Induced pluripotent stem-cell-derived corneal epithelium for transplant surgery: a single-arm, open-label, first-in-human interventional study in Japan

The loss of corneal epithelial stem cells from the limbus at the edge of the cornea has severe consequences for vision, with the pathological manifestations of a limbal stem-cell deficiency (LSCD) difficult to treat. Here, to the best of our knowledge, we report the world's first use of corneal epithelial cell sheets derived from human induced pluripotent stem cells (iPSCs) to treat LSCD. This non-randomised, single-arm, clinical study involved four eyes of four patients with LSCD at the Department of Ophthalmology, Osaka University Hospital. They comprised a woman aged 44 years with idiopathic LSCD (patient 1), a man aged 66 years with ocular mucous membrane pemphigoid (patient 2), a man aged 72 years with idiopathic LSCD (patient 3), and a woman aged 39 years with toxic epidermal necrosis (patient 4). Allogeneic human iPSC-derived corneal epithelial cell sheets (iCEPSs) were transplanted onto affected eyes. This was done sequentially in two sets of HLA-mismatched surgeries, with patients 1 and 2 receiving low-dose cyclosporin and patients 3 and 4 not. The primary outcome measure was safety, ascertained by adverse events. These were monitored continuously throughout the 52-week follow-up period, and during an additional 1-year safety monitoring period. Secondary outcomes, reflective of efficacy, were also recorded. This study is registered with UMIN, UMIN000036539 and is complete. Patients were enrolled between June 17, 2019 and Nov 16, 2020. We had 26 adverse events during the 52-week follow-up period (consisting of 18 mild and one moderate event in treated eyes, and seven mild non-ocular events), with nine recorded in the additional 1-year safety monitoring period. No serious adverse events, such as tumourigenesis or clinical rejection, occurred during the whole 2-year observational period. At 52 weeks, secondary measures of efficacy showed that the disease stage had improved, corrected distance visual acuity was enhanced, and corneal opacification had diminished in all treated eyes. Corneal epithelial defects, subjective symptoms, quality-of-life questionnaire scores and corneal neovascularisation mostly improved or were unchanged. Overall, the beneficial efficacy outcomes achieved for patients 1 and 2 were better than those achieved for patients 3 and 4. iCEPS transplantation for LSCD was found to be safe throughout the study period. A larger clinical trial is planned to further investigate the efficacy of the procedure. The Japan Agency for Medical R