Anti-angiogenic therapy of exudative age-related macular degeneration: current progress and emerging concepts

Abstract

Age-related macular degeneration (AMD) is the leading cause of blindness in elderly patients. The more aggressive exudative form is characterized by abnormal bloodvessel development that occurs beneath the retina as a result of choroidal neovascularization (CNV). Vascular endothelial growth factor (VEGF) has emerged as the key mediator of CNV formation; this has led to intensive research on VEGF and the recent approval of anti-VEGF compounds by the US Food and Drug Administration. Despite this successful introduction of anti-angiogenic therapies into the clinical setting, there is still a lack of treatments that definitively reverse damaged vision. Here, we consider the importance of putative molecular targets other than VEGF that might have been underestimated. Emerging cellular mechanisms offer additional opportunities for innovative therapeutic approaches. GlossaryBruch's membrane: specialized basement membrane that separates the choroid from retinal pigmented epithelial cells. Choroid: a thin vascular layer between the sclera and the retina that supplies oxygen and nutrients to the retinal pigment epithelium and the photoreceptors. Endothelial cells: cells that line the inner lumen of blood vessels. Extracellular matrix: a three-dimensional network of macromolecules that form a structural scaffold and a signaling environment for cells. Matrix metalloproteinases (MMPs): a large family of proteolytic enzymes that degrade extracellular-matrix components and control the activity of important mediators of cell functions. Retinal pigment epithelium (RPE): a monolayer of cells that are specialized to serve the adjacent photoreceptors. Vascular endothelial growth factors (VEGFs): a family of powerful angiogenic proteins that control growth survival and the migration of endothelial cells. Age-related macular degenerationAge-related macular degeneration (AMD) is a leading cause of vision loss in the western world among people aged 50 or older [1]. Ninety per-cent of all vision loss due to AMD results from the exudative form, which is characterized by choroidal neovascularization (CNV), defined as newly formed blood vessels arising from choriocapillaries. The choroid is the vascular layer lying between the retina and the sclera. Exudation of fluid and hemorrhage into the sub-retinal space from hyperpermeable capillaries lead to retinal local detachment and retinal photoreceptor damage, which, in turn, lead to the formation of a disciform scar. The earliest clinically detectable abnormality in AMD, however, is not the consequence of pathological angiogenesis but is the accumulation of abnormal lipopro-teinaceous deposits ('drusen') in the extracellular matrix between the retinal pigment epithelium (RPE) and Bruch's membrane [2].Etiological research suggests that AMD is a complex disease caused by interactions of multiple gene products and environmental factors. Familial aggregation studies, twin studies and segregation analyses have provided strong evidence for AMD heritability [2]. Among several disease-causi...

Laser-induced choroidal neovascularization model to study age-related macular degeneration in mice

“…This achievement, based on the use of the laser-induced CNV assay, has validated angiogenesis as an important target for AMD treatment 6 . Transgenic mouse technologies have since allowed rapid expansion in the exploration of key regulators of CNV, leading to the identification of other important VEGF family members, such as placental growth factor (PlGF) 23,24 and proteases 19,[25][26][27][28] .…”

“…In this model, inflammatory cells are thought to be potent initiators of the angiogenic process partly through their capacity to release a series of pro-angiogenic factors 6 . Both neutrophil and macrophage depletion reduce CNV formation [14][15][16] .…”

“…Experimental animal models rapidly became essential for elucidating the cellular and molecular mechanisms involved in CNV pathogenesis and for the screening of new drugs. Indeed, no in vitro model developed to date recapitulates the complex CNV-associated processes that involve, at a minimum, several cell types, such as inflammatory cells, endothelial cells, pericytes, bone marrow (BM)-derived cells, myofibroblasts and glial cells 5,6 . The in vivo exploration of CNV currently involves several murine models exhibiting the spontaneous development of CNV resulting from a defective complement-activating pathway, deletion in a chemokine/chemokine receptor, oxidative damage or aging 7 .…”

The role of epigenetics in age-related macular degeneration

“…To evaluate the impact of miR-21 in vivo in pathologic angiogenesis, they used a laser-induced murine model of CNV, which mimics AMD pathology. 75 Intravitreal injection of premiR-21 or the control molecule was performed just after laser burns. Seven days after Bruch's membrane rupture at four locations, the mice were injected with fluoresceinlabeled dextran and the eyes were removed and mounted for microscopic analysis.…”

Monocyte/macrophages promote vasculogenesis in choroidal neovascularization in mice by stimulating SDF-1 expression in RPE cells

“…CNV causes 90% of all vision loss in age-related macular degeneration (AMD), which is the most common cause of blindness in the elderly in developed countries [1,2]. As life expectancy increases and the global population ages, CNV, especially secondary to AMD, is increasing as a socio-medical problem.…”