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

Pellegrini, Graziella; Ardigò, Diego; Milazzo, Giovanni; Iotti, Giorgio; Guatelli, Paolo; Pelosi, Danilo; Luca, Michele De

doi:10.1002/sctm.17-0003

Cited by 126 publications

(97 citation statements)

References 25 publications

(26 reference statements)

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“…Therapeutic regeneration of the corneal epithelium primarily using stem cells of limbal origin in various forms has received much attention and gained widespread clinical use, including the first European Medicines Agency approved stem cell product, Holoclar. 1 Likewise, endothelial regeneration therapy promoted through the use of a donor endothelial cell suspension has entered first clinical trials for bullous keratopathy. 2 The bulk of the corneal tissue, however, consists of the corneal stroma, which comprises over 90% of the corneal thickness and imparts to the cornea its transparency, curvature and strength, and additionally protects the inner eye structures from the external environment.…”

Section: Introductionmentioning

confidence: 99%

Corneal Stromal Regeneration: Current Status and Future Therapeutic Potential

Lagali

2019

Current Eye Research

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The corneal stroma comprises 90% of the corneal thickness and is critical for the cornea's transparency and refractive function necessary for vision. When the corneal stroma is altered by disease, injury, or scarring, however, an irreversible loss of transparency can occur. Corneal stromal pathology is the cause of millions of cases of blindness globally, and although corneal transplantation is the standard therapy, a severe global deficit of donor corneal tissue and eye banking infrastructure exists, and is unable to meet the overwhelming need. An alternative approach is to harness the endogenous regenerative ability of the corneal stroma, which exhibits self-renewal of the collagenous extracellular matrix under appropriate conditions. To mimic endogenous stromal regeneration, however, is a challenge. Unlike the corneal epithelium and endothelium, the corneal stroma is an exquisitely organized extracellular matrix containing stromal cells, proteoglycans and corneal nerves that is difficult to recapitulate in vitro. Nevertheless, much progress has recently been made in developing stromal equivalents, and in this review the most recent approaches to stromal regeneration therapy are described and discussed. Novel approaches for stromal regeneration include human or animal corneal and/or non-corneal tissue that is acellular or is decellularized and/or recellularized, acellular bioengineered stromal scaffolds, tissue adhesives, 3D bioprinting and stromal stem cell therapy. This review highlights the techniques and advances that have achieved first clinical use or are close to translation for eventual therapeutic application in repairing and regenerating the corneal stroma, while the potential of these novel therapies for achieving effective stromal regeneration is discussed. ARTICLE HISTORY

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Section: Introductionmentioning

confidence: 99%

Corneal Stromal Regeneration: Current Status and Future Therapeutic Potential

Lagali

2019

Current Eye Research

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“…However, it is possible to substitute AM for mouse feeder cells . As evidence of its safety, in 2015, the CLET technique advanced to become the first stem cell‐based therapy to receive approval for application throughout the European Union (EU) under the trade name “Holoclar” …”

Section: Current Options For Treatment Of Lscdmentioning

confidence: 99%

“…11,12 As evidence of its safety, in 2015, the CLET technique advanced to become the first stem cell-based therapy to receive approval for application throughout the European Union (EU) under the trade name "Holoclar". 13 Several non-limbal cell types have also shown promise in treating LSCD, offering options for treatment of bilateral LSCD using autologous cells and avoiding immunosuppression. 14 Among alternatives, the cultured oral mucosal epithelial transplantation (COMET) technique has been most widely reported.…”

Section: Current Options For Treatment Of Lscdmentioning

confidence: 99%

Simple limbal epithelial transplantation: Current status and future perspectives

Jackson

Ernø

Ringstad

et al. 2019

Stem Cells Translational Medicine

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Damage to limbal stem cells as a result of injury or disease can lead to limbal stem cell deficiency (LSCD). This disease is characterized by decreased vision that is often painful and may progress to blindness. Clinical features include inflammation, neovascularization, and persistent cornea epithelial defects. Successful strategies for treatment involve transplantation of grafts harvested from the limbus of the alternate healthy eye, called conjunctival‐limbal autograft (CLAU) and transplantation of limbal cell sheets cultured from limbal biopsies, termed cultured limbal epithelial transplantation (CLET). In 2012, Sangwan and colleagues presented simple limbal epithelial transplantation (SLET), a novel transplantation technique that combines the benefits of CLAU and CLET and avoids the challenges associated with both. In SLET a small biopsy from the limbus of the healthy eye is divided and distributed over human amniotic membrane, which is placed on the affected cornea. Outgrowth occurs from each small explant and a complete corneal epithelium is typically formed within 2 weeks. Advantages of SLET include reduced risk of iatrogenic LSCD occurring in the healthy cornea at harvest; direct transfer circumventing the need for cell culture; and the opportunity to perform biopsy harvest and transplantation in one operation. Success so far using SLET is comparable with CLAU and CLET. Of note, 336 of 404 (83%) operations using SLET resulted in restoration of the corneal epithelium, whereas visual acuity improved in 258 of the 373 (69%) reported cases. This review summarizes the results of 31 studies published on SLET since 2012. Progress, advantages, challenges, and suggestions for future studies are presented.

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“…This is the case of Alo sel®, a cell therapy product based on adipose-derived mesenchymal stem cells to treat perianal stulas in Crohn's disease, 3 and Holoclar®, a product catalogued as a tissue engineering product used in corneal diseases which is based on the generation of brin membranes coated with a population of corneal tissue cells among which are limbal stem cells. 4 In addition, clinical trials based on ex vivo and in vivo gene therapies have increased due to its wide potential in monogenic disorders such as cystic brosis, adenosine deaminase de ciency (ADA-SCID) or haemophilia B (factor IX de ciency) among others. 5 European Medicines Agency (EMA) and Food and Drug Administration (FDA) regulatory entities have recently approved several gene derived ATMPs.…”

Section: Introductionmentioning

confidence: 99%

Cell Banking of HEK293T Cell Line for Clinical-Grade Lentiviral Particles Manufacturing

Perpiñá

Herranz

Martín‐Ibáñez

et al. 2020

Preprint

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Background: Cell banks have been widely used to preserve cell properties as well as to record and control cell line access in research. However, the generation of cell banks involved in the manufacturing of Advanced therapy medicinal products such as cell or gene therapy products must comply with the current Good Manufacturing Practice regulation. Similarly, the quality of those cell lines used as starting materials in viral-vector manufacturing processes must be also evaluated.Methods: Three batches of both Master Cell Bank and Working Cell Bank of the HEK293T cell line were manufactured under the current Good Manufacturing Practices regulation. Quality control test were performed according to the product specifications. The process validation includes previous qualification of the manufacturing personnel by performing simulation tests as well as the continuous measure of environmental parameters during manufacturing such as air particles and microorganism. Cell number and viability of cryopreserved cells were periodically measured in order to define the stability of these cellular products.Results: All batches of Master Cell Bank and Working Cell Bank fulfilled the acceptance criteria of their specifications showing the robustness and homogeneity of the processes. In addition, both Master and Working cell bank maintain the defined viability and cell number 37 months after cryopreservation. Conclusions: Manufacturing cell banks under Good Manufacturing Practices regulation for its use as raw material or final cellular product is feasible. HEK293T cell banks have been used to manufacture clinical-grade lentiviral particles for Chimeric Antigen Receptor T-cell based clinical trials.

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

Cited by 126 publications

References 25 publications

Corneal Stromal Regeneration: Current Status and Future Therapeutic Potential

Corneal Stromal Regeneration: Current Status and Future Therapeutic Potential

Simple limbal epithelial transplantation: Current status and future perspectives

Cell Banking of HEK293T Cell Line for Clinical-Grade Lentiviral Particles Manufacturing

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