Soma Takeshi, Oie Yoshinori, Takayanagi Hiroshi, Matsubara Shoko, Yamada Tomomi, Nomura Masaki, Yoshinaga Yu, Maruyama Kazuichi, Watanabe Atsushi, Takashima Kayo, Mao Zaixing, Quantock Andrew J, Hayashi Ryuhei, Nishida Kohji
Department of Ophthalmology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Department of Medical Innovation, Osaka University Hospital, Suita, Osaka, Japan.
Lancet. 2024 Nov 16;404(10466):1929-1939. doi: 10.1016/S0140-6736(24)01764-1. Epub 2024 Nov 7.
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 Research and Development, the Ministry of Education, Culture, Sports, Science, and Technology-Japan, and the UK Biotechnology and Biological Sciences Research Council.
角膜边缘角膜缘上皮干细胞的缺失会对视力造成严重后果，角膜缘干细胞缺乏症（LSCD）的病理表现难以治疗。在此，据我们所知，我们报告了世界上首次使用源自人诱导多能干细胞（iPSC）的角膜上皮细胞片治疗LSCD。
这项非随机、单臂临床研究纳入了大阪大学医院眼科的4例LSCD患者的4只眼睛。其中包括一名44岁患有特发性LSCD的女性（患者1）、一名66岁患有眼黏膜类天疱疮的男性（患者2）、一名72岁患有特发性LSCD的男性（患者3）以及一名39岁患有中毒性表皮坏死松解症的女性（患者4）。将异体人iPSC来源的角膜上皮细胞片（iCEPS）移植到患眼上。这在两组HLA不匹配的手术中依次进行，患者1和2接受低剂量环孢素治疗，患者3和4未接受。主要结局指标是安全性，通过不良事件来确定。在整个52周的随访期以及额外的1年安全性监测期内持续监测这些不良事件。还记录了反映疗效的次要结局指标。本研究已在UMIN注册，注册号为UMIN000036539，且已完成。
患者于2019年6月17日至2020年11月16日入组。在52周的随访期内我们共记录了26起不良事件（包括治疗眼中的18起轻度事件和1起中度事件，以及7起轻度非眼部事件），在额外的1年安全性监测期内记录了9起。在整个2年的观察期内未发生严重不良事件，如肿瘤发生或临床排斥反应。在52周时，疗效的次要指标显示疾病阶段有所改善，所有治疗眼的矫正远视力提高，角膜混浊减轻。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大多有所改善或未改变。总体而言，患者1和2取得的有益疗效结果优于患者3和4。
在整个研究期间，发现iCEPS移植治疗LSCD是安全的。计划开展一项更大规模的临床试验以进一步研究该手术的疗效。
日本医疗研究与开发机构、日本文部科学省、英国生物技术与生物科学研究委员会。
