Mutations in RPE65 cause Leber’s congenital amaurosis, a progressive retinal degenerative disease that severely impairs sight in children. Gene therapy can result in modest improvements in night vision, but knowledge of its efficacy in humans is limited. We performed a phase 1–2 open-label trial involving 12 participants to evaluate the safety and efficacy of gene therapy with a recombinant adeno-associated virus 2/2 (rAAV2/2) vector carrying the RPE65 complementary DNA, and measured visual function over the course of 3 years. Four participants were administered a lower dose of the vector, and 8 were administered a higher dose. In a parallel study in dogs, we investigated the relationship among vector dose, visual function, and electroretinography (ERG) findings. Improvements in retinal sensitivity were evident, to varying extents, in six participants for up to 3 years, peaking at 6 to 12 months after treatment and then declining. No associated improvement in retinal function was detected by means of ERG. Three participants had intraocular inflammation, and two had clinically significant deterioration of visual acuity. The reduction in central retinal thickness varied among participants. In dogs, RPE65 gene therapy with the same vector at lower doses improved vision-guided behavior, but only higher doses resulted in improvements in retinal function that were detectable with the use of ERG. Gene therapy with rAAV2/2 RPE65 vector improved retinal sensitivity, albeit modestly and temporarily. Comparison with the results obtained in the dog model indicates that there is a species difference in the amount of RPE65 required to drive the visual cycle and that the demand for RPE65 in affected persons was not met to the extent required for a durable, robust effect. (Funded by the National Institute for Health Research and others; ClinicalTrials.gov number, NCT00643747.)

Human adults can go beyond the limits of individual sensory systems’ resolutions by integrating multiple estimates (e.g., vision and touch) to reduce uncertainty. Little is known about how this ability develops. Although some multisensory abilities are present from early infancy, it is not until age ≥8 y that children use multiple modalities to reduce sensory uncertainty. Here we show that uncertainty reduction by sensory integration does not emerge until 12 y even within the single modality of vision, in judgments of surface slant based on stereoscopic and texture information. However, adults’ integration of sensory information comes at a cost of losing access to the individual estimates that feed into the integrated percept (“sensory fusion”). By contrast, 6-y-olds do not experience fusion, but are able to keep stereo and texture information separate. This ability enables them to outperform adults when discriminating stimuli in which these information sources conflict. Further, unlike adults, 6-y-olds show speed gains consistent with following the fastest-available single cue. Therefore, whereas the mature visual system is optimized for reducing sensory uncertainty, the developing visual system may be optimized for speed and for detecting sensory conflicts. Such conflicts could provide the error signals needed to learn the relationships between sensory information sources and to recalibrate them while the body is growing.

Purpose.: To longitudinally characterize retinal structure and function in achromatopsia (ACHM) in preparation for clinical gene therapy trials. Methods.: Thirty-eight molecularly confirmed ACHM subjects underwent serial assessments, including spectral domain optical coherence tomography (SD-OCT), microperimetry, and fundus autofluorescence (FAF). Foveal structure on SD-OCT was graded and compared for evidence of progression, along with serial measurements of foveal total retinal thickness (FTRT) and outer nuclear layer (ONL) thickness. Fundus autofluorescence patterns were characterized and compared over time. Results.: Mean follow-up was 19.5 months (age range at baseline, 6–52 years). Only 2 (5%) of 37 subjects demonstrated change in serial foveal SD-OCT scans. There was no statistically significant change over time in FTRT (P = 0.83), ONL thickness (P = 0.27), hyporeflective zone diameter (P = 0.42), visual acuity (P = 0.89), contrast sensitivity (P = 0.22), mean retinal sensitivity (P = 0.84), and fixation stability (P = 0.58). Three distinct FAF patterns were observed (n = 30): central increased FAF (n = 4), normal FAF (n = 11), and well-demarcated reduced FAF (n = 15); with the latter group displaying a slow increase in the area of reduced FAF of 0.03 mm² over 19.3 months (P = 0.002). Conclusions.: Previously published cross-sectional studies have described conflicting findings with respect to the age-dependency of progression. This study, which constitutes the largest and longest prospective longitudinal study of ACHM to date, suggests that although ACHM may be progressive, any such progression is slow and subtle in most patients, and does not correlate with age or genotype. We also describe the first serial assessment of FAF, which is highly variable between individuals, even of similar age and genotype.