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Abstract: TH-PO414

Treatment of Autosomal Recessive Polycystic Kidney Disease With CFTR Modulators

Session Information

Category: Genetic Diseases of the Kidneys

  • 1101 Genetic Diseases of the Kidneys: Cystic


  • Cebotaru, Liudmila, Johns Hopkins University, Baltimore, Maryland, United States
  • Yanda, Murali K., Johns Hopkins University, Baltimore, Maryland, United States

ARPKD is associated with systemic and portal hypertension, fibrosis of the liver and kidney and enlarged kidneys, with fusiform dilation of the collecting ducts. Although it has been postulated that CFTR plays a role in fluid secretion in ADPKD, the opposite is true in ARPKD. For example, a double mutant of CFTR and polycystin/polyductin mice develop massively enlarged kidneys and die from renal failure at ~24 days after birth (Nakanishi et. al (2001). J. Am. Soc. Nephrol. 12, 719-725). Thus, knocking down CFTR makes the disease worse.


We conducted experiments in pkhd1Pkhd1del3-4/del3-4 deletion model and cholangiocyte cultures from pkhd1del/4/del4 mice. We injected male and female mice with 30 mg/kg of VX-809 every other day for 30 days beginning at 5 days old and necropsied them at 35 days. Cultured cholangiocytes were treated with VX-809 (10 µM).


The del3-4 mice develop biliary cysts by 35 days old. The biliary cysts were reduced by VX-809. To understand the factors responsible, we stained liver sections with Ki67 a marker of proliferation and CK19, a marker of cholangiocytes to evaluate proliferation. We detected a 50-fold higher % of cells staining positive for both Ki67 and CK 19, a substantial increase compared to WT, demonstrating that increased proliferation had occurred within the bile duct. The proliferation as indicated by a reduction in positive staining was significantly reduced by VX-809. Significantly, less CFTR protein was detected in the total cell lysate by western blot in the del4 cholangiocytes compared to wt cells, showing that in the absence of functional FPC, the steady-state levels of CFTR fall. Next, we determined the location of CFTR in del3-4 mouse cholangiocytes using confocal microscopy. CFTR co-localization with the apical membrane marker WGA in del3-4 cholangiocytes was greater than in wt. Importantly, the co-localization was reduced in the presence of VX-809. VX-809 increased the co-localization of CFTR with the basolateral membrane marker Na+/K+ ATPase in del3-4 cholangiocytes.


These data indicate that VX-809 reduces proliferation and the presence of CFTR at the apical membrane while increasing CFTR at the basolateral membrane. These data suggest that in the absence of FPC, CFTR is degraded and mislocalized. Demonstration of liver cyst reduction increases the therapeutic potential of VX-809 as a treatment of ARPKD.


  • NIDDK Support