title: Subretinal AAV2.COMP-Ang1 suppresses choroidal neovascularization and vascular endothelial growth factor in a murine model of age-related macular degeneration.
abstract: To assess whether Tie2-mediated vascular stabilization ameliorates neovascular age-related macular degeneration (AMD), we investigated the impact of adeno-associated virus-mediated gene therapy with cartilage oligomeric matrix protein angiopoietin-1 (AAV2.COMP-Ang1) on choroidal neovascularization (CNV), vascular endothelial growth factor (VEGF), and hypoxia-inducible factor (HIF) in a mouse model of the disease. We treated mice with subretinal injections of AAV2.COMP-Ang1 or control (AAV2.AcGFP, AAV2.LacZ, and phosphate-buffered saline). Subretinal AAV2 localization and plasmid protein expression was verified in the retinal pigment epithelium (RPE)/choroid of mice treated with all AAV2 constructs. Laser-assisted simulation of neovascular AMD was performed and followed by quantification of HIF, VEGF, and CNV in each experimental group. We found that AAV2.COMP-Ang1 was associated with a significant reduction in VEGF levels (29-33%, p < 0.01) and CNV volume (60-70%, p < 0.01), without a concomitant decrease in HIF1-α, compared to all controls. We concluded that a) AAV2 is a viable vector for delivering COMP-Ang1 to subretinal tissues, b) subretinal COMP-Ang1 holds promise as a prospective treatment for neovascular AMD, and c) although VEGF suppression in the RPE/choroid may be one mechanism by which AAV2.COMP-Ang1 reduces CNV, this therapeutic effect may be hypoxia-independent. Taken together, these findings suggest that AAV2.COMP-Ang1 has potential to serve as an alternative or complementary option to anti-VEGF agents for the long-term amelioration of neovascular AMD.
authors.affiliation: Ambati Lab, John A. Moran Eye Center, Salt Lake City, UT, USA.
authors.forename: Nathan G
authors.initials: NG
authors.lastname: Lambert
authors.affiliation: Ambati Lab, John A. Moran Eye Center, Salt Lake City, UT, USA; Department of Ophthalmology & Visual Sciences, University of Utah, Salt Lake City, UT, USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Ambati Lab, John A. Moran Eye Center, Salt Lake City, UT, USA; Department of Ophthalmology & Visual Sciences, University of Utah, Salt Lake City, UT, USA.
authors.forename: Ruju R
authors.initials: RR
authors.lastname: Rai
authors.affiliation: Ambati Lab, John A. Moran Eye Center, Salt Lake City, UT, USA; Department of Ophthalmology & Visual Sciences, University of Utah, Salt Lake City, UT, USA.
authors.forename: Hironori
authors.initials: H
authors.lastname: Uehara
authors.affiliation: Ambati Lab, John A. Moran Eye Center, Salt Lake City, UT, USA; Department of Ophthalmology & Visual Sciences, University of Utah, Salt Lake City, UT, USA.
authors.forename: Susie
authors.initials: S
authors.lastname: Choi
authors.affiliation: Ambati Lab, John A. Moran Eye Center, Salt Lake City, UT, USA; Department of Ophthalmology & Visual Sciences, University of Utah, Salt Lake City, UT, USA.
authors.forename: Lara S
authors.initials: LS
authors.lastname: Carroll
authors.affiliation: Ambati Lab, John A. Moran Eye Center, Salt Lake City, UT, USA; Department of Ophthalmology & Visual Sciences, University of Utah, Salt Lake City, UT, USA.
authors.forename: Subrata K
authors.initials: SK
authors.lastname: Das
authors.affiliation: Ambati Lab, John A. Moran Eye Center, Salt Lake City, UT, USA.
authors.forename: Judd M
authors.initials: JM
authors.lastname: Cahoon
authors.affiliation: Ambati Lab, John A. Moran Eye Center, Salt Lake City, UT, USA.
authors.forename: Brian H
authors.initials: BH
authors.lastname: Kirk
authors.affiliation: Ambati Lab, John A. Moran Eye Center, Salt Lake City, UT, USA.
authors.forename: Blaine M
authors.initials: BM
authors.lastname: Bentley
authors.affiliation: Ambati Lab, John A. Moran Eye Center, Salt Lake City, UT, USA; Department of Ophthalmology & Visual Sciences, University of Utah, Salt Lake City, UT, USA. Electronic address: bala.ambati@utah.edu.
authors.forename: Balamurali K
authors.initials: BK
authors.lastname: Ambati
mesh_terms: D042683:Angiopoietin-1 / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D064236:Cartilage Oligomeric Matrix Protein / Q000378:metabolism / Q000627:therapeutic use*; D020256:Choroidal Neovascularization / Q000378:metabolism / Q000628:therapy*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D008268:Macular Degeneration / Q000378:metabolism / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055213:Retinal Pigment Epithelium / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D042683:Angiopoietin-1; D064236:Cartilage Oligomeric Matrix Protein; D051793:Hypoxia-Inducible Factor 1; D042461:Vascular Endothelial Growth Factor A; C577553:TSP5 protein, human
keywords: Adeno-associated virus; Age-related macular degeneration; Angiopoietin-1; Cartilage oligomeric matrix protein; Choroidal neovascularization; Subretinal injection; Vascular endothelial growth factor