RARE DISEASE
Limbal stem cell deficiency
Limbal stem cell deficiency
Limbal stem cell deficiency
Drug discovery
9
drugs
With orphan designations
Overview
Limbal stem cell deficiency (LSCD) is a vision-threatening condition caused by dysfunction or loss of limbal stem cells, impairing corneal epithelial regeneration. This leads to conjunctivalization, neovascularization, and opacity, with symptoms including chronic pain, photophobia, and irreversible vision loss. Etiologies range from trauma (chemical burns, surgery) to autoimmune disorders (Stevens-Johnson syndrome) and congenital conditions (aniridia). Diagnosis relies on clinical evaluation and staging systems, while treatment combines medical optimization of the ocular surface and surgical stem cell transplantation [1][4][9][12].
Population
Primarily affects young, working-age males (mean age ~35 years), with higher incidence in rural populations and those with limited education [12][16][19].
Unilateral cases (50–60%) are more common than bilateral, often linked to chemical injuries or contact lens misuse; bilateral cases typically stem from autoimmune/inflammatory conditions [2][4][12].
Categories: rare ophthalmic disorders
Research Papers
1,463 drug discovery papers about Limbal stem cell deficiency, with 3 first-in-class and 10 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,463 drug discovery papers about Limbal stem cell deficiency, with 3 first-in-class and 10 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-09 | State-of-the-art advances in tissue-engineered corneal substitutes: a systematic review (2020-2025).
Corneal blindness remains a major global health burden, limited by donor shortage and graft-related complications. Tissue-engineered corneal substitutes have emerged as a promising alternative, aiming to restore corneal structure and function through bioengineered constructs. To systematically review recent advances (2020-2025) in tissue-engineered corneal substitutes, classifying them according to the corneal layer replaced and evaluating their biological, optical, and functional performance, as well as their translational potential for clinical application. A systematic review. A systematic review was conducted following Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) 2020 guidelines. Searches were performed in PubMed/MEDLINE, Scopus, and Web of Science using predefined keywords related to corneal tissue engineering. Eligible studies included experimental, preclinical, or clinical studies published between January 2020 and June 2025 describing cell-based corneal substitutes. Studies focused on keratoprostheses (KPros), acellular scaffolds, or non-cellular biomaterials were excluded. Fourteen studies met the inclusion criteria: five endothelial, three stromal, one epithelial, and five epithelium-stroma substitutes. Endothelial models demonstrated cell viability, expression of tight junction proteins (ZO-1, Na+/K+-ATPase), and partial restoration of corneal transparency in animal and ex vivo systems. Stromal models incorporated advanced biofabrication techniques such as 3D bioprinting and neuronal co-culture, achieving > 80% optical transmittance and adequate biomechanical properties. The single epithelial model achieved complete re-epithelialization in a rabbit limbal deficiency model. Multilayered epithelium-stroma substitutes, including the NANOULCOR (Tissue Engineering Group, University of Granada, Granada, Spain) construct, exhibited safety and feasibility in preclinical and early clinical studies. Recent progress in corneal tissue engineering has yielded increasingly functional and biocompatible substitutes that replicate native corneal architecture. However, most studies remain limited by small sample sizes, short follow-up, and reliance on animal models. Further standardized clinical trials are required for clinical translation. Not applicable.
2026-08-04 | Refining How We Diagnose and Classify Limbal Stem Cell deficiency.
Refining How We Diagnose and Classify Limbal Stem Cell deficiency CLINICAL RELEVANCE: With the development of multimodal anterior segment imaging modalities and molecular diagnostic tests for the diagnosis and staging of limbal stem cell deficiency (LSCD), and better understanding of LSCD presentation and pathophysiology, a comprehensive step-by-step algorithm is established to more precisely evaluate the ocular surface environment and stage the disease. This is a review of the most relevant publications on the method of diagnosing and staging LSCD. Clinical presentation and pathophysiology of LSCD were reviewed. Factors that impact LSC function and survival were discussed and outlined. The International LSCD Working Group has put forth the first guidelines on the clinical definition, classification, diagnosis, staging, and management of LSCD. Precise diagnosis and staging of LSCD is limited by subjective nature of the fluorescein staining test. As other comorbidities negatively impact the function of both corneal epithelial cells and LSCs, assessment of these comorbidities such as dry eye disease, ocular surface inflammation, corneal innervation, conjunctival health, medication toxicity, and eyelid abnormalities should be included in the initial evaluation of LSC function. Advances in anterior segment imaging, including anterior segment optical coherence tomography and in vivo confocal microscopy allow objective evaluation of epithelial phenotype, cellular morphology, basal cell density, corneal innervation, and inflammatory cell infiltration in both the cornea and limbus. The knowledge of ocular surface microstructure provides important information regarding the corneal and limbal epithelial cell function, remaining LSC reserve, and factors associated with LSCD improvement after all comorbidities are treated. Impression cytology remains a valuable tool for objectively confirming conjunctivalization through assessment of epithelial phenotype. LSCD diagnosis and classification have advanced beyond the simple fluorescein staining test for the detection of abnormal epithelial cells on the corneal surface. A comprehensive assessment of the LSC function and the ocular surface environment by integrating multimodal imaging and molecular testing enables precise staging of LSC function and identification of factors that influence LSCD reversibility. Adoption of a standardized multimodal diagnostic framework will improve diagnostic accuracy, guide the management of the disease, facilitate comparisons across clinical studies, and support the development and evaluation of emerging cell-based and cell-free regenerative therapies for LSCD.
2026-07-29 | Enhancing the Outgrowth of Oral Mucosal Cell Sheets for Cultivated Rabbit Oral Mucosal Epithelial Transplantation with ROCK Inhibitor.
Cultivated oral mucosal epithelial transplantation (COMET) is an effective way to treat limbal stem cell deficiency (LSCD), but its clinical usage is limited due to prolonged cultivation time and complexity. Rho-associated protein kinase (ROCK) inhibitors have been found to enhance cell proliferation, migration, and cytoskeleton maintenance. We investigated whether ROCK inhibitor (Y-27632) can be used to enhance the growth of oral mucosal epithelial cell sheet while remaining their characteristics, optimizing COMET usage for LSCD treatment. Oral mucosal epithelial cells were harvested from rabbits and cultured using a collagenase-based isolation technique. Cells were seeded in a transwell plate with or without amniotic membrane (AM) and Y-27632. The speed of cell sheet outgrowth and cell density were evaluated. Stem cell marker (p63), cytokeratin (K3, K4 and K13) and junctional protein markers (ZO-1, occludin, connexin 43) were analyzed by immunostaining with confocal microscopy. Y-27632 and AM coating facilitated the outgrowth of cell sheets, resulting in a larger expansion area from day 7 to day 15 (p < 0.05). Y-27632 treatment dose-dependently increased basal cell density (p < 0.05) and inhibited the squamous differentiation of the superficial layer, while maintaining cytokeratin and junctional protein markers expression. Y-27632 increased the p63-positive cells population (p < 0.05), which may play a role in maintaining stem cell properties and inhibiting differentiation. Y-27632, together with AM, provides an efficient and supportive environment for producing oral mucosal epithelial cell sheets for transplantation. They might serve as an adjunctive agent to accelerate oral epithelial cell-based therapy for the treatment of limbal stem cell deficiency.
2026-07-15 | Subconjunctival Injection of Mesenchymal Stem Cells for Corneal Wound Healing After Chemical Injury: Impact on Epithelial Coverage, Limbal Ischemia, and Ocular Surface Inflammatory.
Previous studies in animal models have demonstrated that mesenchymal stem cells (MSCs) are beneficial for reconstructing the ocular surface during corneal wound healing; however, clinical evidence remains scarce. This study aimed to evaluate the clinical safety, feasibility, and preliminary outcomes of subconjunctival umbilical-cord delivered-MSC (UC-MSC) injection as an adjunctive therapy for severe corneal chemical injuries. This prospective, single-arm clinical case series enrolled six patients with severe corneal chemical injuries. Human UC-MSCs at passages 5-6 were cultured and verified. A total sample of 4 × 106 cells suspended in 400 μL of 1 × Hanks' Balanced Salt Solution (HBSS) were subconjunctivally delivered adjacent to the limbus using a 360° circumferential injection technique. Concurrently, all patients underwent amniotic membrane transplantation (AMT) and received a standard 4-week topical regimen (Tobradex, recombinant human epidermal growth factor, and Solcoseryl). Clinical safety, limbal ischemia, inflammatory indices, and epithelial defect areas were assessed through a digital slit-lamp examination. No localized or systemic adverse events, such as anterior uveitis, progressive ulceration, intraocular infection, or immunological rejection, were observed in any participant. By 4 weeks post-injection, active ocular surface inflammation had significantly decreased in all eyes. Of the five patients with baseline limbal ischemia, four achieved complete revascularization and resolution; the fifth exhibited a marked reduction in ischemia from 100 to 20%. Furthermore, stable corneal re-epithelialization was achieved in five of six eyes, including one with complete paracentral epithelial coverage. Subconjunctival UC-MSC delivery is a safe and feasible adjunctive therapy for managing severe corneal chemical injuries. This cell-based intervention synergizes with conventional therapies to suppress acute inflammation, rescue limbal perfusion while potentially mitigating subsequent corneal neovascularization, and accelerate the structural reconstruction of the ocular surface microenvironment.
2026-07-13 | Therapeutic Potential of Mesenchymal Stem Cell-Derived Exosomes in Ocular Surface Disorders.
The global burden of ocular surface disorders (OSDs), manifesting as progressive visual impairment and chronic discomfort, has driven urgent exploration of regenerative therapeutic strategies. Mesenchymal stem cell-derived exosomes (MSC-Exos) have emerged as promising candidates for OSD treatment, as they exhibit multifaceted therapeutic properties including immunomodulation, antifibrotic activity, and pro-regenerative capacity. This systematic review consolidates current understanding of MSC-Exo-mediated ocular surface repair mechanisms, with particular emphasis on the molecular dialog established through delivery of bioactive cargo that modulate pivotal signaling pathways. We critically analyze preclinical evidence demonstrating therapeutic efficacy across diverse OSD pathologies, including dry eye disease, corneal epithelial defects, and limbal stem cell deficiency. Notwithstanding these advances, critical barriers to clinical translation persist: (1) methodological heterogeneity arising from variable cell sourcing, culture protocols, and exosome isolation/characterization standards; (2) discordance between animal models and human OSD pathophysiology; and (3) technological limitations in scalable, clinically compatible delivery systems. Addressing these challenges requires interdisciplinary collaboration to standardize exosome production pipelines and establish robust preclinical validation frameworks, thereby accelerating the transition of MSC-Exo therapies from bench to bedside.
2026-08-09 | State-of-the-art advances in tissue-engineered corneal substitutes: a systematic review (2020-2025).
Corneal blindness remains a major global health burden, limited by donor shortage and graft-related complications. Tissue-engineered corneal substitutes have emerged as a promising alternative, aiming to restore corneal structure and function through bioengineered constructs. To systematically review recent advances (2020-2025) in tissue-engineered corneal substitutes, classifying them according to the corneal layer replaced and evaluating their biological, optical, and functional performance, as well as their translational potential for clinical application. A systematic review. A systematic review was conducted following Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) 2020 guidelines. Searches were performed in PubMed/MEDLINE, Scopus, and Web of Science using predefined keywords related to corneal tissue engineering. Eligible studies included experimental, preclinical, or clinical studies published between January 2020 and June 2025 describing cell-based corneal substitutes. Studies focused on keratoprostheses (KPros), acellular scaffolds, or non-cellular biomaterials were excluded. Fourteen studies met the inclusion criteria: five endothelial, three stromal, one epithelial, and five epithelium-stroma substitutes. Endothelial models demonstrated cell viability, expression of tight junction proteins (ZO-1, Na+/K+-ATPase), and partial restoration of corneal transparency in animal and ex vivo systems. Stromal models incorporated advanced biofabrication techniques such as 3D bioprinting and neuronal co-culture, achieving > 80% optical transmittance and adequate biomechanical properties. The single epithelial model achieved complete re-epithelialization in a rabbit limbal deficiency model. Multilayered epithelium-stroma substitutes, including the NANOULCOR (Tissue Engineering Group, University of Granada, Granada, Spain) construct, exhibited safety and feasibility in preclinical and early clinical studies. Recent progress in corneal tissue engineering has yielded increasingly functional and biocompatible substitutes that replicate native corneal architecture. However, most studies remain limited by small sample sizes, short follow-up, and reliance on animal models. Further standardized clinical trials are required for clinical translation. Not applicable.
2026-08-04 | Refining How We Diagnose and Classify Limbal Stem Cell deficiency.
Refining How We Diagnose and Classify Limbal Stem Cell deficiency CLINICAL RELEVANCE: With the development of multimodal anterior segment imaging modalities and molecular diagnostic tests for the diagnosis and staging of limbal stem cell deficiency (LSCD), and better understanding of LSCD presentation and pathophysiology, a comprehensive step-by-step algorithm is established to more precisely evaluate the ocular surface environment and stage the disease. This is a review of the most relevant publications on the method of diagnosing and staging LSCD. Clinical presentation and pathophysiology of LSCD were reviewed. Factors that impact LSC function and survival were discussed and outlined. The International LSCD Working Group has put forth the first guidelines on the clinical definition, classification, diagnosis, staging, and management of LSCD. Precise diagnosis and staging of LSCD is limited by subjective nature of the fluorescein staining test. As other comorbidities negatively impact the function of both corneal epithelial cells and LSCs, assessment of these comorbidities such as dry eye disease, ocular surface inflammation, corneal innervation, conjunctival health, medication toxicity, and eyelid abnormalities should be included in the initial evaluation of LSC function. Advances in anterior segment imaging, including anterior segment optical coherence tomography and in vivo confocal microscopy allow objective evaluation of epithelial phenotype, cellular morphology, basal cell density, corneal innervation, and inflammatory cell infiltration in both the cornea and limbus. The knowledge of ocular surface microstructure provides important information regarding the corneal and limbal epithelial cell function, remaining LSC reserve, and factors associated with LSCD improvement after all comorbidities are treated. Impression cytology remains a valuable tool for objectively confirming conjunctivalization through assessment of epithelial phenotype. LSCD diagnosis and classification have advanced beyond the simple fluorescein staining test for the detection of abnormal epithelial cells on the corneal surface. A comprehensive assessment of the LSC function and the ocular surface environment by integrating multimodal imaging and molecular testing enables precise staging of LSC function and identification of factors that influence LSCD reversibility. Adoption of a standardized multimodal diagnostic framework will improve diagnostic accuracy, guide the management of the disease, facilitate comparisons across clinical studies, and support the development and evaluation of emerging cell-based and cell-free regenerative therapies for LSCD.
2026-07-29 | Enhancing the Outgrowth of Oral Mucosal Cell Sheets for Cultivated Rabbit Oral Mucosal Epithelial Transplantation with ROCK Inhibitor.
Cultivated oral mucosal epithelial transplantation (COMET) is an effective way to treat limbal stem cell deficiency (LSCD), but its clinical usage is limited due to prolonged cultivation time and complexity. Rho-associated protein kinase (ROCK) inhibitors have been found to enhance cell proliferation, migration, and cytoskeleton maintenance. We investigated whether ROCK inhibitor (Y-27632) can be used to enhance the growth of oral mucosal epithelial cell sheet while remaining their characteristics, optimizing COMET usage for LSCD treatment. Oral mucosal epithelial cells were harvested from rabbits and cultured using a collagenase-based isolation technique. Cells were seeded in a transwell plate with or without amniotic membrane (AM) and Y-27632. The speed of cell sheet outgrowth and cell density were evaluated. Stem cell marker (p63), cytokeratin (K3, K4 and K13) and junctional protein markers (ZO-1, occludin, connexin 43) were analyzed by immunostaining with confocal microscopy. Y-27632 and AM coating facilitated the outgrowth of cell sheets, resulting in a larger expansion area from day 7 to day 15 (p < 0.05). Y-27632 treatment dose-dependently increased basal cell density (p < 0.05) and inhibited the squamous differentiation of the superficial layer, while maintaining cytokeratin and junctional protein markers expression. Y-27632 increased the p63-positive cells population (p < 0.05), which may play a role in maintaining stem cell properties and inhibiting differentiation. Y-27632, together with AM, provides an efficient and supportive environment for producing oral mucosal epithelial cell sheets for transplantation. They might serve as an adjunctive agent to accelerate oral epithelial cell-based therapy for the treatment of limbal stem cell deficiency.
2026-07-15 | Subconjunctival Injection of Mesenchymal Stem Cells for Corneal Wound Healing After Chemical Injury: Impact on Epithelial Coverage, Limbal Ischemia, and Ocular Surface Inflammatory.
Previous studies in animal models have demonstrated that mesenchymal stem cells (MSCs) are beneficial for reconstructing the ocular surface during corneal wound healing; however, clinical evidence remains scarce. This study aimed to evaluate the clinical safety, feasibility, and preliminary outcomes of subconjunctival umbilical-cord delivered-MSC (UC-MSC) injection as an adjunctive therapy for severe corneal chemical injuries. This prospective, single-arm clinical case series enrolled six patients with severe corneal chemical injuries. Human UC-MSCs at passages 5-6 were cultured and verified. A total sample of 4 × 106 cells suspended in 400 μL of 1 × Hanks' Balanced Salt Solution (HBSS) were subconjunctivally delivered adjacent to the limbus using a 360° circumferential injection technique. Concurrently, all patients underwent amniotic membrane transplantation (AMT) and received a standard 4-week topical regimen (Tobradex, recombinant human epidermal growth factor, and Solcoseryl). Clinical safety, limbal ischemia, inflammatory indices, and epithelial defect areas were assessed through a digital slit-lamp examination. No localized or systemic adverse events, such as anterior uveitis, progressive ulceration, intraocular infection, or immunological rejection, were observed in any participant. By 4 weeks post-injection, active ocular surface inflammation had significantly decreased in all eyes. Of the five patients with baseline limbal ischemia, four achieved complete revascularization and resolution; the fifth exhibited a marked reduction in ischemia from 100 to 20%. Furthermore, stable corneal re-epithelialization was achieved in five of six eyes, including one with complete paracentral epithelial coverage. Subconjunctival UC-MSC delivery is a safe and feasible adjunctive therapy for managing severe corneal chemical injuries. This cell-based intervention synergizes with conventional therapies to suppress acute inflammation, rescue limbal perfusion while potentially mitigating subsequent corneal neovascularization, and accelerate the structural reconstruction of the ocular surface microenvironment.
2026-07-13 | Therapeutic Potential of Mesenchymal Stem Cell-Derived Exosomes in Ocular Surface Disorders.
The global burden of ocular surface disorders (OSDs), manifesting as progressive visual impairment and chronic discomfort, has driven urgent exploration of regenerative therapeutic strategies. Mesenchymal stem cell-derived exosomes (MSC-Exos) have emerged as promising candidates for OSD treatment, as they exhibit multifaceted therapeutic properties including immunomodulation, antifibrotic activity, and pro-regenerative capacity. This systematic review consolidates current understanding of MSC-Exo-mediated ocular surface repair mechanisms, with particular emphasis on the molecular dialog established through delivery of bioactive cargo that modulate pivotal signaling pathways. We critically analyze preclinical evidence demonstrating therapeutic efficacy across diverse OSD pathologies, including dry eye disease, corneal epithelial defects, and limbal stem cell deficiency. Notwithstanding these advances, critical barriers to clinical translation persist: (1) methodological heterogeneity arising from variable cell sourcing, culture protocols, and exosome isolation/characterization standards; (2) discordance between animal models and human OSD pathophysiology; and (3) technological limitations in scalable, clinically compatible delivery systems. Addressing these challenges requires interdisciplinary collaboration to standardize exosome production pipelines and establish robust preclinical validation frameworks, thereby accelerating the transition of MSC-Exo therapies from bench to bedside.
Access all drug discovery papers and probability of success in trials forecasts:
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Drug Discovery Landscape
9 orphan drug designations for Limbal stem cell deficiency, including 1 approved therapy.
9 orphan drug designations for Limbal stem cell deficiency, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Spironolactone | small molecules | EMA | 2026-02-23 | — | Dan Mejlachowicz |
allogeneic ABCB5-positive limbal stem cells | cell therapies | FDA | 2019-03-28 | — | RHEACELL GmbH & Co. KG |
Allogeneic ABCB5-positive limbal stem cells | cell therapies | EMA | 2018-12-14 | — | Rheacell GmbH & Co. KG |
ex vivo expanded autologous human corneal epithelial cells containing stem cells | cell therapies | FDA | 2018-04-26 | — | Holostem S.r.l. |
Cultured allogeneic corneal limbal stem cells | cell therapies | EMA | 2014-10-15 | — | NHS National Services Scotland Trading as Scottish National Blood Transfusion Service |
Ex-vivo expanded autologous human corneal epithelium containing stem cells | cell therapies | EMA | 2013-07-17 | — | University of Newcastle upon Tyne |
Ex-vivo expanded autologous human corneal epithelium containing stem cells [Holoclar] | cell therapies | EMA | 2008-11-07 | 2015-02-19 | Holostem S.r.l. |
Bio-engineered oral mucosal tissue | cell therapies | FDA | 2006-04-27 | — | TissueTech, Inc. |
Autologous or allogeneic limbal epithelial stem cells expanded ex vivo on human amniotic membrane | cell therapies | FDA | 2005-07-14 | — | TissueTech, Inc. |
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