title: Adenovirus-mediated delivery of catalase to retinal pigment epithelial cells protects neighboring photoreceptors from photo-oxidative stress.
abstract: Oxidative stress is involved in the pathogenesis of many diseases. Overexpression of antioxidant enzymes by gene therapy may protect tissues from oxidative damage. Because the reactive oxygen species hydrogen peroxide can diffuse across cell membranes, we hypothesized that overexpression of the antioxidant catalase within certain cells might protect neighboring cells. To test this hypothesis, we transduced retinal pigment epithelial (RPE) cells in vitro and in vivo with adenovirus carrying the catalase gene (Ad.CMV.catalase). After transduction of only a subset of RPE cells in vitro, all cells in the culture were protected from exogenous hydrogen peroxide. Similarly, in vivo, eyes injected with Ad. CMV. catalase had high catalase levels in the RPE, which protected the adjacent photoreceptors from light damage and reduced photoreceptor oxidative stress as measured by the markers 4-hydroxynonenal and nitrotyrosine. Both in vitro and in vivo, gene therapy with Ad. CMV. catalase protected neighboring cells from oxidative stress-induced terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) positivity. The data provide a paradigm for antioxidant gene therapy with catalase, designed to protect not only transduced cells, but also neighboring cells.
authors.affiliation: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: T S
authors.initials: TS
authors.lastname: Rex
authors.forename: I
authors.initials: I
authors.lastname: Tsui
authors.forename: P
authors.initials: P
authors.lastname: Hahn
authors.forename: A M
authors.initials: AM
authors.lastname: Maguire
authors.forename: D
authors.initials: D
authors.lastname: Duan
authors.forename: J
authors.initials: J
authors.lastname: Bennett
authors.forename: J L
authors.initials: JL
authors.lastname: Dunaief
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000447:Aldehydes / Q000737:chemistry; D000818:Animals; D002374:Catalase / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000494:pharmacology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008027:Light; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D018384:Oxidative Stress; D010786:Photoreceptor Cells / Q000378:metabolism*; D010857:Pigment Epithelium of Eye / Q000378:metabolism*; D012160:Retina / Q000378:metabolism
chemical_list: D000447:Aldehydes; D006861:Hydrogen Peroxide; D002374:Catalase; C027576:4-hydroxy-2-nonenal