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AAV-Mediated Expression of Vascular Endothelial Growth Factor Induces Choroidal Neovascularization in Rat

¹From the School of Optometry and Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California; and the ²Gene Therapy Group, Chiron Corporation, Emeryville, California.

PURPOSE. To develop a small-animal model of choroidal neovascularization (CNV) by injecting adeno-associated virus (AAV)-VEGF into the subretinal space (SRS) of rats.

METHODS. An adeno-associated viral vector encoding human VEGF₁₆₅ was injected into the subretinal space (SRS) of Sprague-Dawley or Long Evans rats. Expression of VEGF was identified by RT-PCR and immunohistochemistry. Physiological and pathologic changes in the retina and choroid were evaluated by electroretinography, fluorescein angiography, light microscopy, and three-dimensional reconstruction of serial sections.

RESULTS. Green fluorescent protein (GFP) and VEGF were expressed for at least 20 months in the retina and retinal pigment epithelium (RPE). Histologic sections showed extensive subretinal neovascularization, degenerating photoreceptors, and proliferating RPE at 5 weeks to 20 months after injection of AAV-VEGF. At 2 to 12 months after injection, leaking blood vessels were detected by fluorescein angiography. Electroretinogram a- and b-wave amplitudes were significantly decreased during this time. Three-dimensional reconstruction of serial sections demonstrated that choroidal blood vessels penetrated Bruch’s membrane, one of them splitting into three branches in the SRS. In the current model, CNV was produced in 95% of the animals tested (19/20). It persisted for more than 20 months, a necessary requirement for modeling the development of CNV in age-related macular degeneration (AMD).

CONCLUSIONS. In this study, a highly reproducible animal model of long-lasting CNV was developed. This model is being used to test antiangiogenic molecules to reduce or inhibit CNV and could be extended to primates.

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