Vascular targeting of ocular neovascularization with a vascular endothelial growth factor121/gelonin chimeric protein.
Tumors provide an extremely abnormal microenvironment that stimulates neovascularization from surrounding vessels and causes altered gene expression within vascular cells. Up-regulation of vascular endothelial growth factor (VEGF) receptors has allowed selective destruction of tumor vessels by administration of a chimeric protein consisting of VEGF121 coupled to the toxin gelonin (VEGF/rGel). We sought to determine whether there is sufficient up-regulation of VEGF receptors in endothelial cells participating in ocular neovascularization to permit a similar strategy. After intravenous injection of 45 mg/kg VEGF/rGel, but not uncoupled recombinant gelonin (rGel), there was immunofluorescent staining for rGel within choroidal neovascularization in mice and regression of the neovascularization occurred, demonstrating successful vascular targeting via the systemic circulation. Intraocular injection of 5 ng of VEGF/rGel also caused significant regression of choroidal neovascularization and regression of retinal neovascularization in two models, transgenic mice with expression of VEGF in photoreceptors and mice with ischemic retinopathy, whereas injection of 5 ng of rGel had no effect. These data suggest that the strategy of vascular targeting can be applied to nonmalignant neovascular diseases and could serve as the basis of a new treatment to reduce established ocular neovascularization.
Akiyama
Hideo
H
Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA.
Mohamedali
Khalid A
KA
E Silva
Raquel Lima
RL
Kachi
Shu
S
Shen
Jikui
J
Hatara
Christina
C
Umeda
Naoyasu
N
Hackett
Sean F
SF
Aslam
Sadia
S
Krause
Melissa
M
Lai
Hong
H
Rosenblum
Michael G
MG
Campochiaro
Peter A
PA
D000818:Animals; D020256:Choroidal Neovascularization / Q000188:drug therapy*; D004195:Disease Models, Animal; D051379:Mice; D010940:Plant Proteins / Q000494:pharmacology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000187:drug effects / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use; D015861:Retinal Neovascularization / Q000188:drug therapy*; D054789:Ribosome Inactivating Proteins, Type 1; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology* / Q000627:therapeutic use
D010940:Plant Proteins; D011993:Recombinant Fusion Proteins; D054789:Ribosome Inactivating Proteins, Type 1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C025674:GEL protein, Gelonium multiflorum; D040262:Receptors, Vascular Endothelial Growth Factor