title: AAV-mediated cone rescue in a naturally occurring mouse model of CNGA3-achromatopsia.
abstract: Achromatopsia is a rare autosomal recessive disorder which shows color blindness, severely impaired visual acuity, and extreme sensitivity to bright light. Mutations in the alpha subunits of the cone cyclic nucleotide-gated channels (CNGA3) are responsible for about 1/4 of achromatopsia in the U.S. and Europe. Here, we test whether gene replacement therapy using an AAV5 vector could restore cone-mediated function and arrest cone degeneration in the cpfl5 mouse, a naturally occurring mouse model of achromatopsia with a CNGA3 mutation. We show that gene therapy leads to significant rescue of cone-mediated ERGs, normal visual acuities and contrast sensitivities. Normal expression and outer segment localization of both M- and S-opsins were maintained in treated retinas. The therapeutic effect of treatment lasted for at least 5 months post-injection. This study is the first demonstration of substantial, relatively long-term restoration of cone-mediated light responsiveness and visual behavior in a naturally occurring mouse model of CNGA3 achromatopsia. The results provide the foundation for development of an AAV5-based gene therapy trial for human CNGA3 achromatopsia.
authors.affiliation: Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, United States of America. jpang@ufl.edu
authors.forename: Ji-jing
authors.initials: JJ
authors.lastname: Pang
authors.forename: Wen-Tao
authors.initials: WT
authors.lastname: Deng
authors.forename: Xufeng
authors.initials: X
authors.lastname: Dai
authors.forename: Bo
authors.initials: B
authors.lastname: Lei
authors.forename: Drew
authors.initials: D
authors.lastname: Everhart
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Umino
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Keqing
authors.initials: K
authors.lastname: Zhang
authors.forename: Song
authors.initials: S
authors.lastname: Mao
authors.forename: Sanford L
authors.initials: SL
authors.lastname: Boye
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Vince A
authors.initials: VA
authors.lastname: Chiodo
authors.forename: Xuan
authors.initials: X
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: Ye
authors.initials: Y
authors.lastname: Tao
authors.forename: Bo
authors.initials: B
authors.lastname: Chang
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
mesh_terms: D000818:Animals; D003117:Color Vision Defects / Q000235:genetics* / Q000628:therapy*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics* / Q000378:metabolism; D000229:Dependovirus; D004195:Disease Models, Animal; D004596:Electroretinography; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D009154:Mutation; D055355:Opsins / Q000235:genetics / Q000378:metabolism; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism / Q000473:pathology
chemical_list: C518237:Cnga3 protein, mouse; D054815:Cyclic Nucleotide-Gated Cation Channels; D055355:Opsins