The successful restoration of visual function with recombinant adeno-associated virus (rAAV)-mediated gene replacement therapy in animals and humans with an inherited disease of the retinal pigment epithelium has ushered in a new era of retinal therapeutics. For many retinal disorders, however, targeting of therapeutic vectors to mutant rods and/or cones will be required. In this study, the primary cone photoreceptor disorder achromatopsia served as the ideal translational model to develop gene therapy directed to cone photoreceptors. We demonstrate that rAAV-mediated gene replacement therapy with different forms of the human red cone opsin promoter led to the restoration of cone function and day vision in two canine models of CNGB3 achromatopsia, a neuronal channelopathy that is the most common form of achromatopsia in man. The robustness and stability of the observed treatment effect was mutation independent, but promoter and age dependent. Subretinal administration of rAAV5-hCNGB3 with a long version of the red cone opsin promoter in younger animals led to a stable therapeutic effect for at least 33 months. Our results hold promise for future clinical trials of cone-directed gene therapy in achromatopsia and other cone-specific disorders.

Objective To develop a quantifiable behavioral test for identification of achromatopsic dogs based on visual performance. Animals 14 dogs. Procedures A 3.6-m-long obstacle-avoidance course with 6 obstacle panels was developed from a preliminary 2.4-m-long course. Achromatopsic and visually normal control dogs were run through the course at 4 ambient light intensities (from dim to bright: 0.2, 25, 65, and 646 lux). Completion of 4 runs ranging from dimmest to brightest light intensity constituted 1 complete trial. Each dog underwent 3 trials. Transit times were measured and compared between dog groups and between light intensities by use of a generalized linear model and ANOVA. Results At the 3 highest light intensities, the achromatopsic dogs needed significantly more time to pass through the obstacle course than the control animals. Compared with the mean transit time at the lowest light intensity, mean transit times were 2.6 times as long at 25 lux, 3.2 times as long at 65 lux, and 5.7 times as long at 646 lux. The achromatopsic dogs had signs of increasing difficulty navigating around the obstacle panels with increasing light intensities; this was not the situation for the control dogs. Conclusions and Clinical Relevance A 3.6-m-long obstacle-avoidance course with 6 movable obstacle panels allowed identification of achromatopsic dogs at ambient light intensities ≥ 25 lux based on transit times. This test could be helpful in the evaluation of new cone photoreceptor–specific treatments.

Objective-To develop a quantifiable behavioral test for identification of achromatopsic dogs based on visual performance. Animals-14 dogs.Procedures-A 3.6-m-long obstacle-avoidance course with 6 obstacle panels was developed from a preliminary 2.4-m-long course. Achromatopsic and visually normal control dogs were run through the course at 4 ambient light intensities (from dim to bright: 0.2, 25, 65, and 646 lux). Completion of 4 runs ranging from dimmest to brightest light intensity constituted 1 complete trial. Each dog underwent 3 trials. Transit times were measured and compared between dog groups and between light intensities by use of a generalized linear model and ANOVA.Results-At the 3 highest light intensities, the achromatopsic dogs needed significantly more time to pass through the obstacle course than the control animals. Compared with the mean transit time at the lowest light intensity, mean transit times were 2.6 times as long at 25 lux, 3.2 times as long at 65 lux, and 5.7 times as long at 646 lux. The achromatopsic dogs had signs of increasing difficulty navigating around the obstacle panels with increasing light intensities; this was not the situation for the control dogs. Conclusions and ClinicalRelevance-A 3.6-m-long obstacle-avoidance course with 6 movable obstacle panels allowed identification of achromatopsic dogs at ambient light intensities ≥ 25 lux based on transit times. This test could be helpful in the evaluation of new cone photoreceptorspecific treatments.The clinical, psychophysical evaluation of visual performance is generally less sophisticated in because of limitations in the assessment of responses to visual stimuli by an untrained animal. The testing of general visual performance in dogs is usually limited to rather simple methods such as the menace response test, the visual placing reaction, and the tracking of objects such as a cotton ball or laser pointer. 1,2 In a clinical setting, dogs may be observed maneuvering around obstacles under different, often ill-defined, ambient light intensities in the examination