title: Vitreal delivery of AAV vectored Cnga3 restores cone function in CNGA3-/-/Nrl-/- mice, an all-cone model of CNGA3 achromatopsia.
abstract: The CNGA3(-/-)/Nrl(-/-) mouse is a cone-dominant model with Cnga3 channel deficiency, which partially mimics the all cone foveal structure of human achromatopsia 2 with CNGA3 mutations. Although subretinal (SR) AAV vector administration can transfect retinal cells efficiently, the injection-induced retinal detachment can cause retinal damage, particularly when SR vector bleb includes the fovea. We therefore explored whether cone function-structure could be rescued in CNGA3(-/-)/Nrl(-/-) mice by intravitreal (IVit) delivery of tyrosine to phenylalanine (Y-F) capsid mutant AAV8. We find that AAV-mediated CNGA3 expression can restore cone function and rescue structure following IVit delivery of AAV8 (Y447, 733F) vector. Rescue was assessed by restoration of the cone-mediated electroretinogram (ERG), optomotor responses, and cone opsin immunohistochemistry. Demonstration of gene therapy in a cone-dominant mouse model by IVit delivery provides a potential alternative vector delivery mode for safely transducing foveal cones in achromatopsia patients and in other human retinal diseases affecting foveal function.
authors: Deparment of Ophthalmology, University of Florida, Gainesville, FL 32610, USA.
authors: Wei
authors: W
authors: Du
authors: Deparment of Ophthalmology, University of Florida, Gainesville, FL 32610, USA.
authors: Ye
authors: Y
authors: Tao
authors: Deparment of Ophthalmology, University of Florida, Gainesville, FL 32610, USA.
authors: Wen-Tao
authors: WT
authors: Deng
authors: Deparment of Ophthalmology, University of Florida, Gainesville, FL 32610, USA.
authors: Ping
authors: P
authors: Zhu
authors: Deparment of Ophthalmology, University of Florida, Gainesville, FL 32610, USA.
authors: Jie
authors: J
authors: Li
authors: Deparment of Ophthalmology, University of Florida, Gainesville, FL 32610, USA, School of Ophthalmology and Optometry, The Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
authors: Xufeng
authors: X
authors: Dai
authors: Deparment of Ophthalmology, University of Florida, Gainesville, FL 32610, USA, Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China.
authors: Yuxin
authors: Y
authors: Zhang
authors: Deparment of Ophthalmology, University of Florida, Gainesville, FL 32610, USA.
authors: Wei
authors: W
authors: Shi
authors: Deparment of Ophthalmology, University of Florida, Gainesville, FL 32610, USA.
authors: Xuan
authors: X
authors: Liu
authors: Deparment of Ophthalmology, University of Florida, Gainesville, FL 32610, USA.
authors: Vince A
authors: VA
authors: Chiodo
authors: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors: Xi-Qin
authors: XQ
authors: Ding
authors: Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China.
authors: Chen
authors: C
authors: Zhao
authors: Munich Center for Integrated Protein Science and Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität München, 81377 Munich, Germany and.
authors: Stylianos
authors: S
authors: Michalakis
authors: Munich Center for Integrated Protein Science and Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität München, 81377 Munich, Germany and.
authors: Martin
authors: M
authors: Biel
authors: Department of Clinical Aerospace Medicine, Fourth Military Medical University, Xi'an 710032, China jpang@ufl.edu.
authors: Zuoming
authors: Z
authors: Zhang
authors: School of Ophthalmology and Optometry, The Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China, jpang@ufl.edu.
authors: Jia
authors: J
authors: Qu
authors: Deparment of Ophthalmology, University of Florida, Gainesville, FL 32610, USA, jpang@ufl.edu.
authors: William W
authors: WW
authors: Hauswirth
authors: Deparment of Ophthalmology, University of Florida, Gainesville, FL 32610, USA, School of Ophthalmology and Optometry, The Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China, Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China, jpang@ufl.edu.
authors: Ji-Jing
authors: JJ
authors: Pang
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D003117:Color Vision Defects / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics* / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017949:Retinal Cone Photoreceptor Cells / Q000502:physiology*
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; C518237:Cnga3 protein, mouse; D054815:Cyclic Nucleotide-Gated Cation Channels; D005136:Eye Proteins; C084884:Nrl protein, mouse