Regeneration and Replacement of the Corneal Endothelium: Advances in Cell Therapy, Tissue Engineering, Molecular and Pharmacologic Strategies.

Endothelial keratoplasty remains the current gold standard for treating corneal endothelial dysfunction, relying on transplantation of cadaveric donor-derived Descemet's membrane with functional corneal endothelial cells (CECs) to restore corneal clarity. However, global shortages of suitable cadaveric donor tissue have accelerated interest in corneal endothelial cell therapy, tissue engineering, and non-surgical, donor-sparing, and potentially donor-independent therapeutic approaches. In this review, we discuss recent advances in corneal endothelial cell therapy, tissue engineering, gene- and RNA-targeted approaches, and pharmacologic therapies aimed at preserving or replacing the corneal endothelium. These modalities span markedly different levels of translational maturity. Cultured donor-derived CEC injection is the most clinically advanced, with regulatory approval and commercial use in Japan and Phase 3 development in the United States. Tissue-engineered endothelial grafts have entered first-in-human evaluation, whereas mitochondrial transfer and extracellular vesicle-based strategies remain preclinical. Molecular and pharmacologic approaches range from Phase 2 evaluation of TCF4-directed transcriptional modulation and clinically studied ROCK inhibitors to preclinical antisense oligonucleotides (ASO) and CRISPR-based strategies. We therefore compare these modalities according to current evidence, translational readiness, scalability, manufacturing requirements, and potential clinical role.