Universität zu Köln

Norrick, Alexandra, Esterlechner, Jasmina, Niebergall-Roth, Elke, Dehio, Ulf, Sadeghi, Samar, Schroeder, Hannes M., Ballikaya, Seda, Stemler, Nicole, Ganss, Christoph, Dieter, Kathrin, Dachtler, Ann-Kathrin, Merz, Patrick, Sel, Saadettin ORCID: 0000-0003-3307-3305, Chodosh, James, Cursiefen, Claus, Frank, Natasha Y., Auffarth, Gerd U., Ksander, Bruce, Frank, Markus H. and Kluth, Mark A. (2021). Process development and safety evaluation of ABCB5(+) limbal stem cells as advanced-therapy medicinal product to treat limbal stem cell deficiency. Stem Cell Res. Ther., 12 (1). LONDON: BMC. ISSN 1757-6512

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Norrick, Alexandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Esterlechner, Jasmina UNSPECIFIED UNSPECIFIED UNSPECIFIED Niebergall-Roth, Elke UNSPECIFIED UNSPECIFIED UNSPECIFIED Dehio, Ulf UNSPECIFIED UNSPECIFIED UNSPECIFIED Sadeghi, Samar UNSPECIFIED UNSPECIFIED UNSPECIFIED Schroeder, Hannes M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ballikaya, Seda UNSPECIFIED UNSPECIFIED UNSPECIFIED Stemler, Nicole UNSPECIFIED UNSPECIFIED UNSPECIFIED Ganss, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Dieter, Kathrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Dachtler, Ann-Kathrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Merz, Patrick UNSPECIFIED UNSPECIFIED UNSPECIFIED Sel, Saadettin UNSPECIFIED orcid.org/0000-0003-3307-3305 UNSPECIFIED Chodosh, James UNSPECIFIED UNSPECIFIED UNSPECIFIED Cursiefen, Claus UNSPECIFIED UNSPECIFIED UNSPECIFIED Frank, Natasha Y. UNSPECIFIED UNSPECIFIED UNSPECIFIED Auffarth, Gerd U. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ksander, Bruce UNSPECIFIED UNSPECIFIED UNSPECIFIED Frank, Markus H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kluth, Mark A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-601023
DOI:	10.1186/s13287-021-02272-2
Journal or Publication Title:	Stem Cell Res. Ther.
Volume:	12
Number:	1
Date:	2021
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	1757-6512
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language Cell & Tissue Engineering; Cell Biology; Medicine, Research & Experimental Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/60102