Embryonic stem cell trials for macular degeneration: a preliminary report
Abstract
Background It has been 13 years since the discovery of human embryonic stem cells (hESCs). Our report provides the first description of hESC-derived cells transplanted into human patients.Methods We started two prospective clinical studies to establish the safety and tolerability of subretinal transplantation of hESC-derived retinal pigment epithelium (RPE) in patients with Stargardt's macular dystrophy and dry age-related macular degeneration--the leading cause of blindness in the developed world. Preoperative and postoperative ophthalmic examinations included visual acuity, fluorescein angiography, optical coherence tomography, and visual field testing. These studies are registered with ClinicalTrials.gov, numbers NCT01345006 and NCT01344993.Findings Controlled hESC differentiation resulted in greater than 99% pure RPE. The cells displayed typical RPE behaviour and integrated into the host RPE layer forming mature quiescent monolayers after transplantation in animals. The stage of differentiation substantially affected attachment and survival of the cells in vitro after clinical formulation. Lightly pigmented cells attached and spread in a substantially greater proportion (>90%) than more darkly pigmented cells after culture. After surgery, structural evidence confirmed cells had attached and continued to persist during our study. We did not identify signs of hyperproliferation, abnormal growth, or immune mediated transplant rejection in either patient during the first 4 months. Although there is little agreement between investigators on visual endpoints in patients with low vision, it is encouraging that during the observation period neither patient lost vision. Best corrected visual acuity improved from hand motions to 20/800 (and improved from 0 to 5 letters on the Early Treatment Diabetic Retinopathy Study [ETDRS] visual acuity chart) in the study eye of the patient with Stargardt's macular dystrophy, and vision also seemed to improve in the patient with dry age-related macular degeneration (from 21 ETDRS letters to 28).Interpretation The hESC-derived RPE cells showed no signs of hyperproliferation, tumorigenicity, ectopic tissue formation, or apparent rejection after 4 months. The future therapeutic goal will be to treat patients earlier in the disease processes, potentially increasing the likelihood of photoreceptor and central visual rescue.Funding Advanced Cell Technology.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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 [21]
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., 2012
Cites
Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors
Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007) · Cell · doi:10.1016/j.cell.2007.11.019 · Cited by 20,221 · see citing works
Embryonic Stem Cell Lines Derived from Human Blastocysts
Thomson, J. A., Itskovitz‐Eldor, J., Shapiro, S. S., Waknitz, M. A., Swiergiel, J. J., Marshall, V. S., & Jones, J. M. (1998) · Science · doi:10.1126/science.282.5391.1145 · Cited by 15,947 · see citing works
The Retinal Pigment Epithelium in Visual Function
Strauss, O. (2005) · Physiological Reviews · doi:10.1152/physrev.00021.2004 · Cited by 2,828 · see citing works
Generation of Human Induced Pluripotent Stem Cells by Direct Delivery of Reprogramming Proteins
Kim, D., Kim, C.-H., Moon, J.-I., Chung, Y.-G., Chang, M.-Y., Han, B.-S., Ko, S., Yang, E., Cha, K. Y., Lanza, R., et al. (2009) · Cell stem cell · doi:10.1016/j.stem.2009.05.005 · Cited by 1,814 · see citing works
Self-citationClinical risk factors for age-related macular degeneration: a systematic review and meta-analysis
Chakravarthy, U., Wong, T. Y., Fletcher, A., Piault, E., Evans, C., Zlateva, G., Buggage, R., Pleil, A., & Mitchell, P. (2010) · BMC Ophthalmology · doi:10.1186/1471-2415-10-31 · Cited by 842 · see citing works
The Retinal Pigment Epithelium in Health and Disease
Sparrrow, J. R., Hicks, D., & Hamel, C. (2010) · Current Molecular Medicine · doi:10.2174/156652410793937813 · Cited by 625 · see citing works
Human embryonic stem cell lines derived from single blastomeres
Klimanskaya, I. V., Chung, Y., Becker, S., et al. (2006) · Nature · doi:10.1038/nature05142 · Cited by 522 · see citing works
Self-citationHentze, H., Soong, P., Wang, S. T., Phillips, B., Putti, T. C., & Dunn, N. R. (2009) · Stem Cell Research · doi:10.1016/j.scr.2009.02.002 · Cited by 474 · see citing works
Lü, B., Malcuit, C. M., Wang, S., Girman, S. V., Francis, P. J., Lemieux, L., Lanza, R., & Lund, R. D. (2009) · Stem Cells · doi:10.1002/stem.149 · Cited by 471 · see citing works
Self-citationHuman Embryonic Stem Cell–Derived Cells Rescue Visual Function in Dystrophic RCS Rats
Lund, R. D., Wang, S., Klimanskaya, I. V., Holmes, T. M., Ramos-Kelsey, R., Lü, B., Girman, S. V., Bischoff, N., Sauvé, Y., & Lanza, R. (2006) · Cloning and Stem Cells · doi:10.1089/clo.2006.8.189 · Cited by 407 · see citing works
Self-citationDrukker, M., Katchman, H., Katz, G., Even-Tov Friedman, S., Shezen, E., Hornstein, E., Mandelboim, O., Reisner, Y., & Benvenisty, N. (2006) · Stem Cells · doi:10.1634/stemcells.2005-0188 · Cited by 402 · see citing works
Maminishkis, A., Chen, S., Jalickee, S., Banzon, T., Shi, G., Wang, F. E., Ehalt, T., Hammer, J. A., & Miller, S. S. (2006) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.05-1622 · Cited by 401 · see citing works
Human embryonic stem cells derived without feeder cells
Klimanskaya, I. V., Chung, Y., Meisner, L. F., Johnson, J., West, M. D., & Lanza, R. (2005) · The Lancet · doi:10.1016/s0140-6736(05)66473-2 · Cited by 350 · see citing works
Self-citationAlgvere, P. V., Berglin, L., Gouras, P., & Sheng, Y. (1994) · Graefe's Archive for Clinical and Experimental Ophthalmology · doi:10.1007/bf00184273 · Cited by 346 · see citing works
Generation of histocompatible tissues using nuclear transplantation
Lanza, R., Chung, H. Y., Yoo, J. J., Wettstein, P. J., Blackwell, C. J., Borson, N. D., Hofmeister, E., Schuch, G., Söker, S., Moraes, C. T., et al. (2002) · Nature Biotechnology · doi:10.1038/nbt703 · Cited by 341 · see citing works
Self-citationBinder, S., Krebs, I., Hilgers, R.-D., Abri, A., STOLBA, U., Assadoullina, A., Kellner, L., Stanzel, B. V., Jahn, C., & Feichtinger, H. G. (2004) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.04-0118 · Cited by 231 · see citing works
Binder, S., STOLBA, U., Krebs, I., Kellner, L., Jahn, C., Feichtinger, H. G., Povelka, M., Frohner, U., Kruger, A., Hilgers, R.-D., et al. (2002) · American Journal of Ophthalmology · doi:10.1016/s0002-9394(01)01373-3 · Cited by 218 · see citing works
Essentials of Stem Cell Biology
Lanza, R. (2009) · Elsevier eBooks · doi:10.1016/c2009-0-00078-6 · Cited by 206 · see citing works
Self-citationThumann, G. (2000) · Archives of Ophthalmology · doi:10.1001/archopht.118.10.1350 · Cited by 116 · see citing works
Adult Retinal Pigment Epithelial Transplantation in Exudative Age-related Macular Degeneration
Tezel, T. H., Priore, L. V. D., Berger, A. S., & Kaplan, H. J. (2007) · American Journal of Ophthalmology · doi:10.1016/j.ajo.2006.12.007 · Cited by 101 · see citing works
MacLaren, R. E., Bird, A. C., Sathia, P. J., et al. (2005) · Ophthalmology · doi:10.1016/j.ophtha.2005.06.029 · Cited by 98 · see citing works
Song, M., & Lui, G. M. (1990) · Journal of Cellular Physiology · doi:10.1002/jcp.1041430127 · Cited by 98 · see citing works
Reattachment Rate of Human Retinal Pigment Epithelium to Layers of Human Bruch's Membrane
Priore, L. V. D. (1998) · Archives of Ophthalmology · doi:10.1001/archopht.116.3.335 · Cited by 94 · see citing works
Age related macular degeneration
Chakravarthy, U., Evans, J., & Rosenfeld, P. J. (2010) · BMJ · doi:10.1136/bmj.c981 · Cited by 85 · see citing works
Immunological properties of human embryonic stem cell-derived oligodendrocyte progenitor cells
Okamura, R. M., LEBKOWSKI, J. S., Au, M., Priest, C. A., Denham, J., & Majumdar, A. S. (2007) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2007.09.030 · Cited by 70 · see citing works
Iris pigment epithelial cell translocation in exudative age-related macular degeneration
Lappas, A., Weinberger, A. W. A., Foerster, A. M. H., Kube, T., Rezai, K. A., & Kirchhof, B. (2000) · Graefe s Archive for Clinical and Experimental Ophthalmology · doi:10.1007/s004170000149 · Cited by 70 · see citing works
Concise Review: Toward Stem Cell-Based Therapies for Retinal Neurodegenerative Diseases
Bull, N. D., & Martin, K. R. G. (2011) · Stem Cells · doi:10.1002/stem.676 · Cited by 69 · see citing works
Gamm, D. M., Wright, L. S., Capowski, E. E., et al. (2008) · Stem Cells · doi:10.1634/stemcells.2008-0300 · Cited by 30 · see citing works
Serum-free Media for Culturing and Serial-Passaging of Adult Human Retinal Pigment Epithelium
Tezel, T. H., & Priore, L. V. D. (1998) · Experimental Eye Research · doi:10.1006/exer.1998.0492 · Cited by 30 · see citing works
Lü, F., Yan, D., Zhou, X., Hu, D., & Qu, J. (2007) · PubMed · Cited by 29 · see citing works
Kaplan, H. J., Tezel, T. H., Berger, A. S., et al. (1999) · KARGER eBooks · doi:10.1159/000058747 · Cited by 24 · see citing works
Fink, D. W., & Bauer, S. R. (2009) · Elsevier eBooks · doi:10.1016/b978-0-12-374729-7.00068-8 · Cited by 10 · see citing works
Streilein, J. W. 1.-2. (1999) · Chemical immunology/Fortschritte der Allergielehre/Progress in allergy/Chemical immunology and allergy · doi:10.1159/isbn.978-3-318-00447-2 · Cited by 8 · see citing works
Iris Pigment Epithelial Translocation in the Treatment of Exudative Macular Degeneration
Aisenbrey, S. (2006) · Archives of Ophthalmology · doi:10.1001/archopht.124.2.183
Flagged first, then by citations
Cited by
Sorted by citations
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., et al. (2015) · The Lancet · doi:10.1016/s0140-6736(14)61376-3 · Cited by 1,327 · see citing works
Self-citationNakagawa, M., Taniguchi, Y., Senda, S., Takizawa, N., Ichisaka, T., Asano, K., Morizane, A., Doi, D., Takahashi, J., Nishizawa, M., et al. (2014) · Scientific Reports · doi:10.1038/srep03594 · Cited by 673 · see citing works
Targeted Disruption of HLA Genes via CRISPR-Cas9 Generates iPSCs with Enhanced Immune Compatibility
Xu, H., Wang, B., Ono, M., Kagita, A., Fujii, K., Sasakawa, N., Ueda, T., Gee, P., Nishikawa, M., Nomura, M., et al. (2019) · Cell stem cell · doi:10.1016/j.stem.2019.02.005 · Cited by 581 · see citing works
Deng, Y., Qiao, L., Du, M., Qu, C., Wan, L., Li, J., & Huang, L. (2022) · Genes & Diseases · doi:10.1016/j.gendis.2021.02.009 · Cited by 411 · see citing works
Song, W. K., Park, K.-M., Kim, H.-J., Lee, J. H., Choi, J., Chong, S. Y., Shim, S. H., Del Priore, L. V., & Lanza, R. (2015) · Stem Cell Reports · doi:10.1016/j.stemcr.2015.04.005 · Cited by 393 · see citing works
Self-citationCuenca, N., Fernández-Sánchez, L., Campello, L., Maneu, V., De la Villa, P., Lax, P., & Pinilla, I. (2014) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2014.07.001 · Cited by 401 · see citing works
Doi, D., Magotani, H., Kikuchi, T., Ikeda, M., Hiramatsu, S., Yoshida, K., Amano, N., Nomura, M., Umekage, M., Morizane, A., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-17165-w · Cited by 350 · see citing works
Buchholz, D. E., Pennington, B. O., Croze, R. H., Hinman, C. R., Coffey, P. J., & Clegg, D. O. (2013) · Stem Cells Translational Medicine · doi:10.5966/sctm.2012-0163 · Cited by 261 · see citing works
Influence of donor age on induced pluripotent stem cells
Lo Sardo, V., Ferguson, W., Erikson, G. A., Topol, E. J., Baldwin, K. K., & Torkamani, A. (2017) · Nature Biotechnology · doi:10.1038/nbt.3749 · Cited by 223 · see citing works
Baghbaderani, B. A., Tian, X., Neo, B. H., Burkall, A., Dimezzo, T., Sierra, G., Zeng, X., Warren, K., Kovarcik, D. P., Fellner, T., et al. (2015) · Stem Cell Reports · doi:10.1016/j.stemcr.2015.08.015 · Cited by 212 · see citing works
Small-Molecule-Driven Hepatocyte Differentiation of Human Pluripotent Stem Cells
Siller, R., Greenhough, S., Naumovska, E., & Sullivan, G. J. (2015) · Stem Cell Reports · doi:10.1016/j.stemcr.2015.04.001 · Cited by 203 · see citing works
“Meanwhile, cell culture and production technologies are rapidly improving, and the first instances of pluripotent-cellderived therapies have entered clinical trials (Schwartz et al., 2012).”
BackgroundHLA-Matched Allogeneic iPS Cells-Derived RPE Transplantation for Macular Degeneration
Sugita, S., Mandai, M., Hirami, Y., Takagi, S., Maeda, T., Fujihara, M., Matsuzaki, M., Yamamoto, M., Iseki, K., Hayashi, N., et al. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9072217 · Cited by 190 · see citing works
Subretinal injection: a review on the novel route of therapeutic delivery for vitreoretinal diseases
Peng, Y., Tang, L., & Zhou, Y. (2017) · Ophthalmic Research · doi:10.1159/000479157 · Cited by 175 · see citing works
Progress and challenges in large-scale expansion of human pluripotent stem cells
Kropp, C., Massai, D., & Zweigerdt, R. (2017) · Process Biochemistry · doi:10.1016/j.procbio.2016.09.032 · Cited by 167 · see citing works
Deinsberger, J., Reisinger, D., & Weber, B. (2020) · npj Regenerative Medicine · doi:10.1038/s41536-020-00100-4 · Cited by 158 · see citing works
Pluripotent stem cell-derived retinal organoids for disease modeling and development of therapies
Kruczek, K., & Swaroop, A. (2020) · Stem Cells · doi:10.1002/stem.3239 · Cited by 148 · see citing works
Binley, K., Widdowson, P., Loader, J., Kelleher, M., Iqball, S., Ferrige, G., de Belin, J., Carlucci, M., Angell-Manning, D., Hurst, F., et al. (2013) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.13-11871 · Cited by 115 · see citing works
Bioengineering strategies for restoring vision
Cehajic-Kapetanovic, J., Singh, M. S., Zrenner, E., & MacLaren, R. E. (2022) · Nature Biomedical Engineering · doi:10.1038/s41551-021-00836-4 · Cited by 79 · see citing works
Immunological aspects of RPE cell transplantation
Sugita, S., Mandai, M., Kamao, H., & Takahashi, M. (2021) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2021.100950 · Cited by 77 · see citing works
Developing cellular therapies for retinal degenerative diseases
Bharti, K., Rao, M., Hull, S. C., Stroncek, D., Brooks, B. P., Feigal, E., van Meurs, J. C., Huang, C. A., & Miller, S. S. (2014) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.13-13481 · Cited by 77 · see citing works
Hazim, R. A., Karumbayaram, S., Jiang, M., Dimashkie, A., Lopes, V. S., Li, D., Burgess, B. L., Vijayaraj, P., Alva-Ornelas, J. A., Zack, J. A., et al. (2017) · Stem Cell Research & Therapy · doi:10.1186/s13287-017-0652-9 · Cited by 66 · see citing works
Sorsby fundus dystrophy—A review of pathology and disease mechanisms
Christensen, D. R. G., Brown, F. E., Cree, A. J., Ratnayaka, J. A., & Lotery, A. J. (2017) · Experimental Eye Research · doi:10.1016/j.exer.2017.08.014 · Cited by 60 · see citing works
Regeneration of the retina: toward stem cell therapy for degenerative retinal diseases
Jeon, S., & Oh, I.-H. (2015) · BMB Reports · doi:10.5483/bmbrep.2015.48.4.276 · Cited by 54 · see citing works
Subretinal therapy: technological solutions to surgical and immunological challenges
Ladha, R., Caspers, L. E., Willermain, F., & de Smet, M. D. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.846782 · Cited by 54 · see citing works
Heier, J. S., Ho, A. C., Samuel, M. A., Chang, T., Riemann, C. D., Kitchens, J. W., Slakter, J. S., Leiderman, Y. I., Spencer, R., Williams, G. A., et al. (2020) · Ophthalmology Retina · doi:10.1016/j.oret.2019.11.011 · Cited by 41 · see citing works
Mechanism and treatment strategy of osteoporosis after transplantation
Song, L., Xie, X.-B., Peng, L.-K., Yu, S.-J., & Peng, Y.-T. (2015) · International Journal of Endocrinology · doi:10.1155/2015/280164 · Cited by 30 · see citing works
Stem cell-based therapy for diseases of the retinal pigment epithelium: from bench to bedside
Sachdeva, M. M., & Eliott, D. (2016) · Seminars in Ophthalmology · doi:10.3109/08820538.2015.1115253 · Cited by 28 · see citing works
Gong, J., Fields, M. A., Moreira, E. F., Bowrey, H. E., Gooz, M., Ablonczy, Z., & Del Priore, L. V. (2015) · PLoS ONE · doi:10.1371/journal.pone.0143272 · Cited by 21 · see citing works
New frontiers of retinal therapeutic intervention: a critical analysis of novel approaches
Nanegrungsunk, O., Au, A., Sarraf, D., & Sadda, S. R. (2022) · Annals of Medicine · doi:10.1080/07853890.2022.2066169 · Cited by 20 · see citing works
- Authors
- Schwartz, S. D., Hubschman, J.-P., Heilwell, G., Franco-Cardenas, V., Pan, C. K., Ostrick, R. M., Mickunas, E., Gay, R., Klimanskaya, I., & Lanza, R.
- Affiliations
- University of California, Los Angeles (US)
- Advanced Cell Technology (United States) (US)
- Corresponding author
- Schwartz, Steven D
- Lanza, Robert
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2012-02
- Volume
- 379
- Issue
- 9817
- Pages
- 713-720
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- OpenAlex
- W2045048112
- Cited by
- 1,409
- References
- 34
- Citations by year
- 2026: 23 · 2025: 36 · 2024: 56 · 2023: 49 · 2022: 55 · 2021: 74 · 2020: 97 · 2019: 67 · 2018: 77 · 2017: 117 · 2016: 118 · 2015: 177 · 2014: 192 · 2013: 164 · 2012: 101
- FWCI
- 81.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- human embryonic stem cells, retinal pigment epithelium, cell transplantation, subretinal transplantation, dry age-related macular degeneration, cell differentiation, visual acuity outcomes
- MeSH terms
- Animals, Cell Differentiation, Humans, Immunosuppressive Agents, Macular Degeneration, Mice, Nude, Visual Acuity, Mice, Rats, Embryonic Stem Cells, Retinal Pigment Epithelium
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
