Improvement and decline in vision with gene therapy in childhood blindness

Abstract

Retinal gene therapy for Leber's congenital amaurosis, an autosomal recessive childhood blindness, has been widely considered to be safe and efficacious. Three years after therapy, improvement in vision was maintained, but the rate of loss of photoreceptors in the treated retina was the same as that in the untreated retina. Here we describe long-term follow-up data from three treated patients. Topographic maps of visual sensitivity in treated regions, nearly 6 years after therapy for two of the patients and 4.5 years after therapy for the third patient, indicate progressive diminution of the areas of improved vision. (Funded by the National Eye Institute; ClinicalTrials.gov number, NCT00481546.).

Figure 1. Time Course of the Changes in Vision after Gene Therapy

Panel A shows maps of visual sensitivity of the treated eye in three patients at baseline (full visual field) and at different times after treatment (in enlarged views of the treated region); time labels for the last two columns have been rounded. All log values are base 10. After an extended period of dark adaptation (>4 hours), visual sensitivity was determined on a 12-degree grid with additional loci at 2-degree intervals along horizontal or vertical meridians; in this figure, the increments shown along the axes at baseline denote 24 degrees. Contours delineate regions of equal sensitivity. Note that the color-scale ranges and contour-sensitivity levels have been expanded for the enlarged views of Patient 3. Ocular fundus landmarks (optic nerve and central retinal vessels) are drawn schematically on the full visual field maps for reference. F denotes fovea. Panel B shows plots of the area of visual sensitivity (the area of contours shown in Panel A) during the post-treatment period. The area was quantified at 44.5, and 5 log sensitivities for Patients 1 and 2 and at 22.5, and 3 log sensitivities for Patient 3. Error bars (denoting 1 SD) were calculated on the basis of variability in sensitivity measures that is specific to RPE65-associated Leber’s congenital amaurosis.

Figure 2. (facing page). Relationship of Photoreceptor Structure to Vision

Panel A shows the outer-nuclear-layer thickness topography of Patient 1 and Patient 3 at baseline and at 5.7 or 4.5 years after treatment. Treated regions, delimited by the availability of data regarding colocalized sensitivity and photoreceptor-layer thickness, are outlined. For a comparison with patient data, a map representing the mean outer nuclear layer (ONL) from three normal controls is shown (upper right). Panel B (upper graphs) shows the time course of change in sensitivity (log unit change from baseline) and ONL thickness (fraction of normal mean) within the treated regions. The lower graph compares the observed rates of slow change in sensitivity (occurring after 1 month) with that expected from the change in the ONL over two distinct periods. In the earlier period, there is an increase in sensitivity despite a decrease expected from the loss of photoreceptors. In the later period, there is a decrease in sensitivity as expected from continued loss of photoreceptors, but the rate of the loss of sensitivity exceeds that predicted from the change in the outer nuclear layer. The rates of change in the outer nuclear layer in the patients are similar to the mean rate reported previously for a cohort of patients with RPE65-associated Leber’s congenital amaurosis (RPE65-LCA cohort). The significance of the differences between the observed and expected rates were assessed with the use of Student’s t-test.