Abstract: SA-PO0136
Next-Generation CFTR Modulators Control Multiple Mechanisms in Improving the Pathophysiology in ADPKD
Session Information
- ADPKD and Cystic Kidney Disease - 3
October 24, 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
- Afshani, Masoud, Johns Hopkins Medicine, Baltimore, Maryland, United States
- Sharma, Abhishek, Johns Hopkins Medicine, Baltimore, Maryland, United States
- Sharma, Tanvi, Johns Hopkins Medicine, Baltimore, Maryland, United States
- Guggino, William B., Johns Hopkins Medicine, Baltimore, Maryland, United States
- Cebotaru, Liudmila, Johns Hopkins Medicine, Baltimore, Maryland, United States
Background
ADPKD is one of the most common genetic kidney diseases. Mutations are majorly in PKD1, and less often in PKD2, encoding PC1 and PC2 proteins, which are important for normal kidney tubular epithelial cell function, calcium signaling, and maintenance of tubular structure. Renal cysts develop from tubular epithelial cells, and cyst enlargement depends on epithelial cell proliferation together with fluid secretion into the cyst lumen. CFTR is an apical chloride channel, and in ADPKD cAMP-stimulated CFTR-dependent chloride secretion helps drive fluid movement into the cyst lumen and promotes cyst growth.
Methods
The aim of this study was to examine the therapeutic effect of the CFTR modulators VX809, VX661, and VX445 in Pkd1 R3277C mouse model treated every other day for 3 months. Immunofluorescence (IF) and H&E staining methods were used for evaluation of cystic area, CFTR localization, proliferation, and biomolecular interaction. Kidney primary cells were isolated and used for cyst experiment, intracellular calcium evaluation, close proximity assay to evaluate the interaction of key proteins involved in pathophysiology of ADPKD.
Results
CFTR modulators significantly reduced cyst area in mouse kidneys compared with untreated controls. Kidney-to-body weight ratio was significantly reduced. CFTR localization changed from the apical membrane to the basolateral membrane after treatment. Proliferation was significantly reduced after treatment. Calcium release from the ER was significantly reduced in primary cells treated with CFTR modulators. Interaction of CFTR with YAP and TAZ, PC1 and PC2, NHERF1 and NHERF 2 were significantly changed after treatment with CFTR modulators.
Conclusion
These findings support the idea that correction of CFTR post translational modification and trafficking can improve the cystic phenotype in RC mice. Next generation of CFTR modulators show potential as therapeutic agents in ADPKD.
Funding
- NIDDK Support