title: High-efficiency transduction of the mouse retina by tyrosine-mutant AAV serotype vectors.
abstract: Vectors derived from adeno-associated viruses (AAVs) have become important gene delivery tools for the treatment of many inherited ocular diseases in well-characterized animal models. Previous studies have determined that the viral capsid plays an essential role in the cellular tropism and efficiency of transgene expression. Recently, it was shown that phosphorylation of surface-exposed tyrosine residues from AAV2 capsid targets the viral particles for ubiquitination and proteasome- mediated degradation, and mutations of these tyrosine residues lead to highly efficient vector transduction in vitro and in vivo. Because the tyrosine residues are highly conserved in other AAV serotypes, in this study we evaluated the intraocular transduction characteristics of vectors containing point mutations in surface- exposed capsid tyrosine residues in AAV serotypes 2, 8, and 9. Several of these novel AAV mutants were found to display a strong and widespread transgene expression in many retinal cells after subretinal or intravitreal delivery compared with their wild-type counterparts. For the first time, we show efficient transduction of the ganglion cell layer by AAV serotype 8 or 9 mutant vectors, thus providing additional tools besides AAV2 for targeting these cells. These enhanced AAV vectors have a great potential for future therapeutic applications for retinal degenerations and ocular neovascular diseases.
authors.affiliation: Department of Ophthalmology, University of Florida, Gainesville, Florida 32610-0284, USA. hildasilva@ufl.edu
authors.forename: Hilda
authors.initials: H
authors.lastname: Petrs-Silva
authors.forename: Astra
authors.initials: A
authors.lastname: Dinculescu
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Li
authors.forename: Seok-Hong
authors.initials: SH
authors.lastname: Min
authors.forename: Vince
authors.initials: V
authors.lastname: Chiodo
authors.forename: Ji-Jing
authors.initials: JJ
authors.lastname: Pang
authors.forename: Li
authors.initials: L
authors.lastname: Zhong
authors.forename: Sergei
authors.initials: S
authors.lastname: Zolotukhin
authors.forename: Arun
authors.initials: A
authors.lastname: Srivastava
authors.forename: Alfred S
authors.initials: AS
authors.lastname: Lewin
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000145:classification / Q000235:genetics*; D045888:Ganglion Cysts; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D007267:Injections; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D012160:Retina / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics*; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
chemical_list: D014443:Tyrosine