Intraocular Adenoviral Vector-Mediated Gene Transfer in Proliferative Retinopathies

• Published in: Investigative ophthalmology & visual science Vol. 43; no. 5; pp. 1610 - 1615
• Main Authors: Mori, Keisuke, Gehlbach, Peter, Ando, Akira, Wahlin, Karl, Gunther, Vicky, McVey, Duncan, Wei, Lisa, Campochiaro, Peter A
• Format: Journal Article
• Language: English
• Published: Rockville, MD ARVO 01.05.2002; Association for Research in Vision and Ophtalmology
• Subjects: Adenoviridae - genetics; Animals; Biological and medical sciences; Eye; Gene Expression; Gene Transfer Techniques; Genes, Reporter - genetics; Genetic Vectors; Injections; Lac Operon - genetics; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Animal; Pharmacology. Drug treatments; Pigment Epithelium of Eye - metabolism; Pigment Epithelium of Eye - pathology; Platelet-Derived Growth Factor - genetics; Retina - metabolism; Retina - pathology; Retinal Diseases - genetics; Retinal Diseases - metabolism; Retinal Diseases - pathology; Vitreous Body; Retinopathy; Adenoviridae; Intraocular; Rodentia; Proliferative vitreoretinopathy; Genetic transfer; Vitreous body disease; Virus; Eye disease; Vertebrata; Mammalia; Treatment; Gene; Mouse; Animal; Gene therapy; Vector
• ISSN: 0146-0404; 1552-5783

The purpose of this study was to compare levels and patterns of expression of reporter genes achieved with an E1-deleted and partially E3-deleted type 5 adenoviral (Ad) vector after intravitreous or subretinal injections, or after intravitreous injections in mouse eyes with proliferative retinopathies. Ad vectors containing reporter gene constructs were injected into the vitreous cavity or subretinal space of wild-type mice or mice with proliferative retinopathies, and quantitative comparisons were made of expression of transgenes. In normal eyes, peak Ad-mediated expression of luciferase, driven by a cytomegalovirus (CMV) promoter, occurred after injection of 10(7) to 10(8) viral particles and was 10 times greater after subretinal injections than after intravitreous injections. Intravitreous injections of Ad containing beta-galactosidase (LacZ) expression constructs (AdLacZ.10) resulted in strong expression of LacZ in epithelial cells of the iris and ciliary body and focal expression in the retina. Subretinal injections of AdLacZ.10 resulted in strong expression in RPE cells. Expression of LacZ after intravitreous injection of AdLacZ.10 was significantly greater in mice with two types of proliferative retinopathy (ischemic retinopathy or transgenic mice with retina-specific expression of platelet-derived growth factor (PDGF)-BB or PDGF-AB) than littermate control animals. Cells within epiretinal membranes and activated Müller cells were preferentially transduced in eyes with proliferative retinopathy. These data suggest that although higher intraocular expression levels can be achieved after subretinal injection of adenoviral vectors, intravitreous injections provide good transduction of cells lining the vitreous cavity. Compared with normal eyes, eyes with proliferative retinopathy showed increased transduction, which occurred preferentially in cells participating in the disease process. Intravitreous injection of adenoviral vectors containing appropriate expression constructs may provide a good strategy for acute treatment of proliferative retinopathies, such as diabetic retinopathy and proliferative vitreoretinopathy.