Choroidal neovascularization (CNV) represents the most common cause of severe vision loss in patients with age-related macular degeneration (AMD). It is also the most common cause of legal blindness in the United States in patients over the age of 60. Therefore, the study of the diagnosis, prevention and treatment of this condition would have a major impact on the public health. The laboratory has been studying a clinically relevant model of CNV associated with AMD using an adenovirus overexpression system. Based on evidence that vascular endothelial growth factor (VEGF) is upregulated in eyes with CNV associated with AMD, we have successfully reproduced this finding by overexpressing VEGF in the retinal pigment epithelium through the use of subretinal delivery of an E-1deleted adenoviral vector encoding VEGF. Animals receiving this vector develop CNV in 2 to 4 weeks with a histologic appearance similar to that seen in humans. The phenotype includes penetration of choroidal neovascularization through Bruch's membrane with sparing of the inner retinal structures. Work has begun on utilizing this model to study the pathogenesis of the condition and to screen for possible treatments. A recent novel finding in human CNV in patients with AMD has been the identification of intrachoroidal new vessel formation. Corroborating this finding has been the discovery that in this animal model of CNV, prominent choroidal changes are noted including intrachoroidal cellular infiltration and the development of intrachoroidal neovascularization. Experiments are presently underway to understand the cellular components of this infiltrate and the relationship of this process to the development of new vessels in the choroid. Additionally, work has also progressed on screening treatment strategies for CNV using this model. 2-methoxyestradiol, a potent anti-angiogenic and antiproliferative agent, delivered through a sustained novel rat intravitreal device, has been shown to prevent the development of CNV in these animals. In addition, the drug appears to be safe with absence of detectable retinal toxicity as measured by histology and electroretinography in rabbits. These results indicate that this treatment approach may have a clinical application and experiments are continuing to confirm and extend these results with t he goal of initiating a Phase I clinical trial in patients with CNVM associated with AMD.
