Work

iPSC-derived RPE as a context-of-use defined NAM framework for RPE-centered drug-induced retinal toxicity assessment

Year: 2026

Type: review

Abstract: The retinal pigment epithelium (RPE) is essential for outer retinal homeostasis and a key target for drug-induced retinal toxicity. However, conventional preclinical models, including immortalized cell lines and animal systems, may incompletely recapitulate human RPE biology because of limited representation of specialized RPE functions and species-specific differences in retinal physiology. Induced pluripotent stem cell-derived RPE (iPSC-RPE) has emerged as a candidate human-relevant platform for New Approach Methodology (NAM) development, with the potential to improve mechanistic relevance by reproducing key structural and functional features of native human RPE. Its translational utility depends on a clearly defined context of use (COU), reproducible differentiation and functional characterization, and benchmark-based frameworks for future assay qualification and validation. This review evaluates the potential of iPSC-RPE as a COU-defined NAM framework for RPE-centered drug-induced retinal toxicity, with particular emphasis on toxicities in which RPE dysfunction represents a primary or mechanistically important component. We summarize differentiation strategies and critical quality attributes that may inform future assay qualification, evaluate disease-modeling evidence supporting physiological relevance, and discuss applications in ocular safety assessment, including chloroquine/hydroxychloroquine-, MEK inhibitor-, and anti-VEGF-associated retinal effects. We further discuss limitations, including cellular immaturity, donor-to-donor variability, incomplete microenvironmental modeling, and the limited validation of long-term exposure paradigms. Current evidence supports mechanistic concordance for selected RPE-centered toxicities, whereas prospective predictive performance across diverse compounds and clinically relevant exposure conditions remains to be established. Further COU-specific qualification and prospective validation will be required to establish the reliability and decision relevance of iPSC-RPE for defined ocular toxicology applications.

Source: Frontiers in Pharmacology

DOI: 10.3389/fphar.2026.1933218