A first-in-human clinical study of an allogenic iPSC-derived corneal endothelial cell substitute transplantation for bullous keratopathy
Masatoshi Hirayama, Shin Hatou, Masaki Nomura, Risa Hokama, Osama Ibrahim Hirayama, Emi Inagaki, Kumi Aso, Tomoko Sayano, Hiromi Dohi, Tadaaki Hanatani, Naoko Takasu, Hideyuki Okano, Kazuno Negishi, Shigeto Shimmura
Abstract
A first-in-human investigator-initiated clinical study of a corneal endothelial cell substitute (CLS001) derived from a clinical-grade induced pluripotent stem cell (iPSC) line shows improvement of visual acuity and corneal stromal edema, with no adverse events for up to 1 year after surgery for the treatment of bullous keratopathy. While preclinical tests, including multiple whole-genome analysis and tumorigenicity tests adhering to the Food and Drug Administration (FDA) draft guidelines, are negative, an additional whole-genome analysis conducted on transplanted CLS001 cells reveals a de novo in-frame deletion of exon22 in the EP300 gene. No adverse events related to the mutation are observed. Our study demonstrates the feasibility of using iPSC-derived cells to replace donor transplant for bullous keratopathy, while shedding light on risk management of gene mutation in cell products. Further follow-up is required for long-term analysis of clinical safety and efficacy. • iPSC-derived corneal endothelial cell substitutes recover pathological corneal edema • No adverse reactions are observed after 1 year follow-up • Gene mutations may appear despite whole-genome sequencing of the master cell bank Shimmura and colleagues demonstrate the feasibility of using iPSC-derived cells for treating bullous keratopathy. Although adverse reactions are not observed, de novo gene mutations can be detected despite extensive whole-genome sequencing of the master cell bank.