Molecular treatment options for patients carrying variants.

Variants in are associated with the ciliopathy Joubert syndrome (JS), which is a genetically heterogeneous disorder. Mutations in more than 40 different genes were associated with JS, genes that are relevant to ciliary assembly, maintenance, or cellular signaling pathways during the development. Genetic variability suggests that gene- and/or mutation-independent treatment strategies could be beneficial to patients. Currently, targeted therapeutic options are not available. In this study, we present molecular treatment options for pathogenic sequence alterations. We compared therapeutic efficacy and side effects using patient-derived fibroblasts from two siblings affected by JS. The patients harbored two compound heterozygous sequence alterations, a non-sense mutation (: c.2353C>T) in exon 18 and a deep-intronic mutation in intron 28 (: c.3990 + 3186G>A). The deep-intronic sequence alteration activates a cryptic exon that causes a frameshift and splicing defect. Both variants are predicted to potentially result in the premature termination of translation. The patient-derived fibroblasts exhibited reduced primary cilia length and altered distribution of PCM1. These cellular defects were responsive to treatments with RNA-based therapeutics and/or readthrough agents (RTAs). Our results highlight the potential of addressing mutations and molecular defects associated with sequence alterations as future perspectives toward treatments of patients.