Dramatic Inhibition of Retinal and Choroidal Neovascularization by Oral Administration of a Kinase Inhibitor

Abstract

The most common cause of new blindness in young patients is retinal neovascularization , and in the elderly is choroidal neovascularization. Therefore, there has been a great deal of attention focused on the development of new treatments for these disease processes. Previous studies have demonstrated partial inhibition of retinal neovascularization in animal models using antagonists of vascular endothelial growth factor or other signaling molecules implicated in the angiogenesis cascade. These studies have indicated potential for drug treatment , but have left many questions unanswered. Is it possible to completely inhibit retinal neovascularization using drug treatment with a mode of administration that is feasible to use in patients? Do agents that inhibit retinal neovascularization have any effect on choroidal neovascularization? In this study , we demonstrate complete inhibition of retinal neovascularization in mice with oxygen-induced ischemic retinopathy by oral administration of a partially selective kinase inhibitor that blocks several members of the protein kinase C family , along with vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinases. The drug also blocks normal vascularization of the retina during development but has no identifiable adverse effects on mature retinal vessels. In addition, the kinase inhibitor causes dramatic inhibition of choroidal neovascularization in a laser-induced murine model. These data provide proof of concept that pharmacological treatment is a viable approach for therapy of both retinal and choroidal neovascularization. (Am J Pathol 1999, 154:1743-1753)The retina receives its blood supply from two vascular beds: retinal vessels, which supply the inner two-thirds of the retina, and choroidal vessels, which supply the outer one-third. Damage to retinal blood vessels resulting in closure of retinal capillaries and retinal ischemia occurs in several disease processes, including diabetic retinopathy, retinopathy of prematurity, branch retinal vein occlusion, and central retinal vein occlusion; they are collectively referred to as ischemic retinopathies. Retinal ischemia results in release of one or more angiogenic factors that stimulate neovascularization. The new vessels break through the internal limiting membrane that lines the inner surface of the retina and grow along the outer surface of the vitreous. They recruit many other cells and produce sheets of vessels, cells, and extracellular matrix that exert traction on the retina, often leading to retinal detachment and severe loss of vision. Panretinal laser photocoagulation increases oxygenation in the retina and can result in involution of neovascularization. 1 However, despite the effectiveness of laser photocoagulation, 2 diabetic retinopathy remains the most common cause of severe vision loss in patients less than 60 years

Suppression of ocular neovascularization with siRNA targeting VEGF receptor 1

“…[1][2][3][4] These data suggest that the VEGF pathway may be an important therapeutic target and results from clinical trials using an aptamer 5 or an antibody fragment 6 that binds VEGF-A have supported this contention. Blocking VEGF receptors is another strategy for antagonizing VEGF-A that has the potential advantage of blocking multiple VEGF family members at once.…”

Preventive Versus Treatment Effect of Ag3340, a Potent Matrix Metalloproteinase Inhibitor in a Rat Model of Choroidal Neovascularization

“…Therefore, recurrent neovascularization and permanent visual loss occur in the majority of patients who initially have had successful treatment (7).…”

Inducible Expression of Vascular Endothelial Growth Factor in Adult Mice Causes Severe Proliferative Retinopathy and Retinal Detachment

“…9 -13 Somewhat surprisingly (because hypoxia is not known to play a role), VEGF signaling was also found to be necessary for development of choroidal neovascularization in a murine model. 12,14 Although these studies clearly implicated VEGF as a stimulatory factor for ocular neovascularization, other studies showed that in some situations expression of VEGF by itself was insufficient to induce retinal neovascularization. The retinas of patients with nonproliferative diabetic retinopathy or other retinal diseases may show elevated levels of VEGF without retinal neovascularization.…”