title: Two animal models of retinal degeneration are rescued by recombinant adeno-associated virus-mediated production of FGF-5 and FGF-18.
abstract: The goal of these experiments was to evaluate the potential of the fibroblast growth factor family members FGF-5 and FGF-18 to rescue photoreceptors from cell death in retinal degenerative disease. Two strains of transgenic rats, expressing either a P23H or an S334ter rhodopsin mutation, were used as model systems. The neurotrophic growth factors were delivered by subretinal injection of adeno-associated virus vectors, driving expression of the genes with a constitutive CMV promoter. Morphological and functional analyses were performed to determine whether FGF-5 or FGF-18 overexpression could ameliorate cell death in the retina. Immunocytochemistry was used to determine the cellular sites of expression of the factors and to test for up-regulation of FGF receptors due to injection. Significant rescue from photoreceptor cell death was found after injections of vectors expressing either FGF-5 or FGF-18 in the animal models. Increased survival of photoreceptors did not produce a significant increase in electroretinographic responses, however, reflecting either trauma due to the surgery or a suppression of signaling due to expression of proteins. Three weeks after injections, both growth factors were localized to the inner and outer segments of photoreceptors, and the receptors FGFR1 and FGFR2 were also found to be up-regulated in these regions. No visible pathological changes were seen in the FGF-5- or FGF-18-treated eyes. These results indicate that the delivery of either FGF-5 or FGF-18 with adeno-associated virus protects photoreceptors from apoptosis in transgenic rat models of retinitis pigmentosa and that the rescue is probably mediated by conventional receptor tyrosine kinase pathways in photoreceptors.
authors.affiliation: Department of Molecular and Cell Biology, University of California at Berkeley, 94720, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Green
authors.forename: K G
authors.initials: KG
authors.lastname: Rendahl
authors.forename: S
authors.initials: S
authors.lastname: Zhou
authors.forename: M
authors.initials: M
authors.lastname: Ladner
authors.forename: M
authors.initials: M
authors.lastname: Coyne
authors.forename: R
authors.initials: R
authors.lastname: Srivastava
authors.forename: W C
authors.initials: WC
authors.lastname: Manning
authors.forename: J G
authors.initials: JG
authors.lastname: Flannery
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival; D003587:Cytomegalovirus / Q000235:genetics; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D004596:Electroretinography; D051521:Fibroblast Growth Factor 5; D005346:Fibroblast Growth Factors / Q000235:genetics*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008957:Models, Genetic; D010957:Plasmids / Q000378:metabolism; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000096:biosynthesis / Q000235:genetics; D012160:Retina / Q000378:metabolism / Q000473:pathology; D012162:Retinal Degeneration / Q000628:therapy*; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000628:therapy*; D012243:Rhodopsin / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection; D015854:Up-Regulation
chemical_list: C496449:FGF5 protein, human; C496451:Fgf5 protein, rat; D017468:Receptors, Fibroblast Growth Factor; C113569:fibroblast growth factor 18; D051521:Fibroblast Growth Factor 5; D005346:Fibroblast Growth Factors; D012243:Rhodopsin; C496348:FGFR1 protein, human; C496353:FGFR2 protein, human; C496350:Fgfr1 protein, rat; C496356:Fgfr2 protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2