This review evaluates a broad range of emerging therapies for corneal endothelial dysfunction, including cultured donor-derived cell injection, tissue-engineered grafts, gene/RNA-targeted approaches (ASOs, CRISPR), and pharmacologic strategies (ROCK inhibitors, TCF4-directed transcriptional modulation), compared across translational maturity, scalability, and clinical role.
Cultured donor-derived corneal endothelial cell (CEC) injection is the most clinically advanced modality—approved and in commercial use in Japan, with Phase 3 trials underway in the US; tissue-engineered endothelial grafts have reached first-in-human evaluation; TCF4-directed transcriptional modulation is in Phase 2; ROCK inhibitors have clinical-stage data; while mitochondrial transfer, extracellular vesicles, ASOs, and CRISPR remain preclinical.
As a narrative review, it does not perform a systematic search or meta-analysis, limiting the ability to quantify comparative efficacy across modalities. Translational maturity varies widely, and most novel strategies lack human clinical trial data.
Clinicians should be aware that CEC injection therapy is now commercially available in Japan and approaching regulatory consideration in the US, offering a potential alternative to cadaveric endothelial keratoplasty. ROCK inhibitors and TCF4-directed approaches represent the nearest-term pharmacologic adjuncts, while gene-editing and organelle-transfer strategies remain experimental.
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