Regression of ocular neovascularization in response to increased expression of pigment epithelium-derived factor.
OBJECTIVE
Several pharmacologic treatments have been shown to reduce ocular neovascularization when administered before the onset of angiogenic stimuli, but none have been shown to cause regression of already established ocular neovascularization. In this study, the authors tested the effect of adenoviral vectored pigment epithelium-derived factor (PEDF) gene transfer on established neovascularization in transgenic mice with expression of vascular endothelial growth factor (VEGF) in photoreceptors (rho/VEGF mice) and in a model of choroidal neovascularization.


METHODS
Two weeks after the onset of VEGF transgene expression in rho/VEGF mice or 2 weeks after laser-induced rupture of Bruch's membrane in wild-type mice, subgroups of mice were killed, and the baseline amount of neovascularization was measured by image analysis. The remainder of the mice received an intravitreous or subretinal injection of adenoviral vector containing a PEDF expression construct (AdPEDF.11) or control vector (AdNull.11).


RESULTS
Seven days after injection in rho/VEGF mice or 10 days after injection in the choroidal neovascularization model, the amount of neovascularization in AdPEDF.11-injected eyes was significantly less than the baseline level, indicating that regression of neovascularization had occurred. There was TUNEL staining within choroidal neovascular lesions in eyes injected with AdPEDF.11. Eyes given a subretinal injection of AdNull.11 had TUNEL-positive cells in the retina, but none within areas of choroidal neovascularization.


CONCLUSIONS
These data indicate that increased expression of PEDF causes regression of ocular neovascularization by promoting apoptosis of cells within neovascular lesions and possibly represents a new treatment paradigm for patients with established ocular neovascularization.
Mori
Keisuke
K
Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA.
Gehlbach
Peter
P
Ando
Akira
A
McVey
Duncan
D
Wei
Lisa
L
Campochiaro
Peter A
PA
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D020256:Choroidal Neovascularization / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D020287:In Situ Nick-End Labeling; D053685:Laser Therapy; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D009414:Nerve Growth Factors; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012243:Rhodopsin / Q000378:metabolism; D015843:Serpins / Q000235:genetics* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099174:Pigment Epithelium-Derived Factor
D016228:Endothelial Growth Factors; D005136:Eye Proteins; D008222:Lymphokines; D009414:Nerve Growth Factors; D011506:Proteins; D012243:Rhodopsin; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099174:Pigment Epithelium-Derived Factor