# Disruption of a six-nucleotide miRNA motif improves PKD1 dosage and ameliorates polycystic kidney disease

## TL;DR

Scientists disrupted a six-nucleotide miRNA motif to increase PKD1 protein levels and reduce kidney cysts in a mouse model of polycystic kidney disease.

## Contribution

The study identifies a minimal six-nucleotide miR-17 motif in PKD1's 3′UTR and demonstrates its disruption as a therapeutic strategy for ADPKD.

## Key findings

- Disrupting the six-nucleotide miR-17 motif in PKD1's 3′UTR stabilizes Pkd1 mRNA and increases PC1 protein levels.
- A steric-blocking oligonucleotide targeting the motif reduces cyst growth and preserves kidney function in mouse models.
- The oligonucleotide treatment also mitigates cystic events in patient-derived ADPKD cells.

## Abstract

Disrupting microRNA interactions to restore protein expression from haploinsufficient genes offers a promising precision-therapy strategy for monogenic disorders. PKD1 heterozygosity underlies autosomal dominant polycystic kidney disease (ADPKD), a disorder affecting nearly 12 million people worldwide, where reduced PKD1 dosage drives progressive cyst formation and kidney failure. We previously identified a 55-bp cis-repressive element in the PKD1 3′UTR. Here, we define a six-nucleotide miR-17 seed match within this element that is sufficient to reproduce PKD1 repression. In vivo base substitution of this motif stabilizes Pkd1 messenger RNA and increases polycystin-1 (PC1) protein levels, producing a robust reduction in cyst growth and preservation of kidney function in mouse models. To therapeutically recapitulate this effect, we developed a steric-blocking oligonucleotide that occludes the motif, stabilizes PKD1 transcript levels, increases PC1 expression, and mitigates cyst-pathogenic events in both murine and patient-derived ADPKD cells. Together, these findings establish a minimal, targetable cis-regulatory motif and provide proof of concept for oligonucleotide-mediated PKD1 derepression, while offering a potentially generalizable strategy to restore other haploinsufficient genes.

Graphical Abstract