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
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.
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Since then, other clinical trials have been carried out resulting in clinically measurable visual improvements.
“Since then, other clinical trials have been carried out resulting in clinically measurable visual improvements [76,77].”
From Utility of iPSC-Derived Cells for Disease Modeling, Drug Development, and Cell Therapy (2022) · cites this paper as [76]
If the surgeon does not observe leakage, it is assumed that all the injected volume is successfully delivered.
“If the surgeon does not observe any leakage, it is assumed that all the injected volume is successfully delivered (18–21).”
From Subretinal therapy: technological solutions to surgical and immunological challenges (2022) · cites this paper as [20]
Any reflux should be avoided because release of cells to the vitreous cavity can induce an immune response or lead to formation of epiretinal membranes.
“Ideally, any reflux should be avoided as release of cells to the vitreous cavity can induce an immune response or lead to the formation of epiretinal membranes (20, 26–29).”
From Subretinal therapy: technological solutions to surgical and immunological challenges (2022) · cites this paper as [20]
Injection protocols dating to 2014 called for a 2-step procedure, which largely avoids causing a break in Bruch's membrane but does not completely eliminate the risk.
“Injection protocols dating to 2014 (30, 31) called for a 2-step procedure, which largely avoids causing a break in Bruch's membrane but does not completely eliminate the risk (20, 32).”
From Subretinal therapy: technological solutions to surgical and immunological challenges (2022) · cites this paper as [20]
When Bruch's membrane is breached, there is usually retraction of the underlying choroidal tissue leading to formation of a small white round hole.
“When breached, there is usually retraction of the underlying choroidal tissue leading to the formation of a small white round hole (20, 33).”
From Subretinal therapy: technological solutions to surgical and immunological challenges (2022) · cites this paper as [20]
Increasing subretinal pigmentation developed at the hESC-RPE cell injection site in two dry AMD patients and one SMD patient.
“In the two dry AMD patients and one SMD patient, increasing subretinal pigmentation developed at the hESC-RPE cell injection site as has been noted previously (Schwartz et al., 2012, Schwartz et al., 2015).”
From Treatment of macular degeneration using embryonic stem cell-derived retinal pigment epithelium: Preliminary results in Asian patients (2015) · cites this paper as Schwartz et al., 2015
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BackgroundStargardt macular dystrophy and evolving therapies
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- Authors
- Schwartz, S. D., Regillo, C. D., Lam, B. L., Eliott, D., Rosenfeld, P. J., Gregori, N. Z., Hubschman, J.-P., Davis, J. L., Heilwell, G., Spirn, M., Maguire, J., Gay, R., Bateman, J., Ostrick, R. M., Morris, D., Vincent, M., Anglade, E., Del Priore, L. V., & Lanza, R.
- Affiliations
- University of California, Los Angeles (US)
- Thomas Jefferson University (US)
- University of Miami (US)
- Massachusetts Eye and Ear Infirmary (US)
- Advanced Cell Technology (United States) (US)
- ORCID
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 385
- Issue
- 9967
- Pages
- 509-516
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- OpenAlex
- W2149884610
- Cited by
- 1,327
- References
- 41
- Citations by year
- 2026: 52 · 2025: 81 · 2024: 90 · 2023: 68 · 2022: 99 · 2021: 131 · 2020: 122 · 2019: 111 · 2018: 127 · 2017: 165 · 2016: 147 · 2015: 123 · 2014: 7 · 2013: 1
- FWCI
- 60.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Biogen
- Regeneron Pharmaceuticals
- Alimera Sciences
- Genentech
- Allergan
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- human embryonic stem cells, retinal pigment epithelium, cell transplantation, age-related macular degeneration, subretinal transplantation, cell therapy safety, long-term follow-up, visual acuity, vision-related quality of life, retinal regeneration, dose escalation, immunosuppression, vitrectomy
- MeSH terms
- Stargardt Disease, Adult, Aged, Aged, 80 and over, Cell Differentiation, Female, Follow-Up Studies, Humans, Macular Degeneration, Male, Middle Aged, Prospective Studies, Quality of Life, Visual Acuity, Treatment Outcome, Embryonic Stem Cells, Retinal Pigment Epithelium, Young Adult
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