Process development and safety evaluation of ABCB5+ limbal stem cells as advanced-therapy medicinal product to treat limbal stem cell deficiency
Abstract Background While therapeutic success of the limbal tissue or cell transplantation to treat severe cases of limbal stem cell (LSC) deficiency (LSCD) strongly depends on the percentage of LSCs within the transplanted cells, prospective LSC enrichment has been hampered by the intranuclear loca...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-03-01
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| Series: | Stem Cell Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13287-021-02272-2 |
| _version_ | 1818677679651553280 |
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| author | Alexandra Norrick Jasmina Esterlechner Elke Niebergall-Roth Ulf Dehio Samar Sadeghi Hannes M. Schröder Seda Ballikaya Nicole Stemler Christoph Ganss Kathrin Dieter Ann-Kathrin Dachtler Patrick Merz Saadettin Sel James Chodosh Claus Cursiefen Natasha Y. Frank Gerd U. Auffarth Bruce Ksander Markus H. Frank Mark A. Kluth |
| author_facet | Alexandra Norrick Jasmina Esterlechner Elke Niebergall-Roth Ulf Dehio Samar Sadeghi Hannes M. Schröder Seda Ballikaya Nicole Stemler Christoph Ganss Kathrin Dieter Ann-Kathrin Dachtler Patrick Merz Saadettin Sel James Chodosh Claus Cursiefen Natasha Y. Frank Gerd U. Auffarth Bruce Ksander Markus H. Frank Mark A. Kluth |
| author_sort | Alexandra Norrick |
| collection | DOAJ |
| description | Abstract Background While therapeutic success of the limbal tissue or cell transplantation to treat severe cases of limbal stem cell (LSC) deficiency (LSCD) strongly depends on the percentage of LSCs within the transplanted cells, prospective LSC enrichment has been hampered by the intranuclear localization of the previously reported LSC marker p63. The recent identification of the ATP-binding cassette transporter ABCB5 as a plasma membrane-spanning marker of LSCs that are capable of restoring the cornea and the development of an antibody directed against an extracellular loop of the ABCB5 molecule stimulated us to develop a novel treatment strategy based on the utilization of in vitro expanded allogeneic ABCB5+ LSCs derived from human cadaveric limbal tissue. Methods We developed and validated a Good Manufacturing Practice- and European Pharmacopeia-conform production and quality-control process, by which ABCB5+ LSCs are derived from human corneal rims, expanded ex vivo, isolated as homogenous cell population, and manufactured as an advanced-therapy medicinal product (ATMP). This product was tested in a preclinical study program investigating the cells’ engraftment potential, biodistribution behavior, and safety. Results ABCB5+ LSCs were reliably expanded and manufactured as an ATMP that contains comparably high percentages of cells expressing transcription factors critical for LSC stemness maintenance (p63) and corneal epithelial differentiation (PAX6). Preclinical studies confirmed local engraftment potential of the cells and gave no signals of toxicity and tumorgenicity. These findings were sufficient for the product to be approved by the German Paul Ehrlich Institute and the U.S. Food & Drug Administration to be tested in an international multicenter phase I/IIa clinical trial (NCT03549299) to evaluate the safety and therapeutic efficacy in patients with LSCD. Conclusion Building upon these data in conjunction with the previously shown cornea-restoring capacity of human ABCB5+ LSCs in animal models of LSCD, we provide an advanced allogeneic LSC-based treatment strategy that shows promise for replenishment of the patient’s LSC pool, recreation of a functional barrier against invading conjunctival cells and restoration of a transparent, avascular cornea. |
| first_indexed | 2024-12-17T09:03:12Z |
| format | Article |
| id | doaj.art-05442d04f1184b4784987718c697fe9b |
| institution | Directory Open Access Journal |
| issn | 1757-6512 |
| language | English |
| last_indexed | 2024-12-17T09:03:12Z |
| publishDate | 2021-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Stem Cell Research & Therapy |
| spelling | doaj.art-05442d04f1184b4784987718c697fe9b2022-12-21T21:55:38ZengBMCStem Cell Research & Therapy1757-65122021-03-0112112110.1186/s13287-021-02272-2Process development and safety evaluation of ABCB5+ limbal stem cells as advanced-therapy medicinal product to treat limbal stem cell deficiencyAlexandra Norrick0Jasmina Esterlechner1Elke Niebergall-Roth2Ulf Dehio3Samar Sadeghi4Hannes M. Schröder5Seda Ballikaya6Nicole Stemler7Christoph Ganss8Kathrin Dieter9Ann-Kathrin Dachtler10Patrick Merz11Saadettin Sel12James Chodosh13Claus Cursiefen14Natasha Y. Frank15Gerd U. Auffarth16Bruce Ksander17Markus H. Frank18Mark A. Kluth19TICEBA GmbHTICEBA GmbHTICEBA GmbHRHEACELL GmbH & Co. KGTICEBA GmbHRHEACELL GmbH & Co. KGTICEBA GmbHTICEBA GmbHTICEBA GmbHRHEACELL GmbH & Co. KGRHEACELL GmbH & Co. KGDepartment of Ophthalmology, Lions Eye Bank, University of HeidelbergDepartment of Ophthalmology, University Hospital HeidelbergDepartment of Ophthalmology, Massachusetts Eye & Ear, Harvard Medical SchoolDepartment of Ophthalmology, University Hospital CologneDepartment of Medicine, VA Boston Healthcare SystemDepartment of Ophthalmology, Lions Eye Bank, University of HeidelbergThe Schepens Eye Research Institute, Massachusetts Eye & Ear, Harvard Medical SchoolTransplant Research Program, Boston Children’s Hospital, Harvard Medical SchoolTICEBA GmbHAbstract Background While therapeutic success of the limbal tissue or cell transplantation to treat severe cases of limbal stem cell (LSC) deficiency (LSCD) strongly depends on the percentage of LSCs within the transplanted cells, prospective LSC enrichment has been hampered by the intranuclear localization of the previously reported LSC marker p63. The recent identification of the ATP-binding cassette transporter ABCB5 as a plasma membrane-spanning marker of LSCs that are capable of restoring the cornea and the development of an antibody directed against an extracellular loop of the ABCB5 molecule stimulated us to develop a novel treatment strategy based on the utilization of in vitro expanded allogeneic ABCB5+ LSCs derived from human cadaveric limbal tissue. Methods We developed and validated a Good Manufacturing Practice- and European Pharmacopeia-conform production and quality-control process, by which ABCB5+ LSCs are derived from human corneal rims, expanded ex vivo, isolated as homogenous cell population, and manufactured as an advanced-therapy medicinal product (ATMP). This product was tested in a preclinical study program investigating the cells’ engraftment potential, biodistribution behavior, and safety. Results ABCB5+ LSCs were reliably expanded and manufactured as an ATMP that contains comparably high percentages of cells expressing transcription factors critical for LSC stemness maintenance (p63) and corneal epithelial differentiation (PAX6). Preclinical studies confirmed local engraftment potential of the cells and gave no signals of toxicity and tumorgenicity. These findings were sufficient for the product to be approved by the German Paul Ehrlich Institute and the U.S. Food & Drug Administration to be tested in an international multicenter phase I/IIa clinical trial (NCT03549299) to evaluate the safety and therapeutic efficacy in patients with LSCD. Conclusion Building upon these data in conjunction with the previously shown cornea-restoring capacity of human ABCB5+ LSCs in animal models of LSCD, we provide an advanced allogeneic LSC-based treatment strategy that shows promise for replenishment of the patient’s LSC pool, recreation of a functional barrier against invading conjunctival cells and restoration of a transparent, avascular cornea.https://doi.org/10.1186/s13287-021-02272-2Advanced-therapy medicinal productABCB5GMP manufacturingLimbal stem cell deficiencyLimbal stem cellsp63 |
| spellingShingle | Alexandra Norrick Jasmina Esterlechner Elke Niebergall-Roth Ulf Dehio Samar Sadeghi Hannes M. Schröder Seda Ballikaya Nicole Stemler Christoph Ganss Kathrin Dieter Ann-Kathrin Dachtler Patrick Merz Saadettin Sel James Chodosh Claus Cursiefen Natasha Y. Frank Gerd U. Auffarth Bruce Ksander Markus H. Frank Mark A. Kluth Process development and safety evaluation of ABCB5+ limbal stem cells as advanced-therapy medicinal product to treat limbal stem cell deficiency Stem Cell Research & Therapy Advanced-therapy medicinal product ABCB5 GMP manufacturing Limbal stem cell deficiency Limbal stem cells p63 |
| title | Process development and safety evaluation of ABCB5+ limbal stem cells as advanced-therapy medicinal product to treat limbal stem cell deficiency |
| title_full | Process development and safety evaluation of ABCB5+ limbal stem cells as advanced-therapy medicinal product to treat limbal stem cell deficiency |
| title_fullStr | Process development and safety evaluation of ABCB5+ limbal stem cells as advanced-therapy medicinal product to treat limbal stem cell deficiency |
| title_full_unstemmed | Process development and safety evaluation of ABCB5+ limbal stem cells as advanced-therapy medicinal product to treat limbal stem cell deficiency |
| title_short | Process development and safety evaluation of ABCB5+ limbal stem cells as advanced-therapy medicinal product to treat limbal stem cell deficiency |
| title_sort | process development and safety evaluation of abcb5 limbal stem cells as advanced therapy medicinal product to treat limbal stem cell deficiency |
| topic | Advanced-therapy medicinal product ABCB5 GMP manufacturing Limbal stem cell deficiency Limbal stem cells p63 |
| url | https://doi.org/10.1186/s13287-021-02272-2 |
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