Vitreal delivery of AAV vectored Cnga3 restores cone function in CNGA3-/-/Nrl-/- mice, an all-cone model of CNGA3 achromatopsia

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.

Source: Human Molecular Genetics - June 8, 2015 Category: Genetics & Stem Cells Authors: Du, W., Tao, Y., Deng, W.-T., Zhu, P., Li, J., Dai, X., Zhang, Y., Shi, W., Liu, X., Chiodo, V. A., Ding, X.-Q., Zhao, C., Michalakis, S., Biel, M., Zhang, Z., Qu, J., Hauswirth, W. W., Pang, J.-j. Tags: ARTICLES Source Type: research