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No abstract

PurposeTransplantation of human embryonic stem cell (hESC)-derived retinal pigment epithelial (RPE) cells offers the potential for benefit in macular degeneration. Previous trials have reported improved visual acuity (VA), but lacked detailed analysis of retinal structure and function in the treated area.DesignPhase 1/2 open-label dose-escalation trial to evaluate safety and potential efficacy (clinicaltrials.gov identifier, NCT01469832).ParticipantsTwelve participants with advanced Stargardt disease (STGD1), the most common cause of macular degeneration in children and young adults.MethodsSubretinal transplantation of up to 200 000 hESC-derived RPE cells with systemic immunosuppressive therapy for 13 weeks.Main Outcome MeasuresThe primary end points were the safety and tolerability of hESC-derived RPE cell administration. We also investigated evidence of the survival of transplanted cells and measured retinal structure and function using microperimetry and spectral-domain OCT.ResultsFocal areas of subretinal hyperpigmentation developed in all participants in a dose-dependent manner in the recipient retina and persisted after withdrawal of systemic immunosuppression. We found no evidence of uncontrolled proliferation or inflammatory responses. Borderline improvements in best-corrected VA in 4 participants either were unsustained or were matched by a similar improvement in the untreated contralateral eye. Microperimetry demonstrated no evidence of benefit at 12 months in the 12 participants. In one instance at the highest dose, localized retinal thinning and reduced sensitivity in the area of hyperpigmentation suggested the potential for harm. Participant-reported quality of life using the 25-item National Eye Institute Visual Function Questionnaire indicated no significant change.ConclusionsSubretinal hyperpigmentation is consistent with the survival of viable transplanted hESC-derived RPE cells, but may reflect released pigment in their absence. The findings demonstrate the value of detailed analysis of spatial correlation of retinal structure and function in determining with appropriate sensitivity the impact of cell transplantation and suggest that intervention in early stage of disease should be approached with caution. Given the slow rate of progressive degeneration at this advanced stage of disease, any protection against further deterioration may be evident only after a more extended period of observation.

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When a planar object is rotated with respect to a directional light source, the reflected luminance changes. If surface lightness is to be a reliable guide to surface identity, observers must compensate for such changes. To the extent they do, observers are said to be lightness constant. We report data from a lightness matching task that assesses lightness constancy with respect to changes in object slant. On each trial, observers viewed an achromatic standard object and indicated the best match from a palette of 36 grayscale samples. The standard object and the palette were visible simultaneously within an experimental chamber. The chamber illumination was provided from above by a theater stage lamp. The standard objects were uniformly-painted flat cards. Different groups of naive observers made matches under two sets of instructions. In the Neutral Instructions, observers were asked to match the appearance of the standard and palette sample. In the Paint Instructions, observers were asked to choose the palette sample that was painted the same as the standard. Several broad conclusions may be drawn from the results. First, data for most observers were neither luminance matches nor lightness constant matches. Second, there were large and reliable individual differences. To characterize these, a constancy index was obtained for each observer by comparing how well the data were accounted for by both luminance matching and lightness constancy. The index could take on values between 0 (luminance matching) and 1 (lightness constancy). Individual observer indices ranged between 0.17 and 0.63 with mean 0.40 and median 0.40. An auxiliary slant-matching experiment rules out variation in perceived slant as the source of the individual variability. Third, the effect of instructions was small compared to the inter-observer variability. Implications of the data for models of lightness perception are discussed.