Subretinal AAV2.COMP-Ang1 suppresses choroidal neovascularization and vascular endothelial growth factor in a murine model of age-related macular degeneration.

Autor: Lambert NG; Ambati Lab, John A. Moran Eye Center, Salt Lake City, UT, USA., Zhang X; 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., Rai RR; 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., Uehara H; 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., Choi S; 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., Carroll LS; 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., Das SK; 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., Cahoon JM; Ambati Lab, John A. Moran Eye Center, Salt Lake City, UT, USA., Kirk BH; Ambati Lab, John A. Moran Eye Center, Salt Lake City, UT, USA., Bentley BM; Ambati Lab, John A. Moran Eye Center, Salt Lake City, UT, USA., Ambati BK; 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.
Jazyk: angličtina
Zdroj: Experimental eye research [Exp Eye Res] 2016 Apr; Vol. 145, pp. 248-257. Date of Electronic Publication: 2016 Jan 13.
DOI: 10.1016/j.exer.2016.01.009
Abstrakt: 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.
(Copyright © 2016 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: