Kidney Week

Abstract: FR-PO0147

Genetically Engineered Rat Models of Autosomal Dominant Tubulointerstitial Kidney Disease-Uromodulin (ADTKD-UMOD) for Translational Research

Session Information

• Hereditary Glomerular and Tubulointerstitial Kidney Diseases
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic (Complex and Non-Cystic Monogenic)

Authors

• Vyletal, Petr, Research Unit of Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University, Prague, Czechia

Petr Vyletal, PhD

• Nickl, Petr, Institute of Molecular Genetics of the Czech Academy of Sciences, Vestec, Czechia

Petr Nickl, PhD

• Vaskovicova, Michaela, Institute of Molecular Genetics of the Czech Academy of Sciences, Vestec, Czechia

Michaela Vaskovicova, PhD

• Dolejs, Vojtech, Institute of Molecular Genetics of the Czech Academy of Sciences, Vestec, Czechia

Vojtech Dolejs

• Blazka, Martin, Institute of Physiology of the Czech Academy of Sciences, Prague, Czechia

Martin Blazka, MSc

• Zivna, Martina, Research Unit of Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University, Prague, Czechia

Martina Zivna, MS, MSc, PhD

• Bleyer, Anthony J., Wake Forest University School of Medicine, Section on Nephrology, Winston-Salem, United States

Anthony J. Bleyer, MD, MS, FASN

• Sedlacek, Radislav, Institute of Molecular Genetics of the Czech Academy of Sciences, Vestec, Czechia

Radislav Sedlacek

• Kmoch, Stanislav, Research Unit of Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University, Prague, Czechia

Stanislav Kmoch, MS, MSc, PhD

Background

ADTKD-UMOD is among the most common hereditary kidney diseases (10–20 cases per million) and is caused by the accumulation of mutant uromodulin in renal tubular cells. It is characterized by a highly variable age of onset (20–80 years) and progression to end-stage kidney disease, with heterogeneous rates of decline. Delaying disease onset and slowing progression would substantially improve quality of life. The broad clinical spectrum, with patients presenting at different stages of chronic kidney disease (CKD), highlights the need for stage-specific therapies, ranging from suppression of mutant protein expression and enhancement of its intracellular clearance to cell-based approaches. Rat models can fill an important gap between currently available cellular systems and mouse models by offering advantages in physiological similarity to humans, larger kidney size, and greater experimental flexibility.

Methods

Sprague-Dawley (SD) knock-out animals were generated by electroporation of Cas9/sgRNA ribonucleoprotein complexes (RNPs) into embryos, and knock-in animals by co-electroporation of embryos with AAV-EV donor vectors and Cas9/sgRNA RNPs, followed by transfer into surrogate females. Founders were identified by targeted genotyping and bred to establish stable lines to remove CRISPR/Cas9 off-targets.

Results

Three different rat models were established - SD-Umod^em1Ccpcz lacking UMOD expression; SD-Umod^{em1(C127R)Ccpcz} carrying p.C127R point mutation and SD-Umod^{em1(DelY180-R188)Ccpcz} carrying deletion of 9 amino acids at the position p.Y180-R188. The 2^nd generation animals undergo serial phenotypic evaluation focused on monitoring of renal function, uromodulin expression, and renal anatomy.

Conclusion

Genetically engineered rat models of ADTKD-UMOD enable preclinical testing of therapies across all intervention levels—from gene editing, through RNA-targeting strategies, to protein-level modulation and cell-based approaches—allowing integrated evaluation of efficacy, safety, and delivery in a physiologically relevant setting.

Acknowledgment

The work was supported from the project MULTIOMICS_CZ (Programme Johannes Amos Comenius, Ministry of Education, Youth and Sports of the Czech Republic, ID Project CZ.02.01.01/00/23_020/0008540) – Co-funded by the European Union, and LUC23175 - Advanced genome editing: Extracellular vesicle in disease modelling and mouse models development (MEYS of the Czech Republic).

Funding

• Government Support – Non-U.S.