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Ji-kui Shen, yuanyuan liu, Seth Daniel Fortmann, Stephen Yoo, Karen Kozarsky, Jiangxia Wang, Peter A Campochiaro; RGX-314, an AAV8 expressing an anti-VEGF protein, strongly suppresses subretinal neovascularization and vascular leakage in mouse models. Invest. Ophthalmol. Vis. Sci. 2017;58(8):199.
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© ARVO (1962-2015); The Authors (2016-present)
To test the efficacy of RGX-314, an AAV serotype 8 expressing an anti-VEGF Fab, in transgenic mouse models expressing human VEGF
Transgenic mice in which the rhodopsin promoter drives expression of VEGF165 in photoreceptors (rho/VEGF mice) had a subretinal injection of RGX-314 with doses ranging from 3x106-1x1010 genome copies (GC), 1x1010 GC of null vector, or PBS in one eye (n=10 per group) at P14. At P21, the area of subretinal neovascularization (SNV) per eye was measured. Double transgenic mice with doxycycline (DOX)-inducible expression of VEGF165 in photoreceptors (Tet/opsin/VEGF mice) had a subretinal injection of 1x108-1x1010 GC of RGX-314 in one eye and no injection in the fellow eye or 1x1010 GC of null vector in one eye and PBS in the fellow eye. Ten days after injection, 2mg/ml of DOX was added to drinking water and after 4 days fundus photos were graded for presence of total, partial, or no retinal detachment (RD). RGX-314 transgene product levels were measured one week after subretinal injection of 1x108-1x1010 GC of RGX-314 in adult mice by ELISA analyses of eye homogenates.
Compared to eyes of rho/VEGF mice injected null vector, those injected with ≥1x107 GC of RGX-314 had significant reduction in mean area of SNV, with modest reduction in eyes injected with ≤3x107 and >50% reduction in eyes injected with ≥1x108 GC. Eyes injected with 3x109 or 1x1010 GC had almost complete elimination of SNV (p<0.01). In Tet/opsin/VEGF mice, compared to the null vector group in which 100% of eyes had total RD, there was significant reduction in exudative RD in eyes injected with ≥3x108 GC of RGX-314 and reduction of total detachments by 70-80% in eyes injected with 3x109 or 1x1010 GC (p<0.01). The majority of eyes injected with ≤1x109 GC of RGX-314 had protein levels below the limit of detection, but all eyes injected with 3x109 or 1x1010 GC had detectable levels with mean level per eye 342.7ng and 286.2ng.
Gene therapy by subretinal injection of RGX-314 caused dose dependent suppression of SNV in rho/VEGF mice with near complete suppression with doses of 3x109 or 1x1010 GC. These same doses showed robust protein product expression and markedly reduced total exudative RD in Tet/opsin/VEGF mice.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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