Targeted exon skipping of a CEP290 mutation rescues Joubert syndrome phenotypes in vitro and in a murine model

Significance The treatment of genetic kidney disease is challenging, as this requires both the correction of the underlying gene defect and the delivery of the treatment. Here we show that by using antisense oligonucleotides, we can induce exon skipping of a mutated exon in CEP290 , within renal epithelial cells derived from a patient with a ciliopathy syndrome called Joubert syndrome. This treatment rescues the truncated CEP290 protein to a near full-length protein and restores the ciliary phenotype. In a Cep290 murine model of Joubert syndrome, exon skipping is achievable with systemic treatment of an antisense oligonucleotide, which rescues both the ciliary and kidney disease phenotypes. This work paves the way toward personalized genetic therapies in patients with inherited kidney diseases.