Pharmaceutical inhibition of the Chk2 kinase mitigates cone photoreceptor degeneration in an iPSC model of Bardet-Biedl syndrome

Bardet-Biedl syndrome (BBS) is a syndromic ciliopathy leading to progressive blindness starting in childhood, but the mechanism leading to photoreceptor degeneration in BBS is unknown. The basal body of the photoreceptor primary cilium originates from the centrosome’s mother centriole, and the BBS-related proteins form a complex present at basal body. Centrosomes organize microtubules of the mitotic spindle and are required for proper cell division. We show here that immature cones, but not rods, from bbs10-/- mouse pups present an early-onset DNA damage response (DDR) that becomes persistent and localizes to the basal body. Using patient-derived induced pluripotent stem cells (iPSCs), we found that BBS10 retinal progenitor cells (RPCs) also present a DDR that correlates with activation of the mitotic spindle checkpoint. Pharmaceutical inhibition of the cell cycle checkpoint kinase 2 (Chk2) in BBS10 RPCs mitigates cell death and genomic instability and largely restores the perturbed phospho-proteome. Drug treatment of BBS10 retinal organoids improves tissue organization, cone photoreceptor survival, and outer segment maturation. These findings reveal an important function for BBS10 in the maintenance of RPCs and cone photoreceptors genomic stability during development and may open new therapeutic avenues to delay photoreceptor degeneration in BBS. DIV 15 RPCs from 2 biological replicates for each genotype (CTL1, CTL2, BBS1 and BBS2 iPSC lines, N = 8 samples) and each treatment (BBS1+C2i, BBS2+C2i, BBS1+ATMi, BBS2+ATMi, N= 8 samples).