Abstract
PURPOSE: To analyze ERG responses from two dog models of retinitis pigmentosa, one due to a PDE6A mutation and the other a CNGB1 mutation, both to assess the effect of these mutations on retinal function and the ability of gene augmentation therapy to restore normal function. METHODS: Scotopic and photopic ERGs from young affected and normal control dogs and affected dogs following AAV-mediated gene augmentation therapy were analyzed. Parameters reflecting rod and cone function were collected by modeling the descending slope of the a-wave to measure receptor response and sensitivity. Rod-driven responses were further assessed by Naka-Rushton fitting of the first limb of the scotopic b-wave luminance-response plot. RESULTS: PDE6A(-/-) dogs showed a dramatic decrease in rod-driven responses with very reduced rod maximal responses and sensitivity. There was a minor reduction in the amplitude of maximal cone responses. In contrast, CNGB1(-/-) dogs had some residual rod responses with reduced amplitude and sensitivity and normal cone responses. Following gene augmentation therapy, rod parameters were substantially improved in both models with restoration of sensitivity parameters log S and log K and a large increase in log R(max) in keeping with rescue of normal rod phototransduction in the treated retinal regions. CONCLUSIONS: Modeling of rod and cone a-waves and the luminance-response function of the scotopic b-wave characterized the loss of rod photoreceptor function in two dog models of retinitis pigmentosa and showed the effectiveness of gene augmentation therapy in restoring normal functional parameters.