Abstract: TH-PO0548
Targeted Gene Delivery to the Juxtaglomerular Apparatus via a Novel Adeno-Associated Virus 9 Vector
Session Information
- Development, Stem Cells, and Regenerative Medicine
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Development, Stem Cells, and Regenerative Medicine
- 600 Development, Stem Cells, and Regenerative Medicine
Authors
- Liu, Shuya, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Lu, Shun, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Wu, Guochao, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Huber, Tobias B., III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Background
Dysfunction of the juxtaglomerular apparatus (JGA) significantly contributes to the progression of chronic kidney disease (CKD). Current CKD therapies lack the ability to specifically target this crucial region. Adeno-associated virus (AAV)-mediated gene therapy in the kidney is complicated by cellular heterogeneity. To address this issue, we have developed an in vivo selection strategy to identify AAV vectors with enhanced kidney tropism.
Methods
We screened a liver-detargeting AAV9 peptide display library in mice following intravenous injection to identify kidney-homing AAVs. Integrative experimental and bioinformatics workflows identified a novel vector, AAV9-JGA. The biodistribution and cellular tropism of AAV9-JGA were characterized. The transduction route to the target cells was investigated. To evaluate the functional impact, the diphtheria toxin receptor (DTR) was expressed for targeted cell ablation. The potential for therapeutic protein delivery was assessed by expressing uromodulin. The relevance to larger animals is being evaluated through ongoing ex vivo normothermic perfusion of pig kidneys.
Results
Following intravenous injection in mice, AAV9-JGA demonstrated highly specific targeting of CLDN16/SLC12A1-positive thick ascending limb (TAL) cells located at the JGA, exhibiting superior specificity compared to AAV9-WT. Mechanistically, circulating AAV9-JGA directly accessed these cells directly via the tubule-afferent arteriole contact, circumventing the glomerular filtration barrier. Ablation of AAV9-JGA-DTR targeted TAL cells led to transient alterations in serum electrolyte levels, demonstrating the vector's capacity to modulate renal function. Furthermore, AAV9-JGA facilitated the secretion of uromodulin into both the urine and the bloodstream. Ongoing ex vivo perfusion of porcine kidneys has been designed to provide further insight into the vector's tropism in a large animal model.
Conclusion
AAV9-JGA is a novel gene delivery tool characterized by its high specificity for TAL cells at the JGA. Its unique access route and capacity to modulate renal function and deliver therapeutic proteins like uromodulin to both the excretory and circulatory systems offer promising avenues for targeted therapies in kidney disease. Evaluating its performance in a large animal model will provide valuable information on its potential for future clinical applications.
Funding
- Government Support – Non-U.S.