Kidney Week

Abstract: FR-PO0100

In Vitro and In Vivo Investigation of Translation-Blocking Antisense Oligonucleotides in Autosomal Dominant Tubulointerstitial Kidney Disease-Uromodulin

Session Information

• ADPKD and Cystic Kidney Disease - 2
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

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

Authors

• Riedhammer, Korbinian M., Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, United States

Korbinian M. Riedhammer, MD

• Lemberg, Katharina, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, United States

Katharina Lemberg, MD

• Kolvenbach, Caroline Maria, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Caroline Maria Kolvenbach, MD, DrMed, PhD

• Sayer, John Andrew, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, United States

John Andrew Sayer, MBChB, PhD

• Lomjansook, Kraisoon, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Kraisoon Lomjansook, MD

• Saida, Ken, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Ken Saida, MD, PhD

• Franken, Gijs A.C., Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, United States

Gijs A.C. Franken

• Marchuk, Daniel, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Daniel Marchuk, MD

• Zion, Elena, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Elena Zion, MD

• Madariaga, Leire, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, United States

Leire Madariaga, MD

• Balbach, Maximilian, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Maximilian Balbach

• Heilbronner, Sophie, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Sophie Heilbronner

• Nelson, Becca, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Becca Nelson

• Prakash, Chiranth M., Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Chiranth M. Prakash, PhD

• Buerger, Florian, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, United States

Florian Buerger, MD, PhD

• Hildebrandt, Friedhelm, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Friedhelm Hildebrandt, MD

Background

UMOD-associated autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD) is an inherited disease leading to chronic kidney disease and kidney failure in adulthood. Heterozygous pathogenic variants in UMOD lead to toxic accumulation of misfolded UMOD in the endoplasmic reticulum (ER). UMOD is nearly exclusively expressed in the epithelial cells of the thick ascending limb of Henle’s loop (TAL).

We investigated a translation-blocking antisense oligonucleotide (ASO) aiming at reducing toxic UMOD accumulation in vitro and in vivo.

Methods

A TAL cell model (PMID: 28437467) that overexpresses human UMOD (wild-type [WT] or C150S mutant) and a knock-in mouse model (PMID: 28325753) carrying the pathogenic Umod variant C125R were investigated. Pan-allelic UMOD-targeting ASOs (Gene Tools, OR, USA) were designed. UMOD knockdown in vitro was studied using qPCR, as was expression of ER stress markers Xbp1 (spliced) and Hspa5. Delivery of fluorescein-labeled Umod-targeting ASOs to kidney was examined by immunofluorescence microscopy in heterozygous mice. qPCR from whole-kidney lysates was done to measure Umod knockdown via Umod-targeting ASOs in vivo, as well as kidney injury markers (Havcr1, Lcn2).

Results

C150S mutant cells treated with UMOD-targeting ASO showed a dose-dependent UMOD knockdown (1, 2, 3, 4 μM). ER stress markers Xbp1 (spliced) and Hspa5 were significantly decreased in targeting ASO-treated mutant cells compared to non-treated cells. In 10-month-old heterozygous C125R mice, fluorescein-labeled Umod-targeting ASO could be detected in proximal tubular (Megalin+) and TAL (UMOD+) cells at a 2:1 ratio 24 hours post i.v. injection at both 12.5 mg/kg and 3 mg/kg (titrated dose). Five consecutive weekly i.v. injections of Umod-targeting ASOs at 3 mg/kg did not result in significant knockdown of Umod in vivo but still led to considerable renal (proximal and distal tubular [Havcr1/Lcn2]) toxicity.

Conclusion

We hypothesized that, due to the pathogenesis of ADTKD-UMOD, the reduction of toxic UMOD-aggregates could alleviate the disease even without allele-specificity. We showed that ASO-mediated pan-allelic UMOD knockdown results in ER-stress reduction in vitro. However, while we showed ASO delivery to target cells in vivo, dose-limiting toxicity of employed ASOs impeded demonstration of knockdown of Umod in vivo. Further studies will require modified ASOs with less toxicity.

Acknowledgment

This research was supported by a grant from the German Research Foundation (DFG) to Korbinian M. Riedhammer (Project No.: 519309154).

Funding

• Government Support – Non-U.S.