Restoration of rod function following gene therapy in patients with mutations in the gene encoding the RPE65 protein required for recycling all-trans-retinal to 11-cis-retinal

Abstract

Rod visual function can be confirmed unequivocally by demonstrating that visual performance measured as a function of wavelength has a rod spectral sensitivity. We have used this test to assess retinal function in some of the patients with early onset severe retinal dystrophy enrolled in an ongoing phase-I/II dose-escalation clinical trial of gene therapy for RPE65 deficiency. The therapy involves subretinal delivery of a recombinant adeno-associated viral vector expressing RPE65. The particular visual performance task used was the threshold detection of 1-Hz flicker following 40 minutes of dark adaptation. The flickering target was 3.55-deg in diameter presented 10-deg in the superior retina (close to the treatment site). We made spectral sensitivity measurements prior to gene therapy and then at 2-monthly intervals following gene therapy in the last five patients enrolled in the trial (to date). Prior to gene therapy, no clear evidence of rod function was found in the spectral sensitivity measurements. The flicker spectral sensitivity functions in all patients were cone-like and similar to those found during the cone plateau after an intense bleach. After gene therapy, however, substantial improvements in flicker sensitivity were found in the first two patients tested. One patient showed a 1000-fold improvement in dark-adapted flicker sensitivity at 500 nm, 4 months after treatment and the second a 100-fold improvement, 6 months after treatment. In both cases, the spectral sensitivity became clearly rod-like, indicative of restored rod function. To date, the other patients have not shown an improvement using this test. The trial is ongoing.