Journal article
Using Patient iPSC-derived Retinal Pigment Epithelium to Evaluate Differential Susceptibility to MEK Inhibitor-Associated Retinopathy
Experimental eye research, Vol.272(November 2026), 111217
09/19/2026
DOI: 10.1016/j.exer.2026.111217
PMID: 42731653
Abstract
Compare the effect of MEK inhibition on iPSC-derived retinal pigment epithelial (RPE) cells generated from a patient who developed MEK inhibitor-Associated Retinopathy (MEKAR) versus a patient who did not develop retinopathy. This is an exploratory, hypothesis-generating comparison of one donor line per clinical phenotype.
Exploratory case-control comparison (one patient-derived line per phenotype) SUBJECTS: Two female patients with Neurofibromatosis Type 1 who were treated with MEK inhibitors. One patient developed MEKAR, the other did not.
RPE were generated from human induced pluripotent stem cells (hiPSCs) from these two patients. These hiPSC-derived RPE were treated with selumetinib for 10 days.
Phagocytic activity and changes in gene expression RESULTS: As previously reported, there was a significant increase in internalized rhodopsin in phagocytosis assays, yet this was only found in hiPSC-derived RPE from the patient who developed MEKAR. Selumetinib decreased expression of genes related to fluid transport and cell volume, including aquaporins and solute transporters. At baseline, cells from the patients without MEKAR had higher expression of these genes. Interestingly, selumetinib-induced changes in gene expression only reached statistical significance in cells from the patient who did not develop MEKAR, suggesting these changes may be a compensatory protective mechanism. Patients susceptible to forming MEKAR may have increased phagocytosis without a compensatory change in expression of genes related to fluid flux, thereby inhibiting their ability to transport fluid out of the subretinal space. Because only one donor line was studied per clinical phenotype, and because the two donors also differ in age, NF1 variant class, and MEK inhibitor exposure, these associations are hypothesis-generating and cannot be attributed to MEKAR status independently of donor background.
These exploratory findings support a testable hypothesis: that MEK inhibitor-Associated Retinopathy preferentially affects susceptible patients whose retinal pigment epithelium cannot sufficiently regulate expression of genes related to fluid transport and cell volume, altering the ability of these cells to properly function. Confirmation will require additional donor lines from each clinical phenotype.
Details
- Title: Subtitle
- Using Patient iPSC-derived Retinal Pigment Epithelium to Evaluate Differential Susceptibility to MEK Inhibitor-Associated Retinopathy
- Creators
- Lola P Lozano - University of IowaTimothy M Boyce - University of IowaAndrew P Groves - University of IowaHenry L Keen - University of IowaCulver Boldt - University of Iowa, Ophthalmology and Visual SciencesRobert F Mullins - University of IowaElaine M Binkley - University of IowaBudd A Tucker - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Experimental eye research, Vol.272(November 2026), 111217
- DOI
- 10.1016/j.exer.2026.111217
- PMID
- 42731653
- NLM abbreviation
- Exp Eye Res
- ISSN
- 1096-0007
- eISSN
- 1096-0007
- Publisher
- Elsevier; LONDON
- Grant note
- Gilbert Family Foundation US National Institutes of Health: T32 GM139776, R01EY033331, EY025580
This work was supported by the Gilbert Family Foundation (Development of novel next generation model systems for study and treatment of NF1) and the US National Institutes of Health (T32 GM139776, EY025580, R01EY033331).
- Language
- English
- Electronic publication date
- 09/12/2026
- Date published
- 09/19/2026
- Academic Unit
- Stead Family Department of Pediatrics; The University of Iowa Institute for Vision Research; Hematology/Oncology; Neuroscience and Pharmacology; Ophthalmology and Visual Sciences; Iowa Institute of Human Genetics
- Record Identifier
- 9985226062002771
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