retina. We propose to use this technology to test several different but not mutually exclusive hypotheses concerning the pathogenesis of experimental primate SRN. SRN results from an imbalance between: (1) inhibitory factors produced by the RPE and (2) mitogens, such as cycloxygenase products, produced by macrophages. Tests of these hypotheses include replacement of RPE by transplantation and chronic intravitreal indomethacin. SRN development requires (3) lysis of the extracellular matrix and basement membrane by proteases produced by endothelial sprouts. This will be tested in our SRN model by chronic intravitreal administration of protease inhibitors. SrN also requires (4) laying down of basement membrane. This will be tested with intraocular proline analogs, which inhibit basement membrane formation. The results of these studies may lead us toward a rational drug-based and/or transplant-based therapy for SRN.
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