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Ophthalmology. 2018 Nov;125(11):1765-1775. doi: 10.1016/j.ophtha.2018.04.037. Epub 2018 Jun 5.

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

Author information

1
NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital and University College London, London, United Kingdom; Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom; Institute of Ophthalmology, University College London, London, United Kingdom.
2
Cambridge Research Systems Ltd., Rochester, United Kingdom.
3
NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital and University College London, London, United Kingdom; Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom.
4
NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital and University College London, London, United Kingdom; Institute of Ophthalmology, University College London, London, United Kingdom.
5
University of Edinburgh, Edinburgh, United Kingdom.
6
Institute of Ophthalmology, University College London, London, United Kingdom.
7
University College Hospital, London, United Kingdom.
8
Newcastle Eye Centre, Newcastle upon Tyne, United Kingdom.
9
Casey Eye Institute, University of Oregon Health & Science University, Portland, Oregon.
10
Newcastle Eye Centre, Newcastle upon Tyne, United Kingdom; Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
11
Astellas Institute for Regenerative Medicine, Marlborough, Massachusetts.
12
NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital and University College London, London, United Kingdom; Institute of Ophthalmology, University College London, London, United Kingdom; Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan.
13
NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital and University College London, London, United Kingdom; Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom; Institute of Ophthalmology, University College London, London, United Kingdom. Electronic address: j.bainbridge@ucl.ac.uk.

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.

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