PKD1 derepression as a potential therapy for Polycystic Kidney Disease

Abstract Autosomal dominant polycystic kidney disease (ADPKD) is amongst the most common monogenetic disorders, with an estimated prevalence of 12.5 million people worldwide. Unfortunately, >50% of ADPKD patients develop end-stage renal failure and treatment options are still limited. Recent studies point to reduced PKD1 gene dosage as the disease mechanism for many ADPKD patients. This revelation opens the door to an exciting possibility that reversing PKD1 decline may arrest ADPKD in these individuals. However, despite the transformative potential, no PKD1-targeting drugs are under clinical investigation. Our goal in this application is to provide a scientific roadmap for developing a novel PKD1-boosting therapeutic approach. We propose a novel idea that along with the germline mutation, inefficient translation of mRNAs produced by the non-inactivated PKD1 allele also contributes to the lower PKD1 dosage and aggravates ADPKD. This idea emanates from our preliminary studies, where we found that deleting the cis-inhibitory miR-17 motif from the PKD1 3’- UTR is sufficient to improve mRNA translation and to raise PC1 levels. In turn, this approach ameliorates cyst growth in mice and in vitro human ADPKD models. Based on these promising observations, we propose: (1) using genetic proof-of-principle approaches to study the impact of PKD1 derepression in ADPKD mouse and human models, and (2) test the feasibility of oligonucleotides that outcompete and prevent miR-17 from binding to PKD1 as novel therapeutics to raise PC1 levels.