New Technologies in Clinical Trials in Corneal Diseases and Limbal Stem Cell Deficiency: Review from the European Vision Institute Special Interest Focus Group Meeting

Ocular injuries caused by chemical and thermal burns are often unmanageable and frequently result in disfigurement, corneal haze/opacification, and vision loss. Currently, a considerable number of surgical and pharmacological approaches are available to treat such injuries at either an acute or a chronic stage. However, these existing interventions are mainly directed at (and limited to) suppressing corneal inflammation and neovascularization while promoting re-epithelialization. Reconstruction of the ocular surface represents a suitable but last-option recourse in cases where epithelial healing is severely impaired, such as due to limbal stem cell deficiency. In this concise review, we discuss how biomechanical modulation therapy (BMT) may represent a more effective approach to promoting the regeneration of ocular tissues affected by burn injuries via restoration of the limbal stem cell niche. Specifically, the scientific basis supporting this new therapeutic modality is described, along with our growing understanding of the role that tissue biomechanics plays in stem cell fate and function. The potential impact of BMT as a future treatment option for the management of injuries affecting tissue compliance is also further discussed.

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“…11 A more extensive review of these practices and outcomes can be found in a recent report from the European Vision Institute. 37…”

Section: Limbal Stem Cell Transplantationmentioning

confidence: 99%

Biomechanical Modulation Therapy—A Stem Cell Therapy Without Stem Cells for the Treatment of Severe Ocular Burns

Gouveia

Connon

2020

Trans. Vis. Sci. Tech.

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“…In the light of this situation, we strived to develop and validate a GMP-compliant manufacturing process, by which ABCB5 + LSCs from cadaveric human limbal tissue can be expanded in vitro, isolated as a homogenous cell population and manufactured as a clinical-grade ATMP (Fig. 1) [45].…”

Section: Discussionmentioning

confidence: 99%

Process Development and Safety Evaluation of ABCB5+ Limbal Stem Cells as Advanced-therapy Medicinal Product to Treat Limbal Stem Cell Deficiency

Norrick¹,

Esterlechner²,

Niebergall-Roth³

et al. 2020

Preprint

Self Cite

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Background: While therapeutic success of 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 Pharmacopoeia-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.

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“…59 Recently, limbal stem cells from cadaver tissues have been isolated exclusively based on the positive expression of ABCB5, expanded in vitro as advanced therapy medicinal product (ATMP), and transplanted in clinical trials in patients with LSCD. 60 Autologous limbal cultures were the first stem cell-based therapy approved by ATMPs (in 2015), and it has also received marketing authorization as Holoclar from the European Medicine Agency. Holoclar uses the patient's own (autologous) limbal stem cells to treat unilateral LSCD.…”

Section: Historical Perspective and Progressive Shift In Limbal Stem Cell Transplantationmentioning

confidence: 99%

Section: Historical Perspective and Progressive Shift In Limbal Stem Cell Transplantationmentioning

confidence: 99%

Current Perspectives of Limbal-Derived Stem Cells and its Application in Ocular Surface Regeneration and Limbal Stem Cell Transplantation

Singh

Tiwari

Kethiri

et al. 2021

Stem Cells Translational Medicine

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Limbal stem cells are involved in replenishing and maintaining the epithelium of the cornea. Damage to the limbus due to chemical/physical injury, infections, or genetic disorders leads to limbal stem cell deficiency (LSCD) with partial or total vision loss.Presently, LSCD is treated by transplanting limbal stem cells from the healthy eye of the recipient, living-related, or cadaveric donors. This review discusses limbal-derived stem cells, the importance of extracellular matrix in stem cell niche maintenance, the historical perspective of treating LSCD, including related advantages and limitations, and our experience of limbal stem cell transplantation over the decades.

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New Technologies in Clinical Trials in Corneal Diseases and Limbal Stem Cell Deficiency: Review from the European Vision Institute Special Interest Focus Group Meeting

Cited by 15 publications

References 203 publications

Biomechanical Modulation Therapy—A Stem Cell Therapy Without Stem Cells for the Treatment of Severe Ocular Burns

Biomechanical Modulation Therapy—A Stem Cell Therapy Without Stem Cells for the Treatment of Severe Ocular Burns

Process Development and Safety Evaluation of ABCB5+ Limbal Stem Cells as Advanced-therapy Medicinal Product to Treat Limbal Stem Cell Deficiency

Current Perspectives of Limbal-Derived Stem Cells and its Application in Ocular Surface Regeneration and Limbal Stem Cell Transplantation

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