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Preclinical Safety Study Provides Support for hESC-RPE as a Vison Loss Treatment

Review of “Preclinical safety studies of human embryonic stem cell-derived retinal pigment epithelial cells for the treatment of age-related macular degeneration” from STEM CELLS Translational Medicine by Stuart P. Atkinson

Several research groups, including that of Fredrik Lanner (Karolinska Institutet, Stockholm, Sweden), have established defined and xeno‐free differentiation protocols for the efficient derivation of in vivo-like retinal pigment epithelium (RPE) from human embryonic stem cells (hESCs) [1-4]. Furthermore, multiple preclinical and clinical studies [5-9] have provided evidence that the subretinal injection of pluripotent stem cell-derived RPE cell suspensions or sheets can prevent the photoreceptor and vision loss associated with age‐related macular degeneration [10]. 

In their new STEM CELLS Translational Medicine article [11], the Lanner team report on their wide-ranging analyses that provided robust evidence of the safety of hESC‐RPE generated through their optimized in vitro differentiation methodology and described a broad strategy for the preclinical evaluation of all PSC‐based therapies.

Petrus‐Reurer et al. performed a range of safety studies, which included evaluations of genome stability by both karyotype analysis and whole‐genome sequencing, cell purity/absence of undifferentiated ESCs by single-cell RNA sequencing, and potential migratory or tumorigenic properties of transplanted hESC‐RPE via biodistribution and tumorigenicity analyses. In summary, this battery of analyses provided substantial preclinical evidence for the safety of hESC‐RPE generated through the laboratory´s in vitro differentiation methodology [1]. 

The whole‐genome sequencing analysis illustrated the higher existing germline variants load when compared to the variants acquired during in vitro culture or differentiation, thereby underscoring the relative importance of examining genome integrity beyond karyotype. Of note, the relatively small number of non-recurrent mutations that appeared in the hESC‐RPE did not locate to any know cancer‐driver gene. Meanwhile, functional studies failed to show any teratoma formation seven months after subcutaneous injection of hESC-RPE in immunodeficient mice or cell migration to other organs in the mouse or following the integration of hESC‐RPE into the subretinal space of the rabbit eye.

Overall, the authors highlight comparative genome‐wide genomic analysis and single‐cell characterization using flow cytometry and transcriptional analysis as perhaps a more informative approach when developing and testing new hPSC‐derived therapies, when compared to “gold standard” functional assays, such as tumorigenicity and biodistribution studies

For more on the safety and efficacy of hESC‐RPE transplantation to battle vision loss, stay tuned to the Stem Cells Portal.


  1. Plaza Reyes A, Petrus-Reurer S, Antonsson L, et al., Xeno-Free and Defined Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells Functionally Integrate in a Large-Eyed Preclinical Model. Stem Cell Reports 2016;6:9-17.
  2. Thomas BB, Zhu D, Zhang L, et al., Survival and Functionality of hESC-Derived Retinal Pigment Epithelium Cells Cultured as a Monolayer on Polymer Substrates Transplanted in RCS Rats. Investigative Ophthalmology & Visual Science 2016;57:2877-2887.
  3. McGill TJ, Bohana-Kashtan O, Stoddard JW, et al., Long-Term Efficacy of GMP Grade Xeno-Free hESC-Derived RPE Cells Following Transplantation. Translational Vision Science & Technology 2017;6:17-17.
  4. Vaajasaari H, Ilmarinen T, Juuti-Uusitalo K, et al., Toward the defined and xeno-free differentiation of functional human pluripotent stem cell-derived retinal pigment epithelial cells. Mol Vis 2011;17:558-75.
  5. da Cruz L, Fynes K, Georgiadis O, et al., Phase 1 clinical study of an embryonic stem cell–derived retinal pigment epithelium patch in age-related macular degeneration. Nature Biotechnology 2018;36:328-337.
  6. Mandai M, Watanabe A, Kurimoto Y, et al., Autologous Induced Stem-Cell–Derived Retinal Cells for Macular Degeneration. New England Journal of Medicine 2017;376:1038-1046.
  7. Schwartz SD, Tan G, Hosseini H, et al., Subretinal Transplantation of Embryonic Stem Cell–Derived Retinal Pigment Epithelium for the Treatment of Macular Degeneration: An Assessment at 4 Years. Investigative Ophthalmology & Visual Science 2016;57:ORSFc1-ORSFc9.
  8. Song Won K, Park K-M, Kim H-J, et al., Treatment of Macular Degeneration Using Embryonic Stem Cell-Derived Retinal Pigment Epithelium: Preliminary Results in Asian Patients. Stem Cell Reports 2015;4:860-872.
  9. Kashani AH, Lebkowski JS, Rahhal FM, et al., A bioengineered retinal pigment epithelial monolayer for advanced, dry age-related macular degeneration. Science Translational Medicine 2018;10:eaao4097.
  10. Ambati J, Ambati BK, Yoo SH, et al., Age-Related Macular Degeneration: Etiology, Pathogenesis, and Therapeutic Strategies. Survey of Ophthalmology 2003;48:257-293.
  11. Petrus-Reurer S, Kumar P, Padrell Sánchez S, et al., Preclinical safety studies of human embryonic stem cell-derived retinal pigment epithelial cells for the treatment of age-related macular degeneration. STEM CELLS Translational Medicine 2020;9:936-953.