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.
Highlights
Subretinal hyperpigmentation is consistent with the survival of viable transplanted hESCderived retinal pigment epithelial (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
The human embryonic stem cell (hESC)-derived RPE cells were reconstituted and administered subretinally by 2 of the authorsdpatients 1 through by J.W.B.B. and patient by D.S.dto the predefined target regions, which were inferior to the inferotemporal vascular arcade in 10 eyes and superior to the superotemporal arcade in 2 eyes
Summary
Subretinal transplantation of up to 200 000 hESC-derived RPE cells with systemic immunosuppressive therapy for 13 weeks. We performed a phase 1/2 open-label multicenter dose-escalation trial in 12 adult participants to evaluate the safety and tolerability of subretinal transplantation of hESC-derived RPE cells. The study received the approval of the Medicines and Health Products Regulatory Authority, the United Kingdom Gene Therapy Advisory Committee, and the Moorfields Eye Hospital Research Governance Committee. We provided potential candidates with detailed information, including an explanation of the aims of the trial and the possible consequences of participation. Participants provided their written informed consent before enrolment. We performed the study in accordance with the tenets of the Declaration of Helsinki and registered the trial at clinicaltrials.gov (identifier, NCT01469832)
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