title: AAV2 delivery of Flt23k intraceptors inhibits murine choroidal neovascularization.
abstract: Long-term inhibition of extracellular vascular endothelial growth factor (VEGF) in the treatment of age-related macular degeneration (AMD) may induce retinal neuronal toxicity and risk other side effects. We developed a novel strategy which inhibits retinal pigment epithelium (RPE)-derived VEGF, sparing other highly sensitive retinal tissues. Flt23k, an intraceptor inhibitor of VEGF, was able to inhibit VEGF in vitro. Adeno-associated virus type 2 (AAV2)-mediated expression of Flt23k was maintained for up to 6 months postsubretinal injection in mice. Flt23k was able to effectively inhibit laser-induced murine choroidal neovascularization (CNV). VEGF levels in the RPE/choroid complex decreased significantly in AAV2.Flt23k treated eyes. Neither retinal structure detected by Heidelberg Spectralis nor function measured by electroretinography (ERG) was adversely affected by treatment with AAV2.Flt23k. Hence AAV2.Flt23k can effectively maintain long-term expression and inhibit laser-induced CNV in mice through downregulation of VEGF while maintaining a sound retinal safety profile. These findings suggest a promising novel approach for the treatment of CNV.
authors.affiliation: Moran Eye Center, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Moran Eye Center, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Subrata K
authors.initials: SK
authors.lastname: Das
authors.affiliation: Moran Eye Center, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Passi
authors.affiliation: Moran Eye Center, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Hironori
authors.initials: H
authors.lastname: Uehara
authors.affiliation: Moran Eye Center, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Austin
authors.initials: A
authors.lastname: Bohner
authors.affiliation: Moran Eye Center, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Marcus
authors.initials: M
authors.lastname: Chen
authors.affiliation: Moran Eye Center, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Tiem
authors.affiliation: Moran Eye Center, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Archer
authors.affiliation: Moran Eye Center, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Balamurali K
authors.initials: BK
authors.lastname: Ambati
mesh_terms: D000818:Animals; D017209:Apoptosis; D002829:Choroid / Q000378:metabolism; D020256:Choroidal Neovascularization / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D015870:Gene Expression; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D006801:Humans; D051379:Mice; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*; D011993:Recombinant Fusion Proteins; D012160:Retina / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000378:metabolism; D014161:Transduction, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000737:chemistry / Q000235:genetics*
chemical_list: D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1