A self-assembling coculture model of retinal fibrosis reveals Bcl-xL inhibitors as cell-selective dual-mechanism antifibrotics.
Abstract
Retinal fibrosis contributes to vision loss in multiple chronic and acute retinal diseases, impacting millions of patients; however, no effective antifibrotic interventions exist. To model retinal fibrosis, we created a self-assembling, coculture model using retinal pigment epithelial (RPE) and Müller cells stimulated with a transforming growth factor-β2 and fibroblast growth factor 2 cocktail to recapitulate the fibrotic milieu. High-content imaging of fibronectin and α-smooth muscle actin enabled quantitative assessment of fibrotic responses. Using this platform, we confirmed that current anti-vascular endothelial growth factor therapies had no measurable effect on fibrosis and evaluated a panel of proposed antifibrotic targets, which showed limited potency and translational potential. In a pilot screen of novel retinal antifibrotic candidates, Bcl-xL (BCL2L1) emerged as a highly promising target. Treatment with the clinical candidate UBX-1325 promoted apoptosis selectively in activated α-smooth muscle actin-expressing Müller cells, while simultaneously blocking fibrotic activation in RPE cells through a noncanonical, apoptosis-independent mechanism. Analysis of patient-derived retinal membranes revealed elevated BCL2L1 expression in proliferative vitreoretinopathy membranes compared with epiretinal membranes, supporting the clinical relevance of this target. Together, these findings identify Bcl-xL as a potent, dual-action target for retinal fibrosis and highlight UBX-1325 as a promising candidate for translation. SIGNIFICANCE STATEMENT: Using a self-assembling retinal fibrosis model, this study demonstrated that currently available anti-vascular endothelial growth factor therapies lack direct antifibrotic activity and identify Bcl-xL as a promising therapeutic target. The clinical-stage molecule UBX-1325 suppresses fibrosis through complementary effects on Müller and RPE cells, providing a strong rationale for clinical evaluation in fibrotic retinal diseases.
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