Kidney Week

Abstract: TH-OR055

Monoallelic Loss of Human PKD1 Causes ADPKD in a Fully Humanized Mouse Model

Session Information

• Genetic Diseases with a Focus on ADPKD Mechanisms, Models, and Medicines
  October 22, 2026 | Location: Mile High Ballroom 4D, Convention Center
  Abstract Time: 04:30 PM - 04:40 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)

Authors

• Song, Chunzi, The University of Texas Southwestern Medical Center, Dallas, Texas, United States

Chunzi Song, MD

• Alvarez, Jesus A., The University of Texas Southwestern Medical Center, Dallas, Texas, United States

Jesus A. Alvarez

• Cobo-Stark, Patricia, The University of Texas Southwestern Medical Center, Dallas, Texas, United States

Patricia Cobo-Stark

• Ostrosky Frid, Mauricio, The University of Texas Southwestern Medical Center, Dallas, Texas, United States

Mauricio Ostrosky Frid, MD, PhD

• Lakhia, Ronak, The University of Texas Southwestern Medical Center, Dallas, Texas, United States

Ronak Lakhia, MD

• Patel, Vishal, The University of Texas Southwestern Medical Center, Dallas, Texas, United States

Vishal Patel, MD

Background

Mouse models are a linchpin of in vivo studies of autosomal dominant polycystic kidney disease (ADPKD), but imperfect conservation of coding, noncoding, and regulatory sequences limits their ability to model human PKD1 dosage sensitivity and therapeutic targeting. This gap is a critical roadblock especially for emerging genetic and RNA-based therapies directed against human PKD1 sequences. To address it, we created a fully humanized mouse model of ADPKD and tested known disease modulators.

Methods

We replaced the ~48 kb mouse Pkd1 locus with its human ortholog in cis, including the human promoter, exons, introns, and 3’UTR, via sequential homologous and Cre-mediated recombination. Correct architecture of the humanized allele (Pkd1^H) and integrity of the adjacent Tsc2 locus were confirmed by whole-genome sequencing. To test whether human 3’UTR-mediated regulation is required for disease, this fragment was deleted in Pkd1^H/- mice using CRISPR. To test this axis pharmacologically, Pkd1^H/- primary kidney cells and inducible haploinsufficient Ksp-rtTA;TetO-Cre;Pkd1^H/F (i-Pkd1^H/-) mice were treated with the anti-miR-17 oligonucleotide RGLS4326.

Results

Human PKD1 rescued the embryonic lethality of mouse Pkd1 loss: Pkd1^H/H and Pkd1^H/- mice, which lack mouse Pkd1, were born at expected Mendelian ratios and developed normally through gestation. In contrast, Pkd1^H/- mice developed severe cystic kidney disease, culminating in renal failure and death by 3 weeks. CRISPR deletion of the human 3’UTR completely prevented cystic disease and kidney failure in Pkd1^H/- mice, demonstrating human 3’UTR-mediated regulation is necessary for ADPKD pathogenesis. Consistent with this, polycystin-1 was reduced in Pkd1^H/- primary kidney cells and restored by anti-miR-17 treatment. RGLS4326 also ameliorated disease progression in i-Pkd1^H/- mice.

Conclusion

This fully humanized PKD1 mouse is the first in vivo system in which monoallelic PKD1 recapitulates ADPKD. Rescue by 3'UTR deletion establishes 3'UTR-mediated regulation as causally required for pathogenesis, and attenuation by anti-miR-17 validates it as a tractable therapeutic target. The model enables studies of human allele-specific biology and direct preclinical testing of human-sequence therapeutics, including ASOs, siRNAs, and gene editors.

Funding

• NIDDK Support