HIV Vector Mediated Expression of Angiostatin Efficiently Inhibits Neovascularization in a Murine Proliferative Retinopathy Model

Abstract

Abstract: : Purpose:Ischemic retinal diseases such as diabetic retinopathy, retinopathy of prematurity and age-related macular degeneration are a major cause of blindness in the world. HIV vectors are able to achieve long-term gene expression in the non-dividing cells and may be most useful for gene therapy of retinal diseases. We generated an HIV vector encoding angiostatin and examined the feasibility of the gene therapy approach to treat retinal neobvascularization in a murine proliferative retinopathy model. Methods:The proliferative retinopathy mouse model was generated by a sequential exposure of newborn mice to hyperoxia and room air. The neovascular response was observed in all treated animals. HIV-angiostatin or HIV-EGFP(enhanced green fluorescent protein) as a control was injected into the left vitrous and PBS for right vitrous. The number of retinal neovascular nuclei was quantified histologically by a masked protocol post HIV injection. Results:HIV mediated gene delivery and expression were confirmed by PCR assay. Histological examination demonstrated that average retinal neovascular nuclei per 6-µm section in the eye injected with HIV-angiostatin was reduced in 90 % (9/10; p=0.025) of animals, compared with the eye injected PBS. No response was observed in the eyes injected with HIV-EGFP. Reduction of neovascular nuclei averaged 68 % with the maximal inhibitory effect of 87 %. No apparent inflammatory reaction was observed by light microscopy. Conclusion:This is the first report that HIV mediated stable expression of angiostatin efficiently reduce retinal neovascularization. These data strongly support the feasibility of anti-angiostatic gene therapy of ischemic retinal diseases.

Keywords: 566 retinal neovascularization • 419 gene transfer/gene therapy • 428 hypoxia