The eye’s cornea is covered with a layered epithelial structure which plays a vital role in sight. At the limbus – referring to a specific region situated at the periphery of the cornea where it meets the sclera, which is the white part of the eye – the corneal epithelium has stem cells that reside at the base. These cells divide and give rise to epithelial cells that replenish the cells in the central cornea. As a result, the cornea remains healthy. Corneal limbal epithelial stem cells are p63 + expression factors with high proliferation ability and holoclone-forming potential.
Such cells are critical and, in the absence, or presence of few cells, patients develop what is known as limbal stem cell deficiency (LSCD). Unilateral LSCD is commonly linked to trauma caused by non-immunogenic factors such as chemical or thermal burns. Bilateral LSCDs could be due to secondary aggressive immune-mediated conditions (for example Stevens-Johnson syndrome or ocular mucous membrane pemphigoid) or classified idiot diseases including congenital aniridia. It is usually followed by the corneal surface being covered in vascularized fibrotic conjunctival scar tissue and compromised vision.
A single-arm, open-label, first-in-human interventional published in The Lancet to report the world’s first use of corneal epithelial cell sheets derived from human induced pluripotent stem cells (iPSCs) to treat LSCD.
The Department of Ophthalmology at Osaka University Hospital conducted this non-randomized, single-arm clinical study with four eyes of four patients suffering from limbal stem cell deficiency (LSCD). These were a 44-year-old woman with idiopathic LSCD (the first patient), a 66-year-old man with ocular mucous membrane pemphigoid (the second patient), a 72-year-old man with idiopathic LSCD (the third patient), and a 39-year-old woman with toxic epidermal necrolysis (the fourth patient). Allogeneic human iPSC-derived corneal epithelial cell sheets (iCEPSs) were transplanted into the affected eyes.
This was done in two sets of HLA-mismatched surgeries, on a sequential basis, with patient 1 and patient 2 receiving low-dose cyclosporin and patient 3 and patient 4 not. The primary outcome measure was safety determined by adverse events. These were carefully examined on a continuous basis during the whole 52-week follow-up period and in an additional period which was meant for safety monitoring of the participants which was one year. Outcomes that were secondary in nature which were related to the treatment effects were also taken. This study has been recorded with the UMIN registry under the ID of UMIN000036539 and is closed.
From June 17, 2019, to Nov 16, 2020, patients were recruited into the study. During the 52-week post-intervention period, we noted 26 adverse events (18 of them being mild, one moderate in treated eyes, and seven mild non-ocular events). Including the 1 additional year of safety monitoring, we accounted for nine more adverse events. During this entire period of observation, which lasted two years, there were no high-level adverse events like the development of a tumour or clinical rejection.
At 52 weeks as measured – secondary measures of efficacy more than one stage improvement in the disease were obtained, the corrected distance visual acuity was better and the corneal opacity in all treated eyes was less than baseline. Corneal epithelial defects, subjective symptoms, scores from quality-of-life questionnaires, and corneal neovascularization were all improved or minimally changed. In general, the favorably efficacy results reached in patients 1 and 2 were higher than in patients 3 and 4.
There are limitations to our study, not least the low number of cases, meaning that the safety and efficacy of iCEPS cannot be categorically concluded. It also means that we cannot compare the current results with those of other allogeneic therapies for bilateral LSCD, such as allogeneic cultivated limbal epithelial cell sheet transplantation or simple limbal epithelial transplantation.
However, we would argue that the study design is appropriate when doing first-in-human surgeries from the perspective of patient safety. A second point, linked to the low initial number of patients concerns generalizability and the need to assess the applicability of iCEPS graft surgery to LSCDs of a range of aetiologies.
Reference: Takeshi Soma et al, Induced pluripotent stem-cell-derived corneal epithelium for transplant surgery: a single-arm, open-label, first-in-human interventional study in Japan, The Lancet (2024). DOI: 10.1016/S0140-6736(24)01764-1
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