Targeting mutation-agnostic disease pathways ameliorates ciliopathy-related mesenchymal drift in RPE

Ciliopathies are a family of disorders involving mutations in over 150 genes affecting the primary cilium, with retinal degeneration as a prominent feature driven by concomitant developmental and maturation defects in photoreceptors and the retinal pigment epithelium (RPE). Current single-gene-targeted therapeutic approaches are expensive with limited scalability. We hypothesized that downstream of primary cilium dysfunction, mutation-agnostic shared pathways initiate tissue defects. To test this hypothesis, we developed induced pluripotent stem cell-derived RPE models (iRPE) from multiple (BBS1, BBS10, BBS16, CEP290, LCA5, MYO7A, PRPF31) ciliopathy patients with severe retinal degeneration. Despite varying in severity, consistent with the structural ciliary defects, all ciliopathy iRPE displayed abnormal epithelial polarization and mitochondrial health initiated by dysregulated TGF-B signaling driven mesenchymal drift. Addressing these gene-agnostic disease phenotypes, our study identifies two drugs, Pioglitazone, a mitochondrial metabolic modulator, and Galunisertib, a TGFBR1 inhibitor, as potential therapeutic candidates for multiple ciliopathy subtypes.