Choroidal Neovascularization - Why does it Grow? New Insights into Angiogenetic Mechanisms and Therapeutic Perspectives

Schlingemann R. O.,
Academic Medical Centre, Department of Ophthalmology, Ocular Angiogenesis Group (Amsterdam)

Purpose: To review the experimental and clinical data providing the rationale for medical inhibition angiogenesis as a therapy for choroidal neovascularization (CNV) in age-related macular degeneration (AMD).
Results: Based on findings in cultured cells, human eyes, and experimental models of over-expression of vascular endothelial growth factor-A (VEGF) in the RPE by viral transfection, we propose the following tentative pathogenesis of CNV in AMD: in physiological conditions, the retinal pigment epithelium (RPE) secretes VEGF towards the choriocapillaris in a paracrine survival relation, modulated by a feedback mechanism driven by changes in tissue oxygen levels. In ageing, the diffusion barrier formed by a thickened, lipid laden Bruch's membrane leads to failure of this feedback mechanism with subsequent choriocapillaris atrophy, increasing local hypoxia and as a result increasing VEGF production by the RPE. Accumulation of VEGF along Bruch’s membrane eventually stimulates formation of CNV. Based on this model, VEGF is an attractive target for therapy. Observations that VEGF is elevated in the vitreous of patients with CNV and inhibition of CNV by an anti-VEGF antibody in a monkey laser model support this notion. Phase I studies of repeated intra-vitreal injections VEGF inhibitors show favourable short-term results with a 3-line improvement in approximately 25% of patients. These two experimental drugs are now in phase II-III clinical trials.

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