Kidney Week

Abstract: TH-OR061

Developing Adeno-Associated Virus (AAV)-Mediated Gene Replacement Therapy in an Hnf1b Knockout 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: 05:30 PM - 05:40 PM

Category: Genetic Diseases of the Kidneys

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

Authors

• 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, Massachusetts, 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

• 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

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

Ken Saida, MD, PhD

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

Kraisoon Lomjansook, MD

• Franken, Gijs AC, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Gijs AC Franken, MSc, PhD

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

Daniel Marchuk, MD

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

Chiranth M. Prakash, PhD

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

Korbinian M. Riedhammer, MD

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

Sophie Heilbronner

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

Heterozygous variants in HNF1B are a leading monogenic cause of cystic kidney disease and congenital anomalies of kidneys and urinary tract, yet no targeted therapies exist. We aimed at establishing an AAV-based gene replacement strategy by targeted delivery of HNF1B to kidney epithelial cells, hypothesizing that AAV-mediated expression of wild-type human HNF1B can ameliorate the cystic phenotype in an Hnf1b knockout mouse model.

Methods

Kidneys of neonatal wildtype (WT) mice were directly injected, aiming at the medulla, at postnatal days 1–3 with AAV-KP1-CAG-tdTomato (tdT) to assess AAV transduction and tdT expression efficiency. Conditional KO mice (KspCre⁺; Hnf1b^fl/fl) were co-injected with AAV-KP1-CAG-tdT and AAV-KP1-CAG-humanHNF1B at ~4.5×10¹³gc/kg. Immunofluorescence staining of kidneys harvested 7-9 days post-injection was used to assess transgene expression and quantify cystic index in transduced (tdT⁺/HNF1B⁺) regions compared to adjacent non-transduced areas and to the uninjected contralateral kidney.

Results

In WT mice (Fig. 1A-B; n=3), tdT expression was seen in the injected area in the medulla with transduction efficiencies of 17% in principal cells (PC) and 59% in intercalated cells (IC). In Hnf1b KO mice (Fig. 1C-D), regional nuclear HNF1B expression was seen in PC, IC, TAL and other tubule cells. Intra-animal analysis showed reduced cystic index in injected regions compared to adjacent areas of the same kidney (median Δ=−4.39%, CI −7.92 to −2.13; p=0.0078) and to the uninjected kidney (median Δ=−6.11%, CI −12.38 to −0.24, p=0.0078; n=8).

Conclusion

AAV-KP1-CAG-tdT enables efficient, cell-type–specific kidney transduction following medullary delivery. AAV-mediated human HNF1B expression results in a consistent, localized reduction in cystic burden in Hnf1b KO mouse model, supporting feasibility of kidney-directed gene replacement therapy for HNF1B-associated disease.

Acknowledgment

Elena Zion is supported by the 2025 ASN Ben J. Lipps Research Fellowship Award for this project.

Fig. 1 (A-B) WT injected kidney, (A) injected area example outlined (yellow); (C-D) KO injected kidney: injected (pink) and uninjected areas (yellow).