Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy

Follow-up of two open-label phase 1/2 studies

Steven D. Schwartz, Carl D. Regillo, Byron L Lam, Dean Eliott, Philip J Rosenfeld, Ninel Gregori, Jean Pierre Hubschman, Janet L Davis, Gad Heilwell, Marc Spirn, Joseph Maguire, Roger Gay, Jane Bateman, Rosaleen M. Ostrick, Debra Morris, Matthew Vincent, Eddy Anglade, Lucian V. Del Priore, Robert Lanza

Research output: Contribution to journalArticle

528 Citations (Scopus)

Abstract

Background Since they were first derived more than three decades ago, embryonic stem cells have been proposed as a source of replacement cells in regenerative medicine, but their plasticity and unlimited capacity for self-renewal raises concerns about their safety, including tumour formation ability, potential immune rejection, and the risk of differentiating into unwanted cell types. We report the medium-term to long-term safety of cells derived from human embryonic stem cells (hESC) transplanted into patients. Methods In the USA, two prospective phase 1/2 studies were done to assess the primary endpoints safety and tolerability of subretinal transplantation of hESC-derived retinal pigment epithelium in nine patients with Stargardt's macular dystrophy (age >18 years) and nine with atrophic age-related macular degeneration (age >55 years). Three dose cohorts (50-000, 100-000, and 150-000 cells) were treated for each eye disorder. Transplanted patients were followed up for a median of 22 months by use of serial systemic, ophthalmic, and imaging examinations. The studies are registered with ClinicalTrials.gov, numbers NCT01345006 (Stargardt's macular dystrophy) and NCT01344993 (age-related macular degeneration). Findings There was no evidence of adverse proliferation, rejection, or serious ocular or systemic safety issues related to the transplanted tissue. Adverse events were associated with vitreoretinal surgery and immunosuppression. 13 (72%) of 18 patients had patches of increasing subretinal pigmentation consistent with transplanted retinal pigment epithelium. Best-corrected visual acuity, monitored as part of the safety protocol, improved in ten eyes, improved or remained the same in seven eyes, and decreased by more than ten letters in one eye, whereas the untreated fellow eyes did not show similar improvements in visual acuity. Vision-related quality-of-life measures increased for general and peripheral vision, and near and distance activities, improving by 16-25 points 3-12 months after transplantation in patients with atrophic age-related macular degeneration and 8-20 points in patients with Stargardt's macular dystrophy. Interpretation The results of this study provide the first evidence of the medium-term to long-term safety, graft survival, and possible biological activity of pluripotent stem cell progeny in individuals with any disease. Our results suggest that hESC-derived cells could provide a potentially safe new source of cells for the treatment of various unmet medical disorders requiring tissue repair or replacement. Funding Advanced Cell Technology.

Original languageEnglish
Pages (from-to)509-516
Number of pages8
JournalThe Lancet
Volume385
Issue number9967
DOIs
StatePublished - Feb 7 2015

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Retinal Pigment Epithelium
Macular Degeneration
Safety
Visual Acuity
Transplantation
Vitreoretinal Surgery
Pluripotent Stem Cells
Aptitude
Regenerative Medicine
Pigmentation
Graft Survival
Embryonic Stem Cells
Human Embryonic Stem Cells
Immunosuppression
Quality of Life
Technology
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy : Follow-up of two open-label phase 1/2 studies. / Schwartz, Steven D.; Regillo, Carl D.; Lam, Byron L; Eliott, Dean; Rosenfeld, Philip J; Gregori, Ninel; Hubschman, Jean Pierre; Davis, Janet L; Heilwell, Gad; Spirn, Marc; Maguire, Joseph; Gay, Roger; Bateman, Jane; Ostrick, Rosaleen M.; Morris, Debra; Vincent, Matthew; Anglade, Eddy; Del Priore, Lucian V.; Lanza, Robert.

In: The Lancet, Vol. 385, No. 9967, 07.02.2015, p. 509-516.

Research output: Contribution to journalArticle

Schwartz, SD, Regillo, CD, Lam, BL, Eliott, D, Rosenfeld, PJ, Gregori, N, Hubschman, JP, Davis, JL, Heilwell, G, Spirn, M, Maguire, J, Gay, R, Bateman, J, Ostrick, RM, Morris, D, Vincent, M, Anglade, E, Del Priore, LV & Lanza, R 2015, 'Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy: Follow-up of two open-label phase 1/2 studies', The Lancet, vol. 385, no. 9967, pp. 509-516. https://doi.org/10.1016/S0140-6736(14)61376-3
Schwartz, Steven D. ; Regillo, Carl D. ; Lam, Byron L ; Eliott, Dean ; Rosenfeld, Philip J ; Gregori, Ninel ; Hubschman, Jean Pierre ; Davis, Janet L ; Heilwell, Gad ; Spirn, Marc ; Maguire, Joseph ; Gay, Roger ; Bateman, Jane ; Ostrick, Rosaleen M. ; Morris, Debra ; Vincent, Matthew ; Anglade, Eddy ; Del Priore, Lucian V. ; Lanza, Robert. / Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy : Follow-up of two open-label phase 1/2 studies. In: The Lancet. 2015 ; Vol. 385, No. 9967. pp. 509-516.
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T1 - Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy

T2 - Follow-up of two open-label phase 1/2 studies

AU - Schwartz, Steven D.

AU - Regillo, Carl D.

AU - Lam, Byron L

AU - Eliott, Dean

AU - Rosenfeld, Philip J

AU - Gregori, Ninel

AU - Hubschman, Jean Pierre

AU - Davis, Janet L

AU - Heilwell, Gad

AU - Spirn, Marc

AU - Maguire, Joseph

AU - Gay, Roger

AU - Bateman, Jane

AU - Ostrick, Rosaleen M.

AU - Morris, Debra

AU - Vincent, Matthew

AU - Anglade, Eddy

AU - Del Priore, Lucian V.

AU - Lanza, Robert

PY - 2015/2/7

Y1 - 2015/2/7

N2 - Background Since they were first derived more than three decades ago, embryonic stem cells have been proposed as a source of replacement cells in regenerative medicine, but their plasticity and unlimited capacity for self-renewal raises concerns about their safety, including tumour formation ability, potential immune rejection, and the risk of differentiating into unwanted cell types. We report the medium-term to long-term safety of cells derived from human embryonic stem cells (hESC) transplanted into patients. Methods In the USA, two prospective phase 1/2 studies were done to assess the primary endpoints safety and tolerability of subretinal transplantation of hESC-derived retinal pigment epithelium in nine patients with Stargardt's macular dystrophy (age >18 years) and nine with atrophic age-related macular degeneration (age >55 years). Three dose cohorts (50-000, 100-000, and 150-000 cells) were treated for each eye disorder. Transplanted patients were followed up for a median of 22 months by use of serial systemic, ophthalmic, and imaging examinations. The studies are registered with ClinicalTrials.gov, numbers NCT01345006 (Stargardt's macular dystrophy) and NCT01344993 (age-related macular degeneration). Findings There was no evidence of adverse proliferation, rejection, or serious ocular or systemic safety issues related to the transplanted tissue. Adverse events were associated with vitreoretinal surgery and immunosuppression. 13 (72%) of 18 patients had patches of increasing subretinal pigmentation consistent with transplanted retinal pigment epithelium. Best-corrected visual acuity, monitored as part of the safety protocol, improved in ten eyes, improved or remained the same in seven eyes, and decreased by more than ten letters in one eye, whereas the untreated fellow eyes did not show similar improvements in visual acuity. Vision-related quality-of-life measures increased for general and peripheral vision, and near and distance activities, improving by 16-25 points 3-12 months after transplantation in patients with atrophic age-related macular degeneration and 8-20 points in patients with Stargardt's macular dystrophy. Interpretation The results of this study provide the first evidence of the medium-term to long-term safety, graft survival, and possible biological activity of pluripotent stem cell progeny in individuals with any disease. Our results suggest that hESC-derived cells could provide a potentially safe new source of cells for the treatment of various unmet medical disorders requiring tissue repair or replacement. Funding Advanced Cell Technology.

AB - Background Since they were first derived more than three decades ago, embryonic stem cells have been proposed as a source of replacement cells in regenerative medicine, but their plasticity and unlimited capacity for self-renewal raises concerns about their safety, including tumour formation ability, potential immune rejection, and the risk of differentiating into unwanted cell types. We report the medium-term to long-term safety of cells derived from human embryonic stem cells (hESC) transplanted into patients. Methods In the USA, two prospective phase 1/2 studies were done to assess the primary endpoints safety and tolerability of subretinal transplantation of hESC-derived retinal pigment epithelium in nine patients with Stargardt's macular dystrophy (age >18 years) and nine with atrophic age-related macular degeneration (age >55 years). Three dose cohorts (50-000, 100-000, and 150-000 cells) were treated for each eye disorder. Transplanted patients were followed up for a median of 22 months by use of serial systemic, ophthalmic, and imaging examinations. The studies are registered with ClinicalTrials.gov, numbers NCT01345006 (Stargardt's macular dystrophy) and NCT01344993 (age-related macular degeneration). Findings There was no evidence of adverse proliferation, rejection, or serious ocular or systemic safety issues related to the transplanted tissue. Adverse events were associated with vitreoretinal surgery and immunosuppression. 13 (72%) of 18 patients had patches of increasing subretinal pigmentation consistent with transplanted retinal pigment epithelium. Best-corrected visual acuity, monitored as part of the safety protocol, improved in ten eyes, improved or remained the same in seven eyes, and decreased by more than ten letters in one eye, whereas the untreated fellow eyes did not show similar improvements in visual acuity. Vision-related quality-of-life measures increased for general and peripheral vision, and near and distance activities, improving by 16-25 points 3-12 months after transplantation in patients with atrophic age-related macular degeneration and 8-20 points in patients with Stargardt's macular dystrophy. Interpretation The results of this study provide the first evidence of the medium-term to long-term safety, graft survival, and possible biological activity of pluripotent stem cell progeny in individuals with any disease. Our results suggest that hESC-derived cells could provide a potentially safe new source of cells for the treatment of various unmet medical disorders requiring tissue repair or replacement. Funding Advanced Cell Technology.

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