An antisense oligodeoxynucleotide against vascular endothelial growth factor in a nonhuman primate model of iris neovascularization.
OBJECTIVE
To evaluate an antisense oligodeoxynucleotide (AS-ODN) targeted against vascular endothelial growth factor for its effects on ocular angiogenesis and its intraocular localization in a nonhuman primate model of iris neovascularization.


METHODS
Bilateral laser retinal vein occlusion was performed in monkeys, followed by intravitreal injections of a vascular endothelial growth factor-specific AS-ODN or control. Serial fluorescein angiograms were graded in a masked manner to measure iris neovascularization. Localization was determined using a fluorescent-labeled AS-ODN and confocal microscopy on fixed tissue.


RESULTS
Intravitreally injected vascular endothelial growth factor-specific AS-ODN localized to the retina, in the ganglion cell layer, inner nuclear layer, outer plexiform layer, photoreceptor outer segments, and retinal pigment epithelium. In 8 animals tested with 3microM ODN, AS-ODN-treated eyes had a significant reduction in iris neovascularization compared with control fellow eyes (P = .006, MIXOR analysis). Overall, in 17 animals tested across a range of ODN concentrations (0.1-50.0microM), AS-ODN-treated eyes were more likely to have lower iris neovascularization grades (P = .006, McNemar test) and the absence of iris neovascularization (P< .001, mixed-effects logistic regression model).


CONCLUSIONS
Antisense ODNs that target vascular endothelial growth factor delivered to the retina via intravitreal injection reduced iris neovascularization in this model. Clinical Relevance Antisense ODNs against vascular endothelial growth factor may have therapeutic potential for neovascular eye diseases.
Bhisitkul
Robert B
RB
Department of Ophthalmology, Beckman Vision Center, University of California San Francisco, 94143, USA. bhisit@itsa.ucsf.edu
Robinson
Gregory S
GS
Moulton
Rachel S
RS
Claffey
Kevin P
KP
Gragoudas
Evangelos S
ES
Miller
Joan W
JW
D000818:Animals; D004195:Disease Models, Animal; D005451:Fluorescein Angiography; D016650:Fluorescein-5-isothiocyanate; D015316:Genetic Therapy; D007267:Injections; D007498:Iris / Q000098:blood supply*; D008252:Macaca fascicularis; D018613:Microscopy, Confocal; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D020319:Oligodeoxyribonucleotides, Antisense / Q000378:metabolism / Q000627:therapeutic use*; D012160:Retina / Q000378:metabolism; D012170:Retinal Vein Occlusion / Q000150:complications; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014822:Vitreous Body / Q000187:drug effects
D020319:Oligodeoxyribonucleotides, Antisense; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016650:Fluorescein-5-isothiocyanate