Transplantation of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in Macular Degeneration

Abstract

Purpose: Transplantation 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.

Design: Phase 1/2 open-label dose-escalation trial to evaluate safety and potential efficacy (clinicaltrials.gov identifier, NCT01469832).

Participants: Twelve participants with advanced Stargardt disease (STGD1), the most common cause of macular degeneration in children and young adults.

Methods: Subretinal transplantation of up to 200 000 hESC-derived RPE cells with systemic immunosuppressive therapy for 13 weeks.

Main outcome measures: The 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.

Results: Focal 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.

Conclusions: Subretinal 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.

Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Fundus photographs of recipient eyes at 12 months after transplantation. In each image, the retinotomy site is indicated by the green dot, and the area of subretinal administration is outlined by the dotted black line. P = patient.

Figure 2

Fundus photographs, OCT images, and fundus autofluorescence images in (A) patient 4 and (B) patient 10. A, In patient 4, fundus images demonstrating the time-course of hyperpigmentation (Ai, Aiv, and Avii) are presented with corresponding OCT line scans, at lower and higher magnification. A progressive increase in optical signal evident in the outer retina consistent with the continued presence of transplanted cells. B, In patient 10, images demonstrating the time-course of hyperpigmentation (Bi, Bii, and Biii) are presented with the associated fundus autofluorescence images demonstrating reduced signal consistent with masking of endogenous autofluorescence.

Figure 3

Microperimetry images showing topography of retinal sensitivity. The retinal sensitivities at test loci in each study eye, measured by microperimetry (Nidek MP-1) at baseline and 12 months, are superimposed on the respective fundus image. Each is presented with a corresponding topographic contour map to illustrate the hill of vision of retinal sensitivity, constructed by interpolation of sensitivities at the test loci using Visual Field Modelling and Analysis (VFMA) software. The blue line outlines the area of recipient retina administered human embryonic stem cell-derived retinal pigment epithelial cell suspension. P = patient; K = thousand.

Figure 4

Boxplots showing the change in retinal sensitivity from the baseline (mean of 3 baseline tests) as measured by microperimetry (Nidek MP-1) for each test locus at month 12. Loci were stratified into 3 groups: outside the transplantation area (solid green dots), within the transplantation and associated with subretinal hyperpigmentation (solid blue dots), or within the transplantation area and without subretinal hyperpigmentation (solid orange dots). Using a selection tool on the Visual Field Modelling and Analysis (VFMA) software, volumetric sensitivity within regions of retinal pigmentation were extracted from regions of pigmentation and nonpigmentation. The boxplots show the median value, quartiles, and range. hESC = human embryonic stem cell; K = thousand; P = patient; RPE = retinal pigment epithelial.