2026/01/06 by Ronak Lakhia, Chunzi Song, Laurence Biggers +6 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Genetic and Kidney Cyst Diseases #Renal and related cancers #Vascular Malformations and Hemangiomas
paper · doi:10.1093/nar/gkaf1538
openalex publication_date 2026/01/06 · openalex created_date 2026/01/22 · openalex updated_date 2026/07/22
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.