Study ID: AAV2-RPE65-DOG-PD-001
Study Title: A Proof-of-Concept, Dose-Response Study of Subretinally Administered Voretigene Neparvovec for the Restoration of Visual Function in the RPE65-Mutant Canine Model of Retinal Dystrophy.

Study Report Body:
Objective: To evaluate the dose-response relationship of voretigene neparvovec on protein expression and visual function restoration following subretinal administration in RPE65-mutant dogs.
Methods: A total of 12 RPE65-mutant canines received a single unilateral subretinal injection of voretigene neparvovec at one of three dose levels (Low, Medium, High). The contralateral eye served as an untreated control. Animals were evaluated for up to 2 years. Endpoints included: 1) RPE65 protein expression via immunohistochemistry (IHC) on retinal tissue; 2) Retinal function via electroretinography (ERG); and 3) Behavioral visual function via navigation through an obstacle-avoidance maze at various light levels.
Results: A clear dose-response relationship was observed. RPE65 protein expression was detected in the RPE cells within the area of the subretinal bleb in all treated eyes, with the highest intensity and largest area of expression in the High dose group. ERG testing showed significant improvement in rod and cone photoreceptor responses in the Medium and High dose groups compared to baseline and control eyes. In the obstacle-avoidance maze, dogs treated with the Medium and High doses demonstrated a marked improvement in their ability to navigate the course successfully at lower light levels, a direct correlate of restored visual function. The effects on both ERG and behavior were durable through the 2-year study period.
Conclusion: Voretigene neparvovec successfully transduces RPE cells, leads to expression of functional RPE65 protein, and restores retinal function and vision-guided mobility in a large animal model of the disease. These results established proof-of-concept and supported the selection of the high dose for clinical development.