title: Long-term retinal function and structure rescue using capsid mutant AAV8 vector in the rd10 mouse, a model of recessive retinitis pigmentosa.
abstract: The retinal degeneration 10 (rd10) mouse is a well-characterized model of autosomal recessive retinitis pigmentosa (RP), which carries a spontaneous mutation in the β subunit of rod cGMP-phosphodiesterase (PDEβ). Rd10 mouse exhibits photoreceptor dysfunction and rapid rod photoreceptor degeneration followed by cone degeneration and remodeling of the inner retina. Here, we evaluate whether gene replacement using the fast-acting tyrosine-capsid mutant AAV8 (Y733F) can provide long-term therapy in this model. AAV8 (Y733F)-smCBA-PDEβ was subretinally delivered to postnatal day 14 (P14) rd10 mice in one eye only. Six months after injection, spectral domain optical coherence tomography (SD-OCT), electroretinogram (ERG), optomotor behavior tests, and immunohistochemistry showed that AAV8 (Y733F)-mediated PDEβ expression restored retinal function and visual behavior and preserved retinal structure in treated rd10 eyes for at least 6 months. This is the first demonstration of long-term phenotypic rescue by gene therapy in an animal model of PDEβ-RP. It is also the first example of tyrosine-capsid mutant AAV8 (Y733F)-mediated correction of a retinal phenotype. These results lay the groundwork for the development of PDEβ-RP gene therapy trial and suggest that tyrosine-capsid mutant AAV vectors may be effective for treating other rapidly degenerating models of retinal degeneration.
authors.affiliation: Eye Hospital, School of Ophthalmology & Optometry, Wenzhou Medical College, Wenzhou, Zhejiang, China. jpang@ufl.edu
authors.forename: Ji-jing
authors.initials: JJ
authors.lastname: Pang
authors.forename: Xufeng
authors.initials: X
authors.lastname: Dai
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Boye
authors.forename: Ilaria
authors.initials: I
authors.lastname: Barone
authors.forename: Sanford L
authors.initials: SL
authors.lastname: Boye
authors.forename: Song
authors.initials: S
authors.lastname: Mao
authors.forename: Drew
authors.initials: D
authors.lastname: Everhart
authors.forename: Astra
authors.initials: A
authors.lastname: Dinculescu
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Umino
authors.forename: Bo
authors.initials: B
authors.lastname: Lei
authors.forename: Bo
authors.initials: B
authors.lastname: Chang
authors.forename: Robert
authors.initials: R
authors.lastname: Barlow
authors.forename: Enrica
authors.initials: E
authors.lastname: Strettoi
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002213:Capsid / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D004596:Electroretinography; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000473:pathology / Q000628:therapy*