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Guy Gingras, Andras M. Komaromy, Ben Tseng, John J. Alexander, Vince V. Chiodo, William W. Hauswirth, Gregory M. Acland, Gustavo D. Aguirre, David H. Brainard, Geoffrey K. Aguirre; Cortical recovery following gene therapy in a canine model of achromatopsia. Journal of Vision 2009;9(8):311. doi: https://doi.org/10.1167/9.8.311.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To measure the cortical response to visual stimulation in dogs with hereditary loss of retinal cone function using rod- and cone-directed stimuli.
Methods: Two normal dogs (CNGB3 null mutant carriers), 5 achromatopsia-affected dogs (CNGB3 mutants with S- and L/M-cone dysfunctions), and 2 CNGB3 mutants treated at 1.5 and 3 months of age (recovered L/M-cone function demonstrated by ERG) were studied using BOLD fMRI. Prior to the imaging studies, the treated animals received unilateral recombinant adeno-associated virus (rAVV) subretinal injections containing human CNGB3 cDNA. During scanning, the animals were sedated with Ketamine/Valium and mechanically ventilated following neuromuscular blockade. Rod- and cone-directed stimuli were developed using the silent-substitution method, determined with respect to published spectral sensitivity properties of the canine L/M-cone and rod opsins. Visual stimulation was a 4-quadrant checkerboard, 5 Hz flicker presented for 30 seconds, alternating with a static gray screen. Scanning was conducted with low (0.41 cd/m2) and high (1194 cd/m2) average luminance stimuli, corresponding to the canine scotopic and photopic range.
Results: Following transformations of functional data to a standardized canine digital atlas, activation was observed in the lateral gyrus (striate/parastriate cortex). Within this region, the response to high luminance, cone-directed stimuli in the normal and treated animals was more than double that of the affected CNGB3 mutants (140 mm3 vs. 310 mm3, p=0.068). No population differences were observed for the rod-directed responses or at low luminance.
Conclusions: These results suggest that rod- and cone-directed cortical responses can be identified and studied in a canine model of achromatopsia. More importantly, the visual recovery that can be measured in affected animals following gene therapy suggests restoration of L/M-cone cortical responses.
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