Long-Term Results of Cultured Limbal Stem Cell Versus Limbal Tissue Transplantation in Stage III Limbal Deficiency

Abstract

We aimed to evaluate efficiency and safety of transplantation of limbal stem cells (LSC) cultured on human amniotic membrane with no feeders and to compare cultured LSC with limbal tissue transplantation. Thirty eyes with stage III LSC deficiency were treated with autologous (autoLSC) or allogeneic (alloLSC) cultured LSC transplantation (prospective phase II clinical trial; average follow-up time, 72 months) or autologous (autoLT) or allogeneic (alloLT) limbal tissue transplantation (retrospective control group; average follow-up time, 132 months) between 1993 and 2014. The 5-year graft survival defined by absence of recurrence of the clinical signs of limbal deficiency was 71% for autoLSC, 0% for alloLSC, 75% for autoLT, and 33% for alloLT. Visual acuity improved by 9.2 lines for autoLSC and 3.3 lines for autoLT. It decreased by 0.7 lines for alloLSC and 1.9 lines for alloLT. Adverse events were recorded in 1/7 autoLSC, 7/7 alloLSC, 6/8 autoLT, and 8/8 alloLT patients. Corneal epithelial defect was the only adverse event recorded after autoLSC, whereas severe sight-threatening adverse events were recorded in the remaining three groups. Compared with failed grafts, successful grafts featured greater decrease in fluorescein staining, greater superficial vascularization-free corneal area, lower variability of the corneal epithelial thickness, and higher corneal epithelial basal cell density. Autologous cultured LSC transplantation was associated with high long-term survival and dramatic improvement in vision and was very safe. Autologous limbal tissue transplantation resulted in similar efficiency but was less safe. Cadaver allogeneic grafts resulted in low long-term success rate and high prevalence of serious adverse events. STEM CELLS TRANSLATIONAL MEDICINE 2019;8:1230-1241 LESSONS LEARNED• Transplantation of autologous cultured limbal stem cells was associated with high long-term survival, dramatic improvement in vision, and high safety. • Transplantation of autologous limbal tissue resulted in similar efficiency but lower safety.• Cadaver allogeneic grafts resulted in low long-term success rate and high prevalence of serious adverse events. SIGNIFICANCE STATEMENTAutologous cultured limbal stem cell transplantation was associated with high long-term survival, vision improvement, and safety, whereas limbal grafts featured lower safety and allogeneic grafts featured low success rate and serious adverse events.

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

“…In bilateral LSCD, where autologous LSCs are not available for transplantation, allogeneic grafts are required. However, clinical studies using allogeneic limbal tissue transplants have often provided only transient corneal restoration [12,15,44], which was suspected to be caused by immunogenic limbal cell subpopulations such as Langerhans cells capable of inducting rejection responses in the recipient. Furthermore, current approaches are often associated with regulatory and logistical obstacles, seeing that the grafts contain variable numbers of LSCs and that the preparations have not been shown to be (cryo) preservable [43].…”

Recent Advances in Stem Cell Therapy for Limbal Stem Cell Deficiency: A Narrative Review

“…As the grafts are expanded from a small biopsy, they presumably contain very low numbers of antigen-presenting Langerhans cells, melanocytes, and vascular endothelium found in the normal LSC niche [4]. Two systematic reviews investigating the outcomes of CLET found no significant difference in treatment success or visual improvement after autologous and allogeneic CLET [10,89], although a phase II clinical trial reported a high risk of graft rejection and subsequent failure after allogeneic CLET [90].…”

“…Failure was defined as 'recurrent epithelial defects and/or superficial corneal neovascularisation or conjunctivalisation encroaching on the central 4 mm of the cornea' [88]. Borderie et al reported a phase II trial comparing autologous and allogeneic CLET with a mean follow-up of 6 years in 14 patients with histologically confirmed LSCD [90]. They found a high rate of adverse events in the allogeneic group, including raised intraocular pressure (IOP), cataract requiring surgery, corneal perforation, and immunologic graft rejection.…”

“…Although further data will be needed to verify the long-term curative rate for CLET, the findings of Behaegal et al and Borderie et al raise concerns that graft longevity may be limited. This lack of a supporting and healthy LSC niche may limit the long-term viability of donor LSCs [88,90]. One solution to the lack of niche protection for transplanted LSCs may lie in bioengineering approaches which aim to synthesise artificial LSC niches with equivalent mechanical properties and adhesive surfaces [93,94].…”

Clinical Outcomes From Cultivated Allogenic Stem Cells vs. Oral Mucosa Epithelial Transplants in Total Bilateral Stem Cells Deficiency

“…Borderie et al (33) aimed to compare outcomes following cultured LESCs transplantation to limbal tissue transplantation. They included 30 eyes with LSCD stage III, which is characterized by vascularization of the entire cornea, irregular epithelium, staining of the entire limbus and central cornea.…”