The Dosage Logic of PKD1: RNA Regulation and Therapeutic Derepression

Autosomal dominant polycystic kidney disease (ADPKD) is driven largely by heterozygous PKD1 mutations and insufficient functional polycystin-1 dosage, yet the mechanisms that regulate output from residual PKD1 alleles are only beginning to be defined. The PKD1 locus is unusually complex, and its transcript contains untranslated regions that actively constrain protein production. This review integrates genetic, molecular, and therapeutic evidence supporting a dosage-threshold model of cystogenesis. We discuss how gene architecture, RNA processing, and protein maturation set functional polycystin-1 levels, then focus on post-transcriptional control by the PKD1 5' and 3' untranslated regions. The 3'UTR contains conserved microRNA-binding sites, including a therapeutically actionable miR-17 site. Genetic disruption or pharmacologic inhibition of miR-17 increases polycystin dosage and attenuates cystic disease in experimental models. Farabursen, an anti-miR-17 oligonucleotide, has produced early clinical pharmacodynamic findings consistent with polycystin-1 and polycystin-2 derepression and is advancing into Phase 3 development. Together, these findings establish endogenous transcript derepression as a mutation-agnostic strategy for restoring gene dosage in ADPKD and provide a framework for treating other dosage-sensitive genetic disorders.