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Subretinal implantation of a monolayer of human embryonic stem cell-derived retinal pigment epithelium: a feasibility and safety study in Yucatán minipigs.
Graefes Arch Clin Exp Ophthalmol. 2016 Aug; 254(8):1553-1565.GA

Abstract

PURPOSE

A subretinal implant termed CPCB-RPE1 is currently being developed to surgically replace dystrophic RPE in patients with dry age-related macular degeneration (AMD) and severe vision loss. CPCB-RPE1 is composed of a terminally differentiated, polarized human embryonic stem cell-derived RPE (hESC-RPE) monolayer pre-grown on a biocompatible, mesh-supported submicron parylene C membrane. The objective of the present delivery study was to assess the feasibility and 1-month safety of CPCB-RPE1 implantation in Yucatán minipigs, whose eyes are similar to human eyes in size and gross retinal anatomy.

METHODS

This was a prospective, partially blinded, randomized study in 14 normal-sighted female Yucatán minipigs (aged 2 months, weighing 24-35 kg). Surgeons were blinded to the randomization codes and postoperative and post-mortem assessments were performed in a blinded manner. Eleven minipigs received CPCB-RPE1 while three control minipigs underwent sham surgery that generated subretinal blebs. All animals except two sham controls received combined local (Ozurdex™ dexamethasone intravitreal implant) and systemic (tacrolimus) immunosuppression or local immunosuppression alone. Correct placement of the CPCB-RPE1 implant was assessed by in vivo optical coherence tomography and post-mortem histology. hESC-RPE cells were identified using immunohistochemistry staining for TRA-1-85 (a human marker) and RPE65 (an RPE marker). As the study results of primary interest were nonnumerical no statistical analysis or tests were conducted.

RESULTS

CPCB-RPE1 implants were reliably placed, without implant breakage, in the subretinal space of the minipig eye using surgical techniques similar to those that would be used in humans. Histologically, hESC-RPE cells were found to survive as an intact monolayer for 1 month based on immunohistochemistry staining for TRA-1-85 and RPE65.

CONCLUSIONS

Although inconclusive regarding the necessity or benefit of systemic or local immunosuppression, our study demonstrates the feasibility and safety of CPCB-RPE1 subretinal implantation in a comparable animal model and provides an encouraging starting point for human studies.

Authors+Show Affiliations

Department of Ophthalmology, University of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany. michael.koss@me.com. USC Eye Institute, University of Southern California, 1450 San Pablo Street, Los Angeles, CA, 90033-4682, USA. michael.koss@me.com.USC Eye Institute, University of Southern California, 1450 San Pablo Street, Los Angeles, CA, 90033-4682, USA.Department of Ophthalmology, Federal University of São Paulo UNIFESP, Rua Botucatu 821, 04023-062, São Paulo, Brazil.USC Eye Institute, University of Southern California, 1450 San Pablo Street, Los Angeles, CA, 90033-4682, USA.USC Eye Institute, University of Southern California, 1450 San Pablo Street, Los Angeles, CA, 90033-4682, USA.USC Eye Institute, University of Southern California, 1450 San Pablo Street, Los Angeles, CA, 90033-4682, USA.Department of Ophthalmology, Federal University of São Paulo UNIFESP, Rua Botucatu 821, 04023-062, São Paulo, Brazil.USC Eye Institute, University of Southern California, 1450 San Pablo Street, Los Angeles, CA, 90033-4682, USA. Department of Pathology, Keck School of Medicine, University of Southern California, 1450 San Pablo Street, Los Angeles, CA, 90033-4682, USA.Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA, 93106-9625, USA.USC Eye Institute, University of Southern California, 1450 San Pablo Street, Los Angeles, CA, 90033-4682, USA. Department of Pathology, Keck School of Medicine, University of Southern California, 1450 San Pablo Street, Los Angeles, CA, 90033-4682, USA.USC Eye Institute, University of Southern California, 1450 San Pablo Street, Los Angeles, CA, 90033-4682, USA. Institute of Biomedical Therapeutics, University of Southern California, 1450 San Pablo Street, Los Angeles, CA, 90033-4682, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27335025

Citation

Koss, Michael J., et al. "Subretinal Implantation of a Monolayer of Human Embryonic Stem Cell-derived Retinal Pigment Epithelium: a Feasibility and Safety Study in Yucatán Minipigs." Graefe's Archive for Clinical and Experimental Ophthalmology = Albrecht Von Graefes Archiv Fur Klinische Und Experimentelle Ophthalmologie, vol. 254, no. 8, 2016, pp. 1553-1565.
Koss MJ, Falabella P, Stefanini FR, et al. Subretinal implantation of a monolayer of human embryonic stem cell-derived retinal pigment epithelium: a feasibility and safety study in Yucatán minipigs. Graefes Arch Clin Exp Ophthalmol. 2016;254(8):1553-1565.
Koss, M. J., Falabella, P., Stefanini, F. R., Pfister, M., Thomas, B. B., Kashani, A. H., Brant, R., Zhu, D., Clegg, D. O., Hinton, D. R., & Humayun, M. S. (2016). Subretinal implantation of a monolayer of human embryonic stem cell-derived retinal pigment epithelium: a feasibility and safety study in Yucatán minipigs. Graefe's Archive for Clinical and Experimental Ophthalmology = Albrecht Von Graefes Archiv Fur Klinische Und Experimentelle Ophthalmologie, 254(8), 1553-1565. https://doi.org/10.1007/s00417-016-3386-y
Koss MJ, et al. Subretinal Implantation of a Monolayer of Human Embryonic Stem Cell-derived Retinal Pigment Epithelium: a Feasibility and Safety Study in Yucatán Minipigs. Graefes Arch Clin Exp Ophthalmol. 2016;254(8):1553-1565. PubMed PMID: 27335025.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Subretinal implantation of a monolayer of human embryonic stem cell-derived retinal pigment epithelium: a feasibility and safety study in Yucatán minipigs. AU - Koss,Michael J, AU - Falabella,Paulo, AU - Stefanini,Francisco R, AU - Pfister,Marcel, AU - Thomas,Biju B, AU - Kashani,Amir H, AU - Brant,Rodrigo, AU - Zhu,Danhong, AU - Clegg,Dennis O, AU - Hinton,David R, AU - Humayun,Mark S, Y1 - 2016/06/22/ PY - 2015/12/16/received PY - 2016/05/11/accepted PY - 2016/03/23/revised PY - 2016/6/24/entrez PY - 2016/6/24/pubmed PY - 2017/3/30/medline KW - Animal model KW - Human embryonic stem cells KW - Macular degeneration KW - Preclinical trial KW - Retinal pigment epithelium SP - 1553 EP - 1565 JF - Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie JO - Graefes Arch Clin Exp Ophthalmol VL - 254 IS - 8 N2 - PURPOSE: A subretinal implant termed CPCB-RPE1 is currently being developed to surgically replace dystrophic RPE in patients with dry age-related macular degeneration (AMD) and severe vision loss. CPCB-RPE1 is composed of a terminally differentiated, polarized human embryonic stem cell-derived RPE (hESC-RPE) monolayer pre-grown on a biocompatible, mesh-supported submicron parylene C membrane. The objective of the present delivery study was to assess the feasibility and 1-month safety of CPCB-RPE1 implantation in Yucatán minipigs, whose eyes are similar to human eyes in size and gross retinal anatomy. METHODS: This was a prospective, partially blinded, randomized study in 14 normal-sighted female Yucatán minipigs (aged 2 months, weighing 24-35 kg). Surgeons were blinded to the randomization codes and postoperative and post-mortem assessments were performed in a blinded manner. Eleven minipigs received CPCB-RPE1 while three control minipigs underwent sham surgery that generated subretinal blebs. All animals except two sham controls received combined local (Ozurdex™ dexamethasone intravitreal implant) and systemic (tacrolimus) immunosuppression or local immunosuppression alone. Correct placement of the CPCB-RPE1 implant was assessed by in vivo optical coherence tomography and post-mortem histology. hESC-RPE cells were identified using immunohistochemistry staining for TRA-1-85 (a human marker) and RPE65 (an RPE marker). As the study results of primary interest were nonnumerical no statistical analysis or tests were conducted. RESULTS: CPCB-RPE1 implants were reliably placed, without implant breakage, in the subretinal space of the minipig eye using surgical techniques similar to those that would be used in humans. Histologically, hESC-RPE cells were found to survive as an intact monolayer for 1 month based on immunohistochemistry staining for TRA-1-85 and RPE65. CONCLUSIONS: Although inconclusive regarding the necessity or benefit of systemic or local immunosuppression, our study demonstrates the feasibility and safety of CPCB-RPE1 subretinal implantation in a comparable animal model and provides an encouraging starting point for human studies. SN - 1435-702X UR - https://www.unboundmedicine.com/medline/citation/27335025/Subretinal_implantation_of_a_monolayer_of_human_embryonic_stem_cell_derived_retinal_pigment_epithelium:_a_feasibility_and_safety_study_in_Yucatán_minipigs_ L2 - https://dx.doi.org/10.1007/s00417-016-3386-y DB - PRIME DP - Unbound Medicine ER -