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

Manjit S. Mehat, Venki Sundaram, Caterina Ripamonti, Anthony G. Robson, Alexander J. Smith, Shyamanga Borooah, Martha Robinson, Adam N. Rosenthal, William Innes, Richard Weleber, Richard W.J. Lee, Michael Crossland, Gary S. Rubin, Baljean Dhillon, David H.W. Steel, Eddy Anglade, Robert P. Lanza, Robin R. Ali, Michel Michaelides, James W.B. Bainbridge

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
JournalOphthalmology
DOIs
StateAccepted/In press - Jan 1 2018

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Retinal Pigments
Macular Degeneration
Hyperpigmentation
Transplantation
Epithelial Cells
Visual Acuity
National Eye Institute (U.S.)
Safety
Spatial Analysis
Cell Transplantation
Immunosuppressive Agents
Immunosuppression
Retina
Young Adult
Cell Survival
Quality of Life
Observation
Outcome Assessment (Health Care)
Human Embryonic Stem Cells
Therapeutics

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Mehat, M. S., Sundaram, V., Ripamonti, C., Robson, A. G., Smith, A. J., Borooah, S., ... Bainbridge, J. W. B. (Accepted/In press). Transplantation of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in Macular Degeneration. Ophthalmology. https://doi.org/10.1016/j.ophtha.2018.04.037

Transplantation of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in Macular Degeneration. / Mehat, Manjit S.; Sundaram, Venki; Ripamonti, Caterina; Robson, Anthony G.; Smith, Alexander J.; Borooah, Shyamanga; Robinson, Martha; Rosenthal, Adam N.; Innes, William; Weleber, Richard; Lee, Richard W.J.; Crossland, Michael; Rubin, Gary S.; Dhillon, Baljean; Steel, David H.W.; Anglade, Eddy; Lanza, Robert P.; Ali, Robin R.; Michaelides, Michel; Bainbridge, James W.B.

In: Ophthalmology, 01.01.2018.

Research output: Contribution to journalArticle

Mehat, MS, Sundaram, V, Ripamonti, C, Robson, AG, Smith, AJ, Borooah, S, Robinson, M, Rosenthal, AN, Innes, W, Weleber, R, Lee, RWJ, Crossland, M, Rubin, GS, Dhillon, B, Steel, DHW, Anglade, E, Lanza, RP, Ali, RR, Michaelides, M & Bainbridge, JWB 2018, 'Transplantation of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in Macular Degeneration', Ophthalmology. https://doi.org/10.1016/j.ophtha.2018.04.037
Mehat, Manjit S. ; Sundaram, Venki ; Ripamonti, Caterina ; Robson, Anthony G. ; Smith, Alexander J. ; Borooah, Shyamanga ; Robinson, Martha ; Rosenthal, Adam N. ; Innes, William ; Weleber, Richard ; Lee, Richard W.J. ; Crossland, Michael ; Rubin, Gary S. ; Dhillon, Baljean ; Steel, David H.W. ; Anglade, Eddy ; Lanza, Robert P. ; Ali, Robin R. ; Michaelides, Michel ; Bainbridge, James W.B. / Transplantation of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in Macular Degeneration. In: Ophthalmology. 2018.
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AU - Mehat, Manjit S.

AU - Sundaram, Venki

AU - Ripamonti, Caterina

AU - Robson, Anthony G.

AU - Smith, Alexander J.

AU - Borooah, Shyamanga

AU - Robinson, Martha

AU - Rosenthal, Adam N.

AU - Innes, William

AU - Weleber, Richard

AU - Lee, Richard W.J.

AU - Crossland, Michael

AU - Rubin, Gary S.

AU - Dhillon, Baljean

AU - Steel, David H.W.

AU - Anglade, Eddy

AU - Lanza, Robert P.

AU - Ali, Robin R.

AU - Michaelides, Michel

AU - Bainbridge, James W.B.

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N2 - 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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