iPSC-derived RPE as a context-of-use defined NAM framework for RPE-centered drug-induced retinal toxicity assessment
- 1TriApex Laboratories Co., Ltd.
- 2Institute of Chemicobiology and Functional Materials, School of Chemistry and Chemical Engineering, Nanjing University of Science and Technology
- 3School of Life Sciences and Biopharmaceuticals, Shenyang Pharmaceutical University
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.
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BibTeX
@article{ding2026ipscderived,
title = {{iPSC-derived RPE as a context-of-use defined NAM framework for RPE-centered drug-induced retinal toxicity assessment}},
author = {Weixiao Ding and Longjun Gu and Tiantian Dong and Minjun Xiong and Chen Wang and Chunlei Ji and Juan Lv and Xuefeng Zhang and Xinjiang Gong},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1933218},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1933218/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - iPSC-derived RPE as a context-of-use defined NAM framework for RPE-centered drug-induced retinal toxicity assessment
AU - Weixiao Ding
AU - Longjun Gu
AU - Tiantian Dong
AU - Minjun Xiong
AU - Chen Wang
AU - Chunlei Ji
AU - Juan Lv
AU - Xuefeng Zhang
AU - Xinjiang Gong
PY - 2026
DA - 2026/10/21
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1933218
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1933218/full
AB - 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.
SN - 1663-9812
ER -