Research Highlight

Drug discovery for ciliopathy, a rare genetic disorder

Ciliopathies are clinically overlapping genetic disorders involving structural and functional abnormalities of the cilia. CEP290, a gene mutated in several ciliopathies, encodes a protein that forms a complex with NPHP5 to support the function of the ciliary transition zone. In this study, the CRISPR/Cas9 system was used to generate a cell line model for CEP290-related ciliopathy, and cell-based chemical library screening identified eupatilin as a lead compound for developing ciliopathy medication. Eupatilin relieved ciliogenesis defects resulting from inactivation of the CEP290 gene. In rd16 mice harboring a blinding Cep290 in-frame deletion, eupatilin treatment improved both opsin transport to the photoreceptor outer segment and electrophysiological responses of the retina to light stimulation. The rescue effect was due to eupatilin-mediated inhibition of calmodulin binding to NPHP5, which promoted NPHP5 recruitment to the ciliary base. These results demonstrate that eupatilin rescues ciliary transition zone defects to ameliorate ciliopathy-related phenotypes....read more