Background

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.

Methods

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.

Findings

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.

Interpretation

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.

Funding

The Japan Agency for Medical Research and Development, the Ministry of Education, Culture, Sports, Science, and Technology—Japan, and the UK Biotechnology and Biological Sciences Research Council.

中文翻译：

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用于移植手术的诱导多能干细胞来源的角膜上皮：一项在日本进行的单臂、开放标签、首次人体介入研究

 背景

角膜缘边缘角膜缘角膜上皮干细胞的丢失对视力有严重影响，角膜缘干细胞缺陷 （LSCD） 的病理表现难以治疗。在这里，据我们所知，我们报道了世界上首次使用源自人类诱导多能干细胞 （iPSC） 的角膜上皮细胞片治疗 LSCD。

 方法

这项非随机、单臂、临床研究涉及大阪大学医院眼科 4 名 LSCD 患者的 4 只眼睛。他们包括一名 44 岁的特发性 LSCD 女性（患者 1），一名 66 岁的眼粘膜类天疱疮男性（患者 2），一名 72 岁的特发性 LSCD 男性（患者 3）和一名 39 岁的中毒性表皮坏死女性（患者 4）。将同种异体人 iPSC 衍生的角膜上皮细胞片 （iCEPS） 移植到受影响的眼睛上。这是在两组 HLA 不匹配的手术中依次进行的，患者 1 和 2 接受低剂量环孢菌素，患者 3 和 4 未接受。主要结局指标是通过不良事件确定的安全性。这些在 52 周的随访期间以及额外的 1 年安全监测期间受到持续监测。还记录了反映疗效的次要结局。这项研究已在 UMIN000036539 UMIN 注册并且已完成。

 发现

患者于 2019 年 6 月 17 日至 2020 年 11 月 16 日期间入组。在 52 周的随访期间，我们发生了 26 起不良事件（包括 18 起治疗眼中的轻度和 1 例中度事件，以及 7 起轻度非眼部事件），其中 9 起记录在额外的 1 年安全监测期内。在整个 2 年观察期内未发生严重的不良事件，例如肿瘤发生或临床排斥反应。在 52 周时，疗效的次要测量显示疾病阶段得到改善，矫正远视力增强，所有接受治疗的眼睛的角膜混浊减少。角膜上皮缺损、主观症状、生活质量问卷评分和角膜新生血管形成大多得到改善或保持不变。总体而言，患者 1 和 2 获得的有益疗效结果优于患者 3 和 4。

 解释

发现 LSCD 的 iCEPS 移植在整个研究期间是安全的。计划进行一项更大规模的临床试验，以进一步研究该程序的疗效。

 资金

日本医疗研究开发机构、日本文部科学省和英国生物技术与生物科学研究委员会。