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 of photoreceptor degeneration remains unclear. The basal body of the photoreceptor primary cilium originates from the centrosome's mother centriole, and BBS-related proteins form a complex at basal body. Centrosomes also organize microtubules of the mitotic spindle. We show here that photoreceptors from Bbs10 (-/-) mouse pups present a DNA damage response (DDR) that becomes persistent and localizes to the basal body. In patient-derived induced pluripotent stem cells (iPSCs) carrying BBS10 mutations, BBS retinal progenitor cells (RPCs) present a DDR that correlates with activation of the mitotic spindle checkpoint. Pharmaceutical inhibition of the Chk2 kinase in BBS RPCs mitigates cell death and genomic instability and restores the phospho-proteome. Drug treatment of BBS retinal organoids improves tissue organization, cone survival, and outer segment maturation, thus opening a possible therapeutic avenue to delay photoreceptor degeneration in BBS.