Angiogenesis is a blinding complication of many eye diseases including diabetic and sickle cell retinopathy, retinopathy of prematurity (ROP) and exudative age-related macular degeneration (ARMID). Although over 50 antiangiogenic factors are currently being evaluated in clinical trials for eir effect on tumors, only two are in clinical trial for angiogenesis in the eye. One needed stepping stone towards antiangiogenic therapy in the eye has been the delivery of the agents to the nieovascularization selectively. This proposal will evaluate the delivery of genes encoding for antiangiogenic agents to sites of angiogenesis in the eye by non-viral means. The genes will be encapsulated in chitosan nanoparticles and the particles injected into vitreous or the subtenon's space. This gene delivery system has several attractive features: 1) ligands can be conjugated to the nanoparticles to stimulate receptor-mediated endocytosis (ex: acetylated LDL); 2) lysosomolytic agents can be incorporated to reduce degradation of the DNA in the endosomal and lysosomal compartments (ex: chloroquine); 3) other bioactive agents (proteinacious or non-proteinacious) or multiple plasmids can be co-encapsulated; 4) bioavailability of the DNA can be improved because of protection from nuclease degradation by the matrix; 5) the nanoparticles can be lyophilized for storage without loss of bioactivity. Pigment epithelial-derived factor (PEDF) will serve as the prototypic gene to be evaluated initially by this novel antiangiogenic therapeutic approach. In summary, chitosan nanoparticles are nontoxic, biodegradable particles that have the potential of delivering large genes to target cells of the eye. The goal of this proposal is to deliver genes for endogenous antiangiogenic agents to sites of ocular neovascularization.
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