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      Navigating Market Authorization: The Path Holoclar Took to Become the First Stem Cell Product Approved in the European Union

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          Abstract

          Gene therapy, cell therapy, and tissue engineering have the potential to revolutionize the treatment of disease and injury. Attaining marketing authorization for such advanced therapy medicinal products (ATMPs) requires a rigorous scientific evaluation by the European Medicines Agency—authorization is only granted if the product can fulfil stringent requirements for quality, safety, and efficacy. However, many ATMPs are being provided to patients under alternative means, such as “hospital exemption” schemes. Holoclar (ex vivo expanded autologous human corneal epithelial cells containing stem cells), a novel treatment for eye burns, is one of the few ATMPs to have been granted marketing authorization and is the first containing stem cells. This review highlights the differences in standards between an authorized and unauthorized medicinal product, and specifically discusses how the manufacture of Holoclar had to be updated to achieve authorization. The result is that patients will have access to a therapy that is manufactured to high commercial standards, and is supported by robust clinical safety and efficacy data. stem cells translational medicine 2018;7:146–154

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          Most cited references20

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          Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells.

          Human diploid epidermis epidermal cells have been successfully grown in serial culture. To initiate colony formation, they require the presence of fibroblasts, but proliferation of fibroblasts must be controlled so that the epidermal cell population is not overgrown. Both conditions can be achieved by the use of lethally irradiated 3T3 cells at the correct density. When trypsinized human skin cells are plated together with the 3T3 cells, the growth of the human fibroblasts is largely suppressed, but epidermal cells grow from single cells into colonies. Each colony consists of keratinocytes ultimately forming a stratified squamous epithelium in which the dividing cells are confined to the lowest layer(s). Hydrocortisone is added to the medium, since in secondary and subsequent subcultures it makes the colony morphology more oderly and distinctive, and maintains proliferation at a slightly greater rate. Under these culture conditions, it is possible to isolate keratinocyte clones free of viable fibroblasts. Like human diploid fibroblasts, human diploid keratinocytes appear to have a finite culture lifetime. For 7 strains studied, the culture lifetime ranged from 20-50 cell generations. The plating efficiency of the epidermal cells taken directly from skin was usually 0.1-1.0%. On subsequent transfer of the cultures initiated from newborns, the plating efficiency rose to 10% or higher, but was most often in the range of 1-5% and dropped sharply toward the end of their culture life. The plating efficiency and culture lifetime were lower for keratinocytes of older persons.
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            p63 identifies keratinocyte stem cells.

            The proliferative compartment of stratified squamous epithelia consists of stem and transient amplifying (TA) keratinocytes. Some polypeptides are more abundant in putative epidermal stem cells than in TA cells, but no polypeptide confined to the stem cells has yet been identified. Here we show that the p63 transcription factor, a p53 homologue essential for regenerative proliferation in epithelial development, distinguishes human keratinocyte stem cells from their TA progeny. Within the cornea, nuclear p63 is expressed by the basal cells of the limbal epithelium, but not by TA cells covering the corneal surface. Human keratinocyte stem and TA cells when isolated in culture give rise to holoclones and paraclones, respectively. We show by clonal analysis that p63 is abundantly expressed by epidermal and limbal holoclones, but is undetectable in paraclones. TA keratinocytes, immediately after their withdrawal from the stem cell compartment (meroclones), have greatly reduced p63, even though they possess very appreciable proliferative capacity. Clonal evolution (i.e., generation of TA cells from precursor stem cells) is promoted by the sigma isoform of the 14-3-3 family of proteins. Keratinocytes whose 14-3-3final sigma has been down-regulated remain in the stem cell compartment and maintain p63 during serial cultivation. The identification of p63 as a keratinocyte stem cell marker will be of practical importance for the clinical application of epithelial cultures in cell therapy as well as for studies on epithelial tumorigenesis.
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              Three clonal types of keratinocyte with different capacities for multiplication.

              Colony-forming human epidermal cells are heterogeneous in their capacity for sustained growth. Once a clone has been derived from a single cell, its growth potential can be estimated from the colony types resulting from a single plating, and the clone can be assigned to one of three classes. The holoclone has the greatest reproductive capacity: under standard conditions, fewer than 5% of the colonies formed by the cells of a holoclone abort and terminally differentiate. The paraclone contains exclusively cells with a short replicative lifespan (not more than 15 cell generations), after which they uniformly abort and terminally differentiate. The third type of clone, the meroclone, contains a mixture of cells of different growth potential and is a transitional stage between the holoclone and the paraclone. The incidence of the different clonal types is affected by aging, since cells originating from the epidermis of older donors give rise to a lower proportion of holoclones and a higher proportion of paraclones.
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                Author and article information

                Contributors
                graziella.pellegrini@unimore.it
                Journal
                Stem Cells Transl Med
                Stem Cells Transl Med
                10.1002/(ISSN)2157-6580
                SCT3
                Stem Cells Translational Medicine
                John Wiley and Sons Inc. (Hoboken )
                2157-6564
                2157-6580
                27 December 2017
                January 2018
                : 7
                : 1 ( doiID: 10.1002/sct3.2018.7.issue-1 )
                : 146-154
                Affiliations
                [ 1 ] Center for Regenerative Medicine ‘‘Stefano Ferrari’’, University of Modena and Reggio Emilia Modena Italy
                [ 2 ] Holostem Terapie Avanzate Modena Italy
                [ 3 ] Chiesi Farmaceutici SpA Parma Italy
                Author notes
                [*] [* ]Correspondence: Graziella Pellegrini, Ph.D., Head of Cell Therapy Program, Center for Regenerative Medicine, Department of Surgical, Medical and Dental Department of Morphological Sciences, University of Modena e Reggio Emilia, via Glauco Gottardi 100, 41125 Modena, Italy. Telephone: 059‐2058064; e‐mail: graziella.pellegrini@ 123456unimore.it
                Author information
                http://orcid.org/0000-0001-9861-0736
                Article
                SCT312245
                10.1002/sctm.17-0003
                5746151
                29280318
                0ead9f4f-ed12-4f7e-8e89-9b0b79dc2b88
                © 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 05 January 2017
                : 18 July 2017
                Page count
                Figures: 3, Tables: 4, Pages: 9, Words: 7837
                Categories
                Tissue Engineering and Regenerative Medicine
                Limbal Epithelial /Corneal Stem Cells
                Adult Stem Cells
                Cell Culture Advances
                Cell Delivery Strategies
                Clinical Application / Translation
                Technological Advancements
                Tissue Engineering and Regenerative Medicine
                Translational Research Articles and Reviews
                Tissue Engineering and Regenerative Medicine
                Custom metadata
                2.0
                sct312245
                January 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.2.8 mode:remove_FC converted:28.12.2017

                adult stem cells,autologous stem cell transplantation,cellular therapy,stem/progenitor cell,tissue regeneration,tissue‐specific stem cells

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