Dramatic inhibition of retinal and choroidal neovascularization by oral administration of a kinase inhibitor.
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.
Seo
M S
MS
Departments of Ophthalmology and Neuroscience,* The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Kwak
N
N
Ozaki
H
H
Yamada
H
H
Okamoto
N
N
Yamada
E
E
Fabbro
D
D
Hofmann
F
F
Wood
J M
JM
Campochiaro
P A
PA
D000284:Administration, Oral; D000818:Animals; D020256:Choroidal Neovascularization / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D012160:Retina / Q000187:drug effects / Q000254:growth & development; D015861:Retinal Neovascularization / Q000517:prevention & control*; D012171:Retinal Vessels / Q000187:drug effects; D019311:Staurosporine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
D004791:Enzyme Inhibitors; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D019311:Staurosporine; C059539:midostaurin