Using Patient iPSC-derived Retinal Pigment Epithelial Cells to Evaluate Differential Susceptibility to MEK...

Area of Science:

• Ophthalmology
• Cell Biology
• Pharmacology

Background:

• MEK inhibitors are used to treat conditions like Neurofibromatosis Type 1.
• MEK inhibitor-Associated Retinopathy (MEKAR) is a potential side effect of these treatments.
• The underlying cellular mechanisms of MEKAR are not fully understood.

Purpose of the Study:

• To compare the effects of MEK inhibition on induced pluripotent stem cell (iPSC)-derived retinal pigmental epithelial (RPE) cells.
• To investigate differences between RPE cells from a patient who developed MEKAR and one who did not.
• To elucidate the cellular basis of MEK inhibitor-associated retinopathy.

Main Methods:

• Generated iPSC-derived RPE cells from two female patients with Neurofibromatosis Type 1, one with MEKAR and one without.
• Treated these hiPSC-derived RPE cells with selumetinib (a MEK inhibitor) for 10 days.
• Assessed phagocytic activity and gene expression changes.

Main Results:

• hiPSC-derived RPE from the patient who developed MEKAR showed increased internalized rhodopsin, indicating impaired phagocytosis.
• Selumetinib treatment decreased expression of fluid transport and cell volume genes (e.g., aquaporins) in RPE cells.
• Gene expression changes were statistically significant only in cells from the patient who did not develop MEKAR, suggesting a compensatory protective mechanism.

Conclusions:

• MEK inhibitor-Associated Retinopathy may affect susceptible patients whose RPE cells cannot adequately regulate fluid transport and cell volume genes.
• This dysregulation in gene expression can impair RPE cell function and contribute to retinopathy development.
• Understanding these cellular mechanisms could inform strategies to prevent or manage MEKAR.