Translational readthrough therapy for ADPKD induces polycystin1 expression and partially rescues functional deficits in PKD1 mutant cells.

Autosomal-Dominant Polycystic Kidney Disease, ADPKD, is the most common genetic kidney disease affecting 1:1000 people worldwide. It is caused by mutations in the PKD1 (~ 80%) or PKD2 gene (~ 15%). Although the germline mutation is inherited in dominant fashion, disabling the second allele is required for emergence of clonal cysts. Presently, no cure exists for ADPKD. In approximately 30% of patients, the heritable ADPKD mutation involves a single nucleotide substitution that converts the normal mRNA triplet encoding an amino acid into a Premature Termination Codon (PTC). The translation machinery poses at the PTC and detaches from the mutant mRNA; the unstable transcript and protein are degraded. Certain aminoglycosides bind to the mammalian ribosome and relax translational fidelity, permitting continued translation and production of a full-length protein. In this study, we tested the ability of aminoglycosides to induce readthrough of the PTC codons in the human PKD1 gene and ascertained the effect of these drugs on pathologic features of PKD1 mutant cells. We report that aminoglycosides induce 8-25% expression of full-length Polycystin1 (PKD1 gene product) and significantly improve aberrant cell adhesion and cell signaling. Based on our observations, we propose that aminoglycoside readthrough drugs show potential as therapeutic agents for ADPKD.