Abstract: FR-OR047
Allele-Selective Antisense Oligonucleotide Targeting Uromodulin Reduces Toxic Aggregates and Rescues Kidney Damage in Models of UMOD-Related Autosomal Dominant Tubulointerstitial Kidney Disease
Session Information
- Monogenic Kidney Disease: Mechanistic Insights and Therapeutic Approaches
November 07, 2025 | Location: Room 360A, Convention Center
Abstract Time: 04:40 PM - 04:50 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases
Authors
- Devuyst, Olivier, Universitat Zurich Physiologisches Institut, Zürich, ZH, Switzerland
- Mariniello, Marta, Universitat Zurich Physiologisches Institut, Zürich, ZH, Switzerland
- Sjöström, Sebastian, Eidgenossische Technische Hochschule Zurich Institut fur Pharmazeutische Wissenschaften, Zürich, ZH, Switzerland
- Schiano, Guglielmo, Universitat Zurich Physiologisches Institut, Zürich, ZH, Switzerland
- Lake, Jennifer, Universitat Zurich Physiologisches Institut, Zürich, ZH, Switzerland
- Hall, Jonathan, Eidgenossische Technische Hochschule Zurich Institut fur Pharmazeutische Wissenschaften, Zürich, ZH, Switzerland
Background
Autosomal dominant tubulointerstitial kidney disease caused by UMOD mutations (ADTKD-UMOD) is a monogenic disorder responsible for ~2% of kidney failure worldwide. Missense mutations in UMOD result in misfolded uromodulin, which forms toxic intracellular aggregates in thick ascending limb (TAL) cells, leading to tubulointerstitial damage and progressive kidney disease. Since wild-type uromodulin mitigates toxic aggregation, allele-selective silencing represents a promising therapeutic strategy in ADTKD-UMOD.
Methods
We designed a library of 53 gapmer antisense oligonucleotides (ASOs) targeting the UMOD transcript. They included 33 “anti-pan-UMOD” ASOs against regions conserved between mice and humans and 20 mutation-specific ASOs against the representative human p.Arg185Ser variant (“anti-R185S-UMOD”), while sparing the wild-type allele. Candidates ASOs were screened in kidney cells expressing wild-type or mutant R185S UMOD and the lead ASO was further tested in humanized knock-in UmodR186S/+ mice – a faithful model of ADTKD-UMOD.
Results
The ASO candidate achieved potent, dose-dependent and allele-selective knockdown of the mutant uromodulin transcript (~80%) and protein (~70%) in vitro, without affecting wild-type levels. In vivo, Cy3-labeled ASO showed kidney-specific uptake and nuclear localization in TAL cells within 24 hours post-i.p. injection. In Umod R186S/+ mice, s.c. dosing for 10 days (50-100 mg/kg) resulted in high ASO accumulation in the kidney, significantly decreased immature uromodulin, and reduced tubular and interstitial damage. A 4-week s.c. regimen further decreased immature uromodulin and aggregates by ~35% in Umod R186S/+ kidneys, without altering wild-type levels. Treated mice showed reduced endoplasmic reticulum stress, lower inflammatory infiltrate, improved urate handling, decreased polyuria, and restored uromodulin secretion in urine versus saline-treated controls.
Conclusion
This study provides proof-of-concept for an allele-selective ASO targeting the major driver of ADTKD-UMOD. Given the kidney-specific expression of uromodulin, this strategy enables precise, tissue-selective silencing with minimal off-target effects, supporting the development of ASO-based therapies for this currently untreatable disease.