title: Intravitreal injection of vascular endothelial growth factor small interfering RNA inhibits growth and leakage in a nonhuman primate, laser-induced model of choroidal neovascularization.
abstract: OBJECTIVE
  To determine the safety and efficacy of small interfering RNA (siRNA) directed against vascular endothelial growth factor (VEGF) in a nonhuman primate model of laser-induced choroidal neovascularization (CNV).
  
  
  METHODS
  Each animal received laser rupture of Bruch's membrane to induce CNV in both eyes. Each animal was then randomized to receive 0.05 mL of either vehicle alone or VEGF siRNA at 70 microg, 150 microg, or 350 microg in both eyes by intravitreal injection. Eyes were monitored weekly by ophthalmic examination, color photography, and fluorescein angiography for 36 days after laser injury. Electroretinograms were measured at baseline and at 5 weeks after laser. CNV on fluorescein angiograms were measured for area and graded for clinically significant leakage in a standardized, randomized, and double-masked fashion on days 15, 22, 29, and 36 after laser.
  
  
  RESULTS
  VEGF siRNA did not cause any change in electroretinographic, hemorrhage, inflammation, or clinical signs of toxicity. A single administration of VEGF siRNA significantly inhibited growth of CNV and attenuated angiographic leakage in a dose-dependent manner.
  
  
  CONCLUSIONS
  Intravitreal injection of VEGF siRNA is capable of inhibiting the growth and vascular permeability of laser-induced CNV in a nonhuman primate in a dose-dependent manner. This study demonstrates preclinical proof of a principle that supports proceeding to clinical studies of VEGF siRNA in patients with exudative age-related macular degeneration.
authors.affiliation: Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, 51 North 39th Street, Philadelphia, PA 19104, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Tolentino
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Brucker
authors.forename: Joshua
authors.initials: J
authors.lastname: Fosnot
authors.forename: Gui-Shuang
authors.initials: GS
authors.lastname: Ying
authors.forename: I-Hui
authors.initials: IH
authors.lastname: Wu
authors.forename: Gulraiz
authors.initials: G
authors.lastname: Malik
authors.forename: Shanhong
authors.initials: S
authors.lastname: Wan
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Reich
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002829:Choroid / Q000098:blood supply / Q000473:pathology; D020256:Choroidal Neovascularization / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004596:Electroretinography; D005451:Fluorescein Angiography; D020868:Gene Silencing / Q000187:drug effects*; D018390:Gene Targeting; D007267:Injections; D007834:Lasers; D008252:Macaca fascicularis; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D011897:Random Allocation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism; D014822:Vitreous Body
chemical_list: D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A