Spectral sensitivity measurements reveal partial success in restoring missing rod function with gene therapy

Rod visual function can be established with some certainty by demonstrating that dark-adapted visual spectral sensitivity has the shape of the rod (scotopic) spectral sensitivity function and that this scotopic shape collapses to a cone (photopic) shape when cones, but not rods, have recovered following an intense bleach. We used these tests to assess retinal function in eight young adult and child patients with early-onset severe retinal dystrophy enrolled in phase II of a clinical gene therapy trial for RPE65 deficiency, an isomerase, the lack of which disrupts the "visual cycle" upon which rods solely depend for regenerating visual pigment after light exposure. The trial involved subretinal delivery of a recombinant adeno-associated viral vector expressing RPE65. After gene therapy, substantial improvements in 1-Hz dark-adapted flicker sensitivity were found in two of the eight patients. One patient showed up to a 1000-fold improvement in sensitivity 4 months after treatment, and the second, up to a 100-fold improvement 6 months after treatment. In both cases, the spectral sensitivity after treatment was rod-like after normal periods of dark adaptation, but remained cone-like during the cone plateau after an intense bleach. The dark-adapted spectral sensitivities of the other six patients were cone-like both before and after treatment with only minimal sensitivity changes. It is not clear why restored rod function was evident in only some patients, but the response may be limited by the extent of retinal degeneration at the locus tested. Meeting abstract presented at VSS 2015.