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Manas Ranjan Biswal, Howard M Prentice, George W Smith, Ping Zhu, Tong Yao, C Kathleen Dorey, Alfred S Lewin, Janet C Blanks; A Novel Hypoxia-Regulated And Cell -Specific Gene Therapy Elicits Reduced Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3965.
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© ARVO (1962-2015); The Authors (2016-present)
To evaluate the prophylactic effectiveness of a novel retinal pigment epithelial cell (RPE) specific, hypoxia-regulated gene therapy in the mouse model of laser-induced choroidal neovascularization (CNV).
An AAV gene therapy vector comprising RPE-specific promoter and HIF-1 response elements (HRE) was designed to regulate production of human endostatin (a powerful angiostatic protein). One eye of C57BL/6J mice was subretinally injected with Regulated-RPE-specific AAV driving endostatin, or with AAV vectors constitutively expressing endostatin or GFP driven by CMV promoter as a positive and vehicle control respectively. Contralateral control eyes were subretinally injected with vehicle; laser photocoagulation induced CNV in all eyes 14 or 90 days later. The areas of CNV present 14 days later were analyzed in images obtained in vivo by spectral domain optical coherence tomography (SD-OCT) and post mortem in RPE flat mounts. Exogenous endostatin expression in RPE/choroid was assayed by quantitative RT-PCR on day 3, 7, 14, and 45 days after laser photocoagulation.
Exogenous endostatin expression by the regulated vector was significantly elevated 3, 7 and 14 days following laser treatment and expression was completely off by 45 days. In both SD-OCT and confocal images of RPE flat mounts, CNV areas were 80% smaller in regulated vector eyes than in untreated control eyes (P<0.001). This inhibition of CNV was comparable to that in eyes treated with the unregulated vector constitutively expressing endostatin, emphasizing that focal delivery of endostatin is sufficient to suppress CNV.
These findings support the possibility of reducing development of CNV by prophylactic treatment with RPE-specific, hypoxia-regulated gene therapy delivery of anti-angiogenic agents at the moment and at the site where CNV arises. This approach would avoid any harmful effect of continuous exposure to anti-angiogenic agents.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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