Dominik Reichert, Sena Gul, Davide Ortolan, David McGaughey, Jair Montford, Jiwon Ryu, Alyssa S Jeffrey, Colby F Lewallen, Kati Veres, Rafael Villasmil, Noor D White Carreiro, Stephen H Tsang, Laryssa A Huryn, Brian P Brooks, Wadih Zein, Helen Louise May-Simera, Ruchi Sharma, Kapil Bharti
Ciliopathies comprise a spectrum 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 hypothesize that downstream of primary cilium dysfunction, mutation-agnostic shared pathways initiate tissue defects. To test this hypothesis, we here develop induced pluripotent stem cell-derived RPE models (iRPE) from nine (BBS1, BBS10, BBS16, CEP290, LCA5, MYO7A, PRPF31) patients with ciliopathy with severe retinal degeneration. Despite heterogeneity in disease severity, consistent with underlying ciliary structural defects, all ciliopathy iRPE exhibit abnormal epithelial polarization and impaired mitochondrial health initiated by dysregulated TGF-β 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.